Asymmetric Oxidation of Enol Derivatives to α-Alkoxy Carbonyls Using Iminium Salt Catalysts: A Synthetic and Computational Study

Article abstract of DOI:10.1021/acs.joc.8b02354

We report herein the first examples of asymmetric oxidation of enol ether and ester substrates using iminium salt organocatalysis, affording moderate to excellent enantioselectivities of up to 98% ee for tetralone-derived substrates in the α-hydroxyketone products. A comprehensive density functional theory study was undertaken to interpret the competing diastereoisomeric transition states in this example in order to identify the origins of enantioselectivity. The calculations, performed at the B3LYP/6-31G(D) level of theory, gave good agreement with the experimental results, in terms of the magnitude of the effects under the specified reaction conditions, and in terms of the preferential formation of the (R)-enantiomer. Just one of the 30 characterized transition states dominates the enantioselectivity, which is attributed to the adoption of an orientation relative to stereochemical features of the chiral controlling element that combines a CH interaction between a CH₂ group in the substrate and one of the aromatic rings of the biaryl section of the chiral auxiliary with a good alignment of the acetoxy group with the other biaryl ring, and places the smallest substituent on the alkene (a hydrogen atom) in the most sterically hindered position.

Full text of DOI:10.1021/acs.joc.8b02354

Subscriber access provided by University of South Dakota
Article
Asymmetric Oxidation of Enol Derivatives to #-Alkoxy Carbonyls
Using Iminium Salt Catalysts: A Synthetic and Computational Study
Philip C. Bulman Page, Saud M. Almutairi, Yohan Chan, G Richard Stephenson, Yannick
Gama, Ross L. Goodyear, Alice Douteau, Steven Mark Allin, and Garth A. Jones
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02354 • Publication Date (Web): 14 Dec 2018
Downloaded from http://pubs.acs.org on December 15, 2018
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 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 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.
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 38
The Journal of Organic Chemistry
Asymmetric Oxidation of Enol Derivatives to -Alkoxy Carbonyls
1
2
3
4
Using Iminium Salt Catalysts: A Synthetic and Computational Study
5
6
7
8
9
Philip C. Bulman Page,a* Saud M. Almutairi,a Yohan Chan,a G. Richard Stephenson,a* Yannick
Gama,a Ross L. Goodyear,a Alice Douteau,a Steven M. Allin,b Garth A. Jones,a*
a School of Chemistry, University of East Anglia, Norwich Research Park, Norwich, Norfolk NR4
7TJ, U.K.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
b Department of Chemistry and Forensics, Nottingham Trent University, Clifton, Nottingham NG11
8NS, U.K.
Abstract: We report herein the first examples of asymmetric oxidation of enol ether and ester
substrates using iminium salt organocatalysis, affording moderate to excellent enantioselectivities of
up to 98% ee for tetralone-derived substrates in the -hydroxyketone products. A comprehensive
density functional theory study was undertaken to interpret the competing diastereoisomeric
transition states in this example in order to identify the origins of enantioselectivity. The calculations,
performed at the B3LYP/6-31G(D) level of theory, gave good agreement with the experimental
results, in terms of the magnitude of the effects under the specified reaction conditions, and in terms
of the preferential formation of the (R)-enantiomer. Just one of the 30 characterized transition states
dominates the enantioselectivity, which is attributed to the adoption of an orientation relative to
stereochemical features of the chiral controlling element that combines a CH‒ interaction between a
CH2 group in the substrate and one of the aromatic rings of the biaryl section of the chiral auxiliary
with a good alignment of the acetoxy group with the other biaryl ring, and places the smallest
substituent on the alkene (a hydrogen atom) in the most sterically-hindered position.
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
Introduction
The α-hydroxycarbonyl motif is present in many natural products and in intermediates towards their
syntheses.1 A simple method to prepare α-hydroxycarbonyls involves the oxidation of silyl enol
ethers, and is known as the Rubottom reaction. Rubottom,2 Brook,3 and Hassner4 first reported the
use of m-chloroperbenzoic acid to oxidize silyl enol ethers to form α-hydroxy-ketones and aldehydes
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 38
in 1974, later followed by the preparation of α-hydroxycarboxylic acids from ketene
bis(trimethylsilyl) acetals.5 Other methodologies include, for example, the oxidation of silyl enol
ethers with sulfonyl oxaziridines,6 osmium tetroxide,7 hypervalent iodine reagents,8 aerobic
oxidation,9 and the use of organic-inorganic hybrid polymers as catalysts;10 and the oxidation of
other enol ethers and esters using various organic peracids11 and dioxiranes.12
1
2
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
A number of asymmetric versions have also been developed using chiral oxidants, metal-based
catalysts, and organocatalysts,13 as well as a chiral electrolyte.14 Davis used chiral sulfonyl
oxaziridines to oxidize a range of enolates, and comprehensively reviewed this topic in 1992.15
Mn(III) (salen) catalysts and various oxidants have been used to obtain α-hydroxycarbonyls in up to
90% ee from silyl enol ethers (Thornton,17 Adam,18), enol ethers and enol acetates (Patonay,16
Katsuki,19). Krawczyk also used Mn(III) (salen) complexes to oxidize enol phosphates in up to 96%
ee.20 Sharpless21 and Curran22 reported the asymmetric oxidation of enol ethers using osmium-based
catalysts. Yamamoto obtained chiral hydroxyketones from tin enolates23 and silyl enol ethers24 using
nitrosobenzene and chiral phosphine-silver catalysts in up to 99% ee. Simpkins used chiral bases to
obtain chiral hydroxyketones through kinetically controlled deprotonation in up to 74% ee.25
Adam,26 Shi,27 and Solladié-Cavallo28 used chiral ketones to catalyse the oxidation of silyl enol
ethers in high enantiomeric excesses. Myers more recently used Shi’s fructose-derived catalyst in a
tandem oxidation-reduction to obtain diols from silyl enol ethers in up to 93% ee.29
We have reported catalysts based on dihydroisoquinolinium (e.g. 1), biphenylazepinium (e.g. 2 and
3), and binaphthylazepinium (e.g. 4) units, each of which contains a chiral substituent on the nitrogen
atom, for aqueous oxone-driven epoxidation reactions. The most successful of these catalysts contain
the (S,S)-acetonamine 1,3-dioxane motif (Figure 1).30
1
2 R=H; 3 R=Me
4
Figure 1: Iminium salt catalysts.
These species provided the first very high enantioselectivities for iminium salt catalysed asymmetric
epoxidation of alkenes. We have also developed non-aqueous conditions for the use of these
2
ACS Paragon Plus Environment

Page 3 of 38
The Journal of Organic Chemistry
catalysts, using tetraphenylphosphonium monoperoxysulfate (TPPP)31 as the oxidant.32 The
asymmetric epoxidation processes utilizing iminium salt catalysts 1 and 2 have been used in
syntheses of levcromakalim,33 (–)-lomatin and (+)-trans-khellactone,34 scuteflorin,35 and mollugin,36.
Alternative oxidants such as hydrogen peroxide or sodium hypochlorite,37 and electrochemically-
generated oxidants,38 may also be used in these iminium salt-catalysed epoxidation reactions.
1
2
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
Herein we report the application of our methodology to the generation of enantiomerically enriched
α-hydroxy carbonyls through catalytic asymmetric oxidation of enol derivatives.
Results and discussion
We chose 1-tetralone and its enol derivatives as test substrates. Silyl enol ethers were first
investigated; silyl enol ether 5 was prepared using tri-isopropyl silyl triflate and triethylamine as the
base.39 Oxidation of 5 with m-CPBA led to O-silyl protected compound 6 In 89% yield. Removal of
the silyl group was achieved using one equivalent of camphorsulfonic acid in methanol to yield α-
hydroxyketone 7 (Scheme 1). Silyl enol ether 8 was prepared similarly.
5, RR’2 = (i-Pr)3, 40%
8, RR’2 = Ph2t-Bu, 45%
6, RR’2 = (i-Pr)3
7
9, RR’2 = Ph2t-Bu
Reagents and conditions: (i): Et3N (2 equiv.), TiPSOTf (1.5 equiv.), CH2Cl2, r.t., 16 h, 40%; (ii): 5, m-CPBA (1.5
equiv.), NaHCO3 (2 equiv.), CH2Cl2, 0 °C to r.t., 16 h, 89% of 6; (iii): Catalyst (see Figure 1, 0.1 equiv.), TPPP (2
equiv.), CHCl3, 0 °C; (iv): 6, CSA (1 equiv.), MeOH, r.t., 16 h, 50%; (v) KHMDS (1.8 equiv.), t-Bu(Ph)2SiCl (1.4
equiv.), THF, −78°C to r.t., 16 h, 45%.
Scheme 1. Generation and oxidation of silyl enol ethers 5 and 8
Asymmetric oxidation of 5 and 8 using our catalytic system proceeded smoothly under non-aqueous
conditions; a selection of the reaction conditions and results is shown in Table 1. No oxidation by
TPPP was observed in the absence of catalyst (entry 1). In some instances using substrate 5, the silyl
group was partially or wholly lost during the reaction/work-up process to give hydroxyketone 7
directly, but in others the intermediate silyloxy species 6 or 9 could be observed. In such cases,
hydrolysis to give 7 was readily achieved using camphorsulfonic acid as above, or other hydrolytic
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 38
conditions. When the reaction was carried out under aqueous conditions, using Oxone as oxidant,
1
2
3
only α-hydroxyketone 7 was obtained after the reaction workup.
4
5
6
Table 1: Optimization of oxidation reaction conditions using substrates 5 and 8
7
8
9
Entry
Absolute
config. of
major
Catalyst
(10
mol%)
Oxidant
(2
equiv.)
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
Temp. Time
Conv. Yield ee
Substrate
Solvent
b
/°C
/h
/% a
/%
%
enantiomerc
1
2
3
4
5
6
7
8
9
No cat.
5
5
5
5
5
5
5
5
TPPP
m-CPBA
TPPP
0
0
24
2
CHCl3
CH2Cl2
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
<5%
100
100
100
88
-
-
-
-
No cat.
52
67
72
65
32
59
63
-
1
1
1
2
2
2
0
12
12
24
72
72
72
20
24
43
35
13
25
(–)-(S)
(–)-(S)
(–)-(S)
(+)-(R)
(+)-(R)
(+)-(R)
TPPP
–10
–70
0
TPPP
TPPP
41
TPPP
0
100
100
TPPP
oxone/
0
MeCN
MeCN/
H2O
2
5
0
24
100
89
25
(+)-(R)
NaHCO3
10
11
2
4
8
8
TPPP
0
0
24
24
CHCl3
91
95
76
78
52
50
(+)-(R)
(+)-(R)
TPPP
CHCl3
(a): Conversions were calculated from 1H NMR spectra of reaction mixtures after work-up for compounds 6, 7, and 9.
(b): Enantioselectivities were measured by CSP HPLC (Daicel Chiralcel OD-H or Knauer Eurocel 01 using
isopropanol/hexane as eluent).
(c): The absolute configuration of the major enantiomer was attributed using optical rotation according to the literature.20
With TIPS-protected substrate 5, moderate enantioselectivities were observed: using catalyst 1 in
chloroform, the reaction was almost complete after 24 h at –70 °C, giving (–)-(S)--hydroxyketone 7
in 65% yield (entry 5) (over the two steps) and 43% ee. The reaction proceeds more rapidly but less
selectively at higher temperatures (entries 3, 4). Using biphenyl catalyst 2 in chloroform, the
enantioselectivity was higher and in the opposite sense (entry 6), but the reaction proceeded more
slowly, precluding the use of low temperatures. As previously observed in our studies of
epoxidation, chloroform was found to be the solvent which gave the highest level of ee: indeed,
changing the solvent improved the conversion at the expense of the selectivity.
4
ACS Paragon Plus Environment

Page 5 of 38
1
The Journal of Organic Chemistry
2
3
4
5
6
7
8
9
Altering the size and shape of the silyl group to tert-butyldiphenylsilyl provided a small
improvement in enantioselectivity. Using catalyst 2 with TBDPS enol ether 8 at 0 °C provided α-
silyloxyketone 9 with 91% conversion (entry 10), from which (+)-(R)-α-hydroxyketone 7 was
obtained in 52% ee (cf 35% ee from enol ether 5). Similar results were observed with binaphthyl
catalyst 4, which provided 9 with 95% conversion and (+)-(R)-7 in 50% ee (entry 11).
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
Given the moderate enantioselectivity observed using silyl enol ethers as substrates, we turned our
attention to the oxidation of enol phosphates.20 -Tetralone was converted into the corresponding
enol phosphate 10 in 69% yield using diethyl phosphorochloridate and LDA as the base, which was
submitted to our non-aqueous epoxidation reaction conditions (Scheme 2, Table 2).40
10
7
Reagents and conditions: (i) LDA (1 equiv.), (EtO)2P(O)Cl (1.5 equiv.), THF, −78 °C to r.t., 1 h, 69%; (ii) Catalyst (0.1
equiv.), TPPP (2 equiv.), CHCl3.
Scheme 2
Table 2. Oxidation of enol phosphate 10
Entry
Absolute config.
of major
Catalyst
Oxidant
Temp. Time
Conv.
/%a
ee
Solvent
(10 mol%) (2 equiv.)
/°C
/h
/%b
enantiomerc
1
2
3
4
1
1
1
2
TPPP
TPPP
TPPP
TPPP
0
48
48
72
72
CHCl3
CHCl3
CHCl3
CHCl3
45
22
-
20
35
-
(–)-(S)
(–)-(S)
-
−30
−50
−30
45
90
(+)-(R)
(a): Conversions were calculated from 1H NMR spectra of reaction mixtures after work-up.
(b): Enantioselectivities were measured by CSP HPLC (Daicel Chiralcel OD-H using isopropanol/hexane as eluent).
(c): The absolute configuration of the major enantiomer was attributed using optical rotation according to the literature.20
In these cases, -hydroxyketone 7 was isolated directly from the oxidation reaction after work-up
and purification. Unfortunately, no increase in enantioselectivity over the silyl enol ether substrates
was observed when enol phosphate 10 and catalyst 1 were used (entries 1, 2). Furthermore, the rate
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 38
of epoxidation of the phosphate was reduced, no conversion being observed at 50 C (entry 3).
When catalyst 2 was used at –30 °C, α-hydroxyketone 7 was obtained in 90% ee (entry 4). Again,
however, no reaction was observed when the temperature was lowered to –50 C.
1
2
3
4
5
6
7
8
9
We next turned our attention to enol esters, with acetate, benzoate and trifluoroacetate derivatives
chosen as suitable substrates. -Tetralone was first converted into the corresponding enol acetate 11
in 75% yield using isopropenyl acetate under acidic conditions, which was subjected to our non-
aqueous oxidation reaction conditions (Scheme 3, Table 3).41
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
11
7
Reagents and conditions: (i) p-Toluene sulfonic acid, isopropenyl acetate, reflux, 16 h, 75%; (ii) Catalyst (0.1 equiv.),
TPPP (2 equiv.), CHCl3.
Scheme 3
Table 3. Oxidation of enol acetate 11
Entry Catalyst
(10
Absolute config.
of major
enantiomerc
(–)-(S)
Temp. Time
Conv. ee
/%a /%b
Solvent
/°C
/h
mol%)
1
2
3
4
5
6
7
8
9
1
1
1
1
2
2
2
4
4
0
24
24
CHCl3
CHCl3
62
42
62
70
99
95
95
12
5
66
72
70
67
88
97
98
31
-
−30
−30
−30
0
(–)-(S)
24 CH2Cl2
(–)-(S)
24
48
48
48
48
48
MeCN
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
(–)-(S)
(+)-(R)
(+)-(R)
(+)-(R)
(+)-(R)
-
−30
−45
0
−30
(a): Conversions were calculated from 1H NMR spectra of reaction mixtures after work-up.
(b): Enantioselectivities were measured by CSP HPLC (Daicel Chiralcel OD-H using isopropanol/hexane as eluent).
(c): The absolute configuration of the major enantiomer was attributed using optical rotation according to the literature.20
Again, -hydroxyketone 7 was isolated directly from the oxidation reaction after work-up and
purification. Although the reaction proceeds more slowly than in the case of the corresponding silyl
6
ACS Paragon Plus Environment

Page 7 of 38
The Journal of Organic Chemistry
enol ethers, the enantioselectivity observed is higher: using catalysts 1 and 2 at 0 ºC, in chloroform,
compound 7 was obtained in 66% (entry 1) and 88% ee (entry 5), respectively. Lowering the
temperature to –45 ºC led to 7 in 98% ee and 95% conversion when catalyst 2 was used (entry 7).
1
2
3
4
5
6
7
8
9
Initial oxidation results were thus promising, and other enol esters were prepared. 1-Tetralone was
converted into the corresponding benzoate and trifluoroacetate enol esters in 26% and 91% yield,
respectively, which were oxidized under our standard conditions (Scheme 4, Table 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
12, R = Bz; 13, R = COCF3
7
Reagents and conditions: (i) (PhCO)2O (1 equiv.), HClO4 (20 mol%), hexanes, r.t., 2 h, 26%; (ii) p-Toluene sulfonic
acid, (CF3CO)2O, reflux, 16 h, 76%; (iii) Catalyst (0.1 equiv.), TPPP (2 equiv.), CHCl3. 0 °C, 24 h.
Scheme 4
Table 4. Oxidation of enol esters 12 and 13
Absolute config.
Catalyst Conv. ee
Substrate
of major
(10 mol%) /%a
/%b
enantiomerc
1
2
23
35
65
88
(–)-(S)
(+)-(R)
4
33
38
(+)-(R)
12
13
1
2
23
65
54
90
(–)-(S)
(+)-(R)
4
63
43
(+)-(R)
(a): Conversions were calculated from 1H NMR spectra of reaction mixtures after work-up.
(b): Enantioselectivities were measured by CSP HPLC (Knauer Eurocel 01 using isopropanol/hexane as eluent).
(c): The absolute configuration of the major enantiomer was attributed using optical rotation according to literature
data.20
Epoxidation of the enol benzoate 12 and enol trifluoroacetate 13 led to the formation of the product 7
in 38-90% ee at 0 °C, similar to the enantioselectivities obtained when the corresponding enol
acetate was oxidized. The reactivity of the enol benzoate 12 appears to be lower as conversions were
below those observed in the case of 11 over the same time period, perhaps a result of steric hindrance
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 38
from the benzoate group. Conversions were higher in the case of the enol trifluoroacetate 13 than the
1
2
3
benzoate, despite the presence of the highly electron-withdrawing trifluoro group.
4
5
6
7
8
A number of further enol acetates 14 to 17 were subsequently prepared and submitted to our standard
epoxidation conditions (Table 5). Enol acetate 16 was prepared from the ketone by a literature route
from 3-bromo-N-phenylpropanamide.
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
Table 5. Oxidation of enol acetates 14 - 17
Yield
/%
Absolute
config.
Temp. Time Conv. ee
Substrate
Product
/°C
/h
/%a /%b of major
enantiomerc
O
OH
OH
75
–30
48
95
97
(+)-(S)
7
11
O
0
24
48
99
95
87
92
(+)-(S)
(+)-(S)
95
80
−30
18
14
15
O
(–)-(S)
OH
−30
−30
48
72
70
65
78
67
19
41
73
(–)
16
20
OAc
O
OH
−30
72
95
59
(–)-(S)
17d
21
Conditions: Catalyst 2 (0.1 equiv.), TPPP (2 equiv.), CHCl3.
(a): Conversions were calculated from 1H NMR spectra of reaction mixtures after work-up.
(b): Enantioselectivities were measured by CSP HPLC (Knauer Eurocel 01 using isopropanol/hexane as eluent).
(c): The absolute configurations of the major enantiomers were attributed using optical rotations according to literature
data.
8
ACS Paragon Plus Environment

Page 9 of 38
The Journal of Organic Chemistry
(d): The Z double bond stereochemistry was established by comparison of NMR data with literature values.
1
2
3
4
5
6
7
8
9
We were pleased to find that the reactions proceeded smoothly, and hydroxyketones were obtained
with enantioselectivities ranging from 57% to 93% ee. Racemic materials were obtained by MCPBA
oxidation. The methodology was applied to the synthesis of the natural product (−)-tatarinoid A 22.42
(−)-Tatarinoid A has previously been prepared using a chiral Weinreb amide,43 and an irregular
Wittig reaction,43,44 respectively. Our synthesis (Scheme 5) began with the nucleophilic addition of
ethylmagnesium bromide to 2,4,5-trimethoxybenzaldehyde 23, forming alcohol 24 in 93% yield.
Oxidation of 24 using MnO2 afforded ketone 25 in 46% yield. Treatment of 25 with LDA and acetic
anhydride led to O-acetylation of the lithium enolate to afford enol acetate 26, a method known to
give Z stereochemistry, which was converted into racemic 27 using MCPBA.
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
OMe O
OMe OH
OMe O
OMe OAc
OMe O
(i)
(ii)
(iii)
MeO
(iv)
MeO
OAc
MeO
MeO
MeO
OMe
OMe
OMe
OMe
OMe
23
24
25
26
27
Reagents and conditions: (i): EtMgBr (3M in Et2O, 2 equiv.), THF, 0 °C to rt, 16 h, 93%; (ii): MnO2
(10 equiv.), CH2Cl2, reflux, 24 h, 46%; (iii): DIPA (1.2 equiv.), n-BuLi (1.6 M in hexane, 1.2
equiv.), THF, −78 °C, then Ac2O (2 equiv.), −78 °C to rt, 36 h, 51%; (iv) NaHCO3 (3 equiv.), m-
CPBA (1.5 equiv.), CH2Cl2, 0 oC to rt, 16 h, 29% over 2 steps.
Scheme 5. Synthesis of the tatarinoid A precursor
Asymmetric oxidation of 26 at –45 °C using TPPP and catalyst 2 took place to give α-acetoxyketone
27 with a moderate enantioselectivity of 50% ee, though in a very low yield of 6%. A 32% yield
could be obtained, with an enantioselectivity of 37% ee, using freshly repurified starting material.
Deacetylation of 27 (Scheme 6) produced from our most enantioselective result furnished Tatarinoid
A in 63% yield with no significant change in ee (48% ee). Optical rotation measurements indicated
that the major enantiomer of our non-racemic mixture of tatarinoid A was the naturally occurring
(R)-(–)-enantiomer.42
OMe OAc
OMe O
OMe O
(ii)
(i)
OAc
OH
MeO
MeO
MeO
OMe
OMe
OMe
26
27
(R)-(–)-Tatarinoid A 22
(i) Catalyst 2 (0.1 equiv.), TPPP (2 equiv.), CHCl3; (ii) CSA, MeOH
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 38
Scheme 6. Synthesis of (R)-(–)-tatarinoid A
1
2
3
4
Computational study of the transition states
5
6
7
8
The chiral iminium ion employed in this study is well suited to computational evaluation. It contains
two principal chiral features (Figure 2): (1) the axial chirality of the biphenyl unit which in this case
is contained in section C7a-C11a-C11b-C4a of the dibenzo[c,e]azepin-6-ium seven-membered ring,
and (2) the 4’-phenyl-1’,3’-dioxane which is attached at C5’ to the nitrogen atom of the azepinium
moiety. This dioxane has two stereogenic centres (C4’ and C5’). In this examination of asymmetric
oxidation of enol ether and ester substrates, iminium ion 2 was used in the 4’S,5’S configuration (see
Figure 1). The C4’ phenyl substituent is important for two reasons. First, it desymmetrizes the
otherwise symmetrical 5’-substituted 2’,2’-dimethyl-1’,3’-dioxane ring. Secondly, in combination
with the C2’ methyl groups, it serves as a conformational lock since the axial orientation of the Ph
group would be highly disfavoured (see red box, Figure 2) by the 1,3-diaxial interaction between
with the axial methyl group (with two methyl groups at C2’, one must always be axial). Given these
structures are highly energetically unfavourable, they were excluded from the computational
analysis. This considerably simplified the task of assessing the relevant conformations of the
iminium ion, and of the derived oxaziridinium ions, in preparation for our study of the transition
states for the epoxidation reaction.
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
1,3-diaxial interaction
11a
Me
Ph
7a
N
O
11b
7
Me
4a
O
5
N
1'
two stereogenic centers
in the chiral dioxane ring
O
Me
6'
5'
Ph
O
4'
2'
3'
axial chirality
in the biaryl
Me
Figure 2. Axial and carbon-centered chirality in the iminium ion 2 (box: potential for a 1,3 diaxial
interaction in an alternative chair conformation).
In iminium ion 2, the two key features of conformational mobility are the possibilities of
atropisomeric epimerisation within the dibenzo[c,e]azepin-6-ium ring by variation of the dihedral
angle C10a-C11a-C11b-C1 and movement around the C-N bond that connects the azepinium ring to
C5’ of the dioxane, i.e. variation of the dihedral angle C7-N-C5’-C6’. These two possibilities were
examined first in a gas phase DFT study employing the widely used and computationally rapid
Becke B3LYP functional45 with Pople’s 6-31G(D)46 basis set. Four distinct structures for 2 were
identified (Table 6, entries 1-4) and were characterised by comparing the 7a-11a-11b-4a (−42.2 -
40.3°) and 7-N-5’-4’ (−105.5 - 84.8°) dihedral angles. All four conformations of the iminium ion 2
are within 16 kJ mol−1, and therefore must be considered as potentially important contributors to the
10
ACS Paragon Plus Environment

Page 11 of 38
The Journal of Organic Chemistry
epoxidation mechanism for oxygen atom transfer from the oxaziridinium ion to the alkene.
1
2
3
4
Table 6. Energies and selected dihedral angles for the four conformations of the iminium ion 2 at
5
6
optimized geometries.a
7
8
9
Entry /
Numbering
for the
7a-11a-
11b-4a
7-N-
5’-4’
4a-5-
N-5'
N-5'-
4'-1”
5'-4'-
1”-2”
5'-6'-
1'-2'
Structure
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
iminium ion
Relative
Energy
(kJ mole−1)
0.00
(°)
(°)
(°)
(°)
(°)
(°)
1
40.3
−39.7
−42.2
39.3
84.8 −111.6
49.5
46.1
51.0
47.4
80.1
74.8
59.8
71.5
53.8
53.5
59.9
52.9
2
3
4
4.20
−99.1
34.1
141.0
113.1
6.56
15.2
−100.4 −118.8
a the absence of imaginary (negative) vibrational frequencies determined by frequency calculations using the
atomic coordinates of the optimised geometries confirmed that in each case true energy minima had been
identified.
Table 7. Energies and selected dihedral angles for the four conformations of the oxaziridinium ions
30a,d,e,ga and 30b,c,f,hb at optimized geometries.c
Entry /
Numbering
for the
4a-11b-
11a-7a
4-4a-
4b-O
4b-N-
5'-4'
7a-7-
N-5'
N-5'-
4'-1”
5'-4'-
1”-2”
5'-6'-
1'-2'
Structure
oxaziridinium
ion
Relative
Energy
(kJ mole−1)
0.00d
(°)
(°)
(°)
(°)
(°)
(°)
(°)
1 30a
2 30b
3 30c
4 30d
5 30e
6 30f
7 30g
8 30h
−40.7
41.1
152.5 −94.3
−153.8
−151.9 −156.4 −147.0
137.3
48.0
50.0
50.1
50.9
50.4
56.1
49.4
45.9
72.7
75.5
53.6
74.1
75.9
47.6
62.8
77.6
53.4
55.3
56.8
55.9
56.8
52.6
54.2
52.1
7.09e
74.8 −139.5
14.97f
41.1
17.85g
−41.1
41.7
153.3
71.8
104.0
106.8
6.5
146.7
−79.6
82.9
21.00e
30.46g
−41.1
39.3
−72.6
35.44f
74.8 −94.8 −98.5
36.76d
−40.5
−71.2 −133.7
91.8
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 38
a positive value for the dihedral angle 4-4a-4b-O; b negative value for the dihedral angle 4-4a-4b-O; c the
absence of imaginary (negative) vibrational frequencies determined by frequency calculations using the
atomic coordinates of the optimised geometries confirmed that in each case true energy minima had been
identified; d conformation corresponds to that of the iminium ion in Table 6, entry 2; e conformation
corresponds to that of the iminium ion in Table 6, entry 1; f conformation corresponds to that of the iminium
ion in Table 6, entry 4; g: conformation corresponds to that of the iminium ion in entry 3.
1
2
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
The reactive oxaziridinium ions, which were generated in situ in the epoxidation process, were
evaluated next, at the same level of theory. In the absence of experimental data to guide the choice of
diastereoisomers, each iminium ion provided two possible oxaziridinium ions which differed by
whether the oxygen was added to the front or rear diastereoface of the C=N double bond (see Figure
3). The energies and key geometric features for the optimized geometries of all eight resulting
structures (30a-h) are presented in entries 1-8 of Table 7. The range of energies for these eight
oxaziridinium ions was broader than in the case of the iminium ions, but was still <40 kJ mole−1. As
expected, the central dihedral angle of the biaryl section of these structures was relatively consistent
throughout (39.3 - 41.7° or −39.7 - −42.2°), as was C5'-C6'-C1'-C2' (52.1 - 59.9°) which was chosen
to illustrate the consistency of the chair character of the 1’,3’-dioxane six-membered ring. The
dihedral angle C4-C4a-C4b-O (oxaziridinium ion numbering) conveniently indicates the orientation
of the additional oxygen atom of the oxaziridinium ion relative to the azepinium ring. Values of
about 70° (or –70°) and 150° (or –150°) in the optimised structures show that there is considerable
variation in the stereochemical environment of the oxygen (the positive and negative angles reflect
the fact that the oxygen is either pointing forwards or pointing backwards). Since this oxygen
occupies a position directly beside the point of rotational motion between the two halves of the chiral
auxiliary (see Figure 3B and 3C), it is to be expected that its position will significantly influence the
conformational preferences about the N-C5’ bond. The broader range of dihedral angles at this
position (6.5 - 106.8° and –94.3 - –156.4°) observed in the optimised structures of the oxaziridinium
ions compared to those of the iminium ions further supports the view that a wide selection of
stereochemical environments are present. This will have important consequences for the direction of
the approach of the alkene in the competing pathways for the transition states of the epoxidation
reaction. Similarly, the C4’ phenyl substituent takes up a position close to the oxygen atom in some
of the structures and although it reliably occupies an equatorial position [see the narrow range of
values for N-C5'-C4'-C1” (45.9 – 56.1°)]. The tilt of the plane of the benzene ring relative to the
equatorial plane of the chair six-membered ring shows much more variation and, for example, the
C5'-C4'-C1”-C2” dihedral angles range from about 50 to 80°. Interestingly, this variation is present
both the iminium ion and oxaziridinium ion series (Figure 3).
12
ACS Paragon Plus Environment

Page 13 of 38
The Journal of Organic Chemistry
1
2
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
Figure 3. Optimised geometries [B3LYP/ 6-31G(D)] of the most stable conformation of the iminium
ion 2 (A) and two derived oxaziridinium ions (B: C4-C4a-C4b-O = 152.5°; C: C4-C4a-C4b-O =
−71.2°), 30a, with the oxygen behind atom (B) and 30h in front (C) of the dibenzo[c,e]azepin-6-ium
ring system.
With the set of eight oxaziridinium ion structures (30a-h) now calculated, the influence of the steric
effects of the biaryl and phenyl aromatic rings, and the conformation of the molecule about the
central N-C5’ bond, on the energies of transition states for transfer of O from the oxygen donor (the
oxaziridinium ion) to the oxygen acceptor (the alkene), and the relative orientations between the
alkene and the C-N-O three-membered ring were now assessed. The extreme possibilities for this
latter conformational issue are ‘bow-tie’47 (‘butterfly’) structures in which all five atoms (the C-N-O
ring and the C=C) lie roughly in the same plane (i.e. a central angle of ~180°), and the alternative
spiro conformer48,49 in which the angle between the two planes is about 90°. The latter have already
been identified for the enantioselective epoxidation of 1,2-dihydronaphthalene by an oxaziridinium
ion.50 In order to compare our system directly with that of Houk’s in his classic computational
study49 of the epoxidation of ethene (using a simpler oxygen donor), all eight transition states for
transfers of oxygen from 30a-h to ethene were calculated. The through-space dihedral angles N-C7-
C3’”-C4’” and N-C7-C4’”-C3’” were used to assess whether the transition states were of the ‘bow-
tie’ or ‘spiro’ types. Despite the variety of steric environments about the C-N-O three-membered
ring, it is clear from the data presented in Table 8 that all eight transition states (TSs) for the
epoxidation of our model alkene ethene were spiro-like (the magnitudes of the dihedral angles range
from 82 to 109°). Each transition state was confirmed by the presence of a negative vibrational
frequency, with the reaction coordinate corresponding to the concerted lengthening of the N-O bond
upon the approach of the alkene. The reaction paths were confirmed by computing points along each
reaction pathway by determining the intrinsic reaction coordinates51 (IRCs) in both directions.
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 38
Table 8. Energies and key geometric features of the transition states for the epoxidation of ethene by
2.
1
2
3
4
Level
of B3LYP / 6-31G(D)
TS
5
6
theory:
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
Oxazirid- Relative TS
inium ion
energies
(kJ mole−1)
(Ǻ)
(Ǻ)
(°)
(°)
75.0
72.5
72.0
74.8
72.1
76.5
75.3
72.7
(°)
47.3
48.5
(°)
−91.8 102.4 spiro
−98.5 95.7 spiro
(°)
1
2
3
4
5
6
7
8
30aa
30bb
30cc
30dd
30ee
30ff
0.00
3.41
1.89 2.12 159.4
1.87 2.19 160.1
1.87 2.17 158.9
1.83 2.21 157.7
1.89 2.15 158.7
1.87 2.12 160.1
1.91 2.12 159.9
1.91 2.11 160.3
14.70
19.95
30.46
33.87
39.91
41.48
52.7 −100.2 93.3 spiro
52.6
50.4
−94.6
98.7 spiro
−82.1 108.3 spiro
48.1 −100.4 89.5 spiro
50.6 −108.5 82.1 spiro
30hg
30gh
46.6
−87.3 103.0 spiro
a: see Table 7, entry 1; b: see Table 7, entry 2; c: see Table 7, entry 3; d: see Table 7, entry 4; e: see
Table 7, entry 5; f: see Table 7, entry 6; g: see Table 7, entry 8; h: see Table 7, entry 7.
The highest enantioselectivity (98% ee) in the experimental survey of epoxidation reactions
described above (Table 3) was achieved by the epoxidation of the enol acetate 11 using iminium salt
2 and TPPP to generate the oxaziridinium ions. In order to extend the computational study to
unsymmetrical prochiral substrates such as 11, analogous transition states to those in Table 7 were
calculated using enol acetate as the oxygen atom acceptor (see Figure 4).
AcO
H
OAc
H
NW
SW
NE
SE
H
H
= oxygen
of the oxazirid-
inium ion
OAc
AcO
Figure 4. Four different orientations of the enol acetate 11 relative to the chiral features (not drawn)
14
ACS Paragon Plus Environment

Page 15 of 38
The Journal of Organic Chemistry
of each of the proposed oxaziridinium ions 30a-h in which the acetoxy substituent lies in the SE,
SW, NW or NE quadrants, respectively, working clockwise from the top-left structure (box: key to
the quadrants relative to the central ethene TS, and the representation of the oxaziridinium ion lying
below the alkene).
1
2
3
4
5
6
7
8
9
The transition state calculations were again performed using the B3LYP/ 6-31G(D) level of theory,
but with solvent effects (chloroform) taken into account by employing the polarizable continuum
model,52 and with a temperature of 233.15 K (−45° C). Of the 32 possible transition states that could
in principle contribute to the enantioselectivity, thirty were located. In the remaining two
possibilities, the enol acetate ring system clashes with structural features of the oxaziridinium ion.
While there was room for ethene to approach the oxygen atom, the larger enol acetate structure 11,
was sterically hindered. Consequently, these two transition states were removed from the analysis
under the assumption that they would be so high in energy, as not to contribute to the population
statistics.
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 results are presented in Table 9 and indicate that the oxygen transfer process is dominated by
just one of the transition state structures (entry 1). This corresponds to the oxaziridinium ion 30a,
which was also responsible for the most significant transition state identified for the epoxidation of
ethene (Table 7, entry 1). The oxaziridinium ions relating to the top four entries in Table 9 (30a and
30b) are derived from two most stable iminium ion conformations (Table 6, entries 1 and 2). In this
respect, the outcomes of the transition state calculations for ethene and the enol acetate 11 are
similar, but there are also significant differences. Because of the interactions between the prochiral
alkene and the chiral features of the oxaziridinium ion, almost all the transition states are displaced
away from the expected spiro form, taking on twisted conformations intermediate between spiro and
bow-tie. Indeed, three of the TSs were sufficiently flat around the central oxygen atom to be regarded
as bow-tie. Neither of the two spiro TSs (entries 14, 22) and none of the bow-tie TSs (entries 17, 19
and 30) contribute significantly to the R/S selectivity. It is the distortion of the spiro conformation
into the twisted structures that provides evidence for the presence of strong controlling interactions
that underlie the enantioselectivity of the reaction. The results obtained for 11 also reveal a
significant mechanistic difference. Analysis of the reaction pathways for each transition state by the
intrinsic reaction coordinate method shows that the oxygen transfer process no longer directly forms
the epoxide products, but instead, in almost all cases, a cationic intermediate was identified at the
end of each pathway. An example corresponding to Table 9, entry 1 is presented in Figure 5B. The
presence of the aromatic ring in 11 would be expected to stabilise positive charge  to the ring (i.e. at
C4’”) and so displace the transfer of the oxygen atom to C3’”. Although not so strongly electron-
donating as an ether substituent, the OAc group, which is also present at C4’”, can similarly be
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 38
expected to contribute to the stabilisation of the developing C4’” cation in the transition states.
1
2
3
4
5
6
Table 9. Energies and conformations of the transition states for the epoxidation of 4-acetoxy-1,2-
dihydronaphthalene 11.
7
8
Level of theory:
B3LYP/6-31G(D); solventa = CHCl3; temp. = 233.15 K (−45 °C)
TS
9
Oxazirid- Relative TS
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
inium ion
energies
(kJ mole−1)
(Ǻ)
1.75 2.31 100.8
1.77 2.35 88.7 −176.6 −80.0 107.3 twisted
1.74 2.34 100.7 −124.4 134.4 −55.7
(Ǻ)
(°)
(°)
(°)
(°)
1
2
3
30ab
30ab
30bf
30ab
30ci
30bf
0.00c
6.95e
R
S
S
128.1 −136.8
52.5 twistedd
twisted
twisted
7.46g
8.81h
10.34
4
5
6
R
R
R
1.75 2.34
1.76 2.35
92.2
91.6
61.0
115.6 −78.3
123.1 −58.2 −139.1 twisted
1.77 2.29 102.6
125.2 −136.5
99.7 −43.8 −142.8
87.7 171.2
52.9 twisted
46.0 twisted
11.46
12.83j
7
8
9
30bf
30bf
30ci
S
R
S
1.77 2.34
1.74 2.42
12.83h,k
12.83l
17.14
17.15
26.50
27.12
31.55
33.27
35.10
35.35
37.28
38.20
38.60
39.12
40.20
42.25
42.44
42.76s
76.6 −114.0 twisted
1.75 2.31 102.4
120.0 140.9 −48.9 twisted
10 30ci
11 30ci
12 30dm
13 30dm
14 30dm
15 30dm
16 30go
17 30go
18 30eq
19 30eq
20 30fr
21 30fr
22 30fr
23 30fr
24 30go
25 30go
S
1.77 2.29
93.7 −49.7 −140.3
48.9 twisted
R
S
1.74 2.31 101.3
94.6 −159.4
26.4 twisted
twisted
83.8 −102.3 twisted
1.75 2.34 101.9 −108.4 150.1 −38.0
S
1.76 2.40
1.77 2.38
1.79 2.40
1.78 2.33
94.9 −130.4
95.1 148.4 −91.1
94.5 −156.5 107.5 −82.1
89.2 179.7
117.0 173.0
164.1 70.0 −115.6 twisted
169.0 −171.7 10.1
1.81 2.27 103.4 −152.3 166.9 −15.6
S
98.7
spiron
R
S
twisted
59.2 −125.5 twisted
−8.4 bow-tiep
R
S
1.85 2.25 107.6
1.79 2.35 99.3
1.83 2.27 106.8
R
S
bow-tie
twisted
R
R
R
S
1.77 2.33
1.76 2.34
93.8
168.4 −108.4
79.7 twisted
93.5 −175.9 −95.3
91.6
spiro
1.82 2.29 101.3
132.7 138.1 −47.6
twisted
1.81 2.27 101.8 −174.2 −153.3
30.7 twisted
R
1.77 2.41
16
82.1
123.5 −45.5 138.1 twisted
ACS Paragon Plus Environment

Page 17 of 38
The Journal of Organic Chemistry
26 30ht
43.12
45.69s
48.87
50.64
76.27
S
R
R
R
S
1.86 2.25 110.8 −106.1 −116.6
16.4 twisted
1
2
3
4
5
6
7
8
27 30eq
28 30ht
29 30ht
30 30ht
1.80 2.34
1.77 2.33
88.6
95.5
128.6 −61.0 124.8 twisted
173.0 −62.1 123.5 twisted
1.83 2.31 100.6
166.5 129.2 −57.6
twisted
1.78 2.36 92.4 −176.4
1.0 −179.1 bow-tie
9
a: using the polarizable continuum model as implemented by Gaussian 09; b: see Table 7, entry 1; c: Boltzman
population: 0.811; d: (magnitude of dihedral ~11-89 or 99-171); e: Boltzman population: 0.06; f: see Table 7, entry 2; g:
Boltzman population: 0.03; h: taken from a single point calculation using the coordinates from a transition state
characterised in the gas phase at 233.15 K; i: see Table 7, entry 3; j: 12.831 kJ mole−1; k: 12.832 kJ mole−1; l: 12.833 kJ
mole−1; m: see Table 7, entry 4; n: (magnitude of dihedral ~ 90); o: see Table 7, entry 7; p: (magnitude of dihedral ~180)
bow-tie; q: see Table 7, entry 5; r: see Table 7, entry 6; s: path goes directly to the epoxide (no cationic intermediate was
identified); t: see Table 7, entry 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
OH
O
R
7
(R)-
O
O
1
H
=
3
H2C
2
AcOC
CH2
COAc
R
Figure 5. A: The twisted transition state (derived from the approach of the enol acetate 11 to the
oxaziridinium ion 30a with the acetoxy group in the NE quadrant) which dominates the
enantioselectivity. B: Oxygen transfer to 11 initially forms a cationic intermediate. C: The induced
stereogenic center of the structure shown in B is redrawn to illustrate its conversion into (R)-7. The
calculations were performed at the B3LYP/6-31G(D) level of theory.
The transition state enthalpies from Table 9 were corrected with zero-point energies and Gibbs free
energies. These thermodynamically corrected energies were then used to calculate Boltzmann
populations at 233.15 K, for each of the transition states. In these calculations we assume that all
eight reactant oxaziridinium ion conformations interconvert under the reaction conditions, and hence
the contribution of all of the transition states to the overall enantioselectivity was then calculated,
resulting in a predicted ee of 81% in favour of the (R)-enantiomer. This is in qualitative agreement
with the experimental value of 98% ee. The data presented here is sufficient to establish which one
of the 30 characterised transition states is primarily responsible for the control of enantioselectivity,
and so provide a sound basis to explore in future work the structural issues that account for the
exceptionally high efficiency of the epoxidation reaction presented in Table 3.
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 38
1
2
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
Figure 6. A: The dominant transition state (shown in Figure 5A) viewed from the top looking down
on the 4-acetoxy-1,2-dihydronaphthalene substrate (hydrogen atoms removed for clarity). B: As in
A, but with the hydrogen atoms shown and the substrate removed to reveal the oxaziridinium ion 11
more clearly (quadrants labelled as in Figure 4). C: Side view showing the close approach of one of
the methylene hydrogen atoms at C1”’ in the 4”’-acetoxy-1”’,2”’-dihydronaphthalene to the C4
position in one of the aromatic rings in the biphenyl section of 11 (H··C4 distance: 3.20 Å), and the
overlap of the acetoxy substituent with the second arene in 11. The calculations were performed at
the B3LYP/6-31G(D) level of theory.
Inspection of the conformation of the dominant transition state (Figure 6; see also Figure 5A and
Table 9, entry 1) shows that the acetoxy group of the 1,2-dihydronaphthalene occupies in the NW
quadrant, and the arene of the 1,2-dihydronaphthalene occupies the SW quadrant, which allows the
C3’” C-H substituent of the C3’”=C4’” double bond to be directed towards the NE and SE quadrants
which are partially blocked by the phenyl substituent (NE) and the 2’,2’-dimethyl-1’,3’-dioxane ring
of the oxaziridinium ion (SE). This is the orientation of the 1,2-dihydronaphthalene that suffers the
least from steric interactions, so allowing the alkene to come close to the oxygen of the lowest
energy oxaziridinium ion (the C··O distance is 2.31 Å). The NW quadrant is occupied by one of the
arenes of the biaryl section of the oxaziridinium ion, but this is oriented so that its -system is side-
on, raising the possibility of a favourable association with the carbonyl group of the acetoxy
substituent (closest O··C distance, 3.45 Å). Figure 6A also shows, in the SW quadrant, the overlap of
aromatic rings of the substrate and the chiral auxiliary (closest C··C distance, 3.99 Å), when viewed
from the top. These -system interactions may provide supplementary positive stabilising effects but
the main steric contribution to enantioselectivity is the adoption of an orientation relative to
stereochemical features of the chiral auxiliary that orientates the smallest substituent on the alkene (a
hydrogen atom) towards the most hindered quadrants. NCI calculations were performed to compare
through-space non-covalent interactions in the lowest energy (R)-selective and the lowest two (S)-
selective transition states (Entries 1, 2 and 3, respectively, in Table 9).53 This identified the presence
18
ACS Paragon Plus Environment

Page 19 of 38
The Journal of Organic Chemistry
of CH‒ interactions54 (Figure 7) which bring the one of the hydrogens of the CH2 group at C1”’ of
the 4”’-acetoxy-1’”,2’”-dihydronaphthalene close to the six carbons (C1, C2, C3, C4, C4a, C11b) of
the biaryl section of the iminium ion to form a stabilizing interaction. Additional details are provided
in the Supporting Information.
1
2
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
Figure 7. Non-covalent interactions (pale green surfaces) in the three most accessible competing
transition states for the oxygen transfer step of the epoxidation of the enol acetate 11 calculated at the
B3LYP/6-31G(D) level of theory (solvent: CHCl3; temperature: 233.15 K). A: (R)-selective
transition state (Table 9, entry 1); B: (S)-selective transition state (Table 9, entry 2); C: (S)-selective
transition state (Table 9, entry 3).
CH‒ interactions can contribute as much as 4 kJ mole−1 to the energy difference that accounts for
enantioselectivity.55 Figure 7B (viewing the iminium ion in the same orientation as in Figure 7A)
shows that this CH‒ interaction is more off-centre than in Figure 7A (see Supporting Information).
The third lowest energy transition state, (Table 9, entry 3), like its lowest energy counterpart, also
has a well-formed CH‒ interaction but has a noticeably less extensive interaction surface between
the acetoxy group of the substrate and the second aromatic ring of the biaryl section of the
oxaziridinium ion. On this basis, it seems probable that the presence of the CH‒ interactions shown
in Figure 7 make a substantial contribution to the conformational restrictions that control the oxygen
transfer process, with the steric effects discussed above accounting for the differences between them,
and ultimately the (R)-selectivity of epoxidation. Further synthetic work to develop a new generation
of biphenylazepinium-based chiral auxiliaries to improve enantioselectivity for the other enol
acetate, trifluorocetate and benzoate substrates shown in Tables 4 and 5, and the synthetically
valuable example 26, can now be based on strategies that retain the CH‒ interaction and employ it
as a pivot point to determine the nature of stereocontrolling steric interactions with other features
introduced into the chiral auxiliary.
Conclusions
Oxaziridinium ions generated in situ from the chiral iminium salt (4’S,5’S)-2 by oxidation with TPPP
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 38
are efficient oxygen donors for the epoxidation of alkenes, particularly the 4-acetoxy-1,2-
dihydronaphthalene 11, which, after hydrolysis, affords the (R)-hydroxyketone product 12 in 98% ee.
The most stable of the eight possible oxariridinium ions plays by far the most significant role in the
control of enantioselctivity in this reaction, adopting an orientation relative to stereochemical
features of the chiral auxiliary that places the smallest substituent on the alkene (a hydrogen atom) in
the more hindered quadrants. In the more accessible transition states, the substrate and the
oxaziridinium unit are brought together by CH‒ interactions between a CH2 group in the substrate
and one of the aromatic rings of the biaryl section of the chiral auxiliary. The combination of CH‒
interactions with the avoidance of adverse steric clashes between the substrate and the chiral
auxiliary explains why this most accessible transitions states so strongly dominate the induction of
asymmetry in the oxygen-transfer process. The chiral iminium ions used in this study are effective in
promoting the epoxidation of a range of enol esters and other alkenes, often providing products in
high ee. The reaction has been successfully employed in the synthesis of the natural product
tatarinoid A.
1
2
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
Experimental Detail
General procedure for the synthesis of enol acetates 56
The ketone (approx. 20 mmol), isopropenyl acetate (100 mL) and p-toluenesulfonic acid
monohydrate (0.1 equiv) were heated using a heating mantle in a Dean-Stark apparatus overnight.
The mixture was poured into saturated aqueous NaHCO3 (50 mL) and diethyl ether (100 mL). The
organic phase was separated and the aqueous layer extracted with diethyl ether (3 × 100 mL). The
combined ethereal solutions were washed with saturated aqueous NaHCO3, saturated aqueous NaCl,
dried over anhydrous MgSO4, filtered, and the solvents removed under reduced pressure. The enol
acetate was isolated by column chromatography on silica gel (eluent: hexanes/ethyl acetate 5:1).
3,4-Dihydronaphth-1-yl acetate 11 57
Prepared according to the general procedure for the synthesis of enol acetates using 1-tetralone (2.5
g, 17 mmol), isopropenyl acetate (100 mL) and p-toluenesulfonic acid monohydrate (0.3 g, 0.1
equiv., 1.7 mmol) to give the desired product as a colourless oil (2.4 g, 75%). νmax (film)/cm−1 3100,
1
2900, 1740, 1650, 1570, 1200; H NMR (400 MHz, CDCl3) δ 7.21 – 7.10 (m, 4H), 5.73 (t, J = 4.7
Hz, 1H), 2.89 (t, J = 8.1 Hz, 2H), 2.53 – 2.43 (m, 2H), 2.32 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 169.2, 145.6, 136.3, 130.1, 128.6, 127.8, 126.2, 120.4, 115.1, 26.9, 23.4, 20.3.
6,7-Dihydro-5H-benzo[7]annulen-9-yl acetate 14 58
Prepared according to the general procedure for the synthesis of enol acetates using 1-benzosuberone
(2.5 g, 15 mmol), isopropenyl acetate (100 mL) and p-toluenesulfonic acid monohydrate (0.26 g, 0.1
20
ACS Paragon Plus Environment

Page 21 of 38
The Journal of Organic Chemistry
equiv., 1.5 mmol) to give the desired product as a colourless oil (3.0 g, 95%). νmax (film) /cm−1: 2930,
2858, 1755; 1H NMR (500 MHz, CDCl3) δ 7.42 (d, J = 6.3 Hz, 1H), 7.32 – 7.25 (m, 3H), 5.91 (t, J =
6.2 Hz, 1H), 2.92 (t, J = 1.7 Hz, 2H), 2.24 (s, 3H), 2.23 – 2.19 (m, 2H), 2.16 – 2.10 (m, 2H); 13C{1H}
NMR (126 MHz, CDCl3) δ 169.6, 146.0, 141.9, 134.6, 129.2, 128.2, 126.1, 125.5, 119.7, 33.8, 31.3,
25.4, 20.9.
1
2
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
1H-Inden-3-yl acetate 15 59
Prepared according to the general procedure for the synthesis of enol acetates using 1-indanone (2.5
g, 19 mmol), isopropenyl acetate (100 mL) and p-toluenesulfonic acid monohydrate (0.3 g, 0.1
equiv., 1.9 mmol) to give the desired product as a yellow oil (2.66 g, 80%). νmax (film)/cm−1: 2991,
1700, 1450, 1200; 1H NMR (500 MHz, CDCl3) δ 7.51 (d, J = 6.5 Hz, 1H), 7.44 – 7.30 (m, 3H), 6.42
(t, J = 2.3 Hz, 1H), 3.47 (d, J = 2.4 Hz, 2H), 2.39 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 168.2,
149.1, 141.8, 139.1, 126.3, 125.7, 124.1, 118.1, 115.5, 35.0, 21.1.
1-Phenylprop-1-enyl acetate 17 60
Prepared according to the general procedure for the synthesis of enol acetates using propiophenone
(2.5 g, 18 mmol), isopropenyl acetate (100 mL) and p-toluenesulfonic acid monohydrate (0.3 g, 0.1
equiv., 1.8 mmol) to give the desired product, a yellow oil, as a 10:1 mixture of Z:E isomers (2.4 g,
73%). νmax (film) /cm−1: 3000, 1696, 1500. For the major isomer: 1H NMR (500 MHz, CDCl3) δ 7.45
– 7.31 (m, 5H), 7.31 – 7.29 (m, 0.5H), 5.93 (q, J = 7.0 Hz, 1H), 5.57 (q, J = 7.4 Hz, 0.1H), 2.34
(s,3H), 2.18 (s, 0.3H), 1.85 (d, J = 7.4 Hz, 0.3H), 1.75 (d, J = 7.0 Hz, 3H); C{1H} NMR (126
13
MHz, CDCl3) δ 168.6, 146.9, 146.2, 128.4, 128.0, 124.2, 112.6, 20.6, 11.5.
3,4-Dihydronaphthalen-1-yl 2,2,2-trifluoroacetate 13
A mixture of 1-tetralone (1:0 g, 6.8 mmol) and trifluoroacetic anhydride (50 mL) was heated
overnight and poured into saturated aqueous NaHCO3 (50 mL) and diethyl ether (100 mL). The
organic phase was separated, and the aqueous layer extracted with diethyl ether (3 × 100 mL). The
combined ethereal solutions were washed with aqueous saturated NaHCO3, saturated aqueous NaCl,
dried over anhydrous MgSO4, filtered, and the solvents removed under reduced pressure. The
corresponding enol trifluoroacetate was isolated by column chromatography on silica gel (eluent:
hexanes/ethyl acetate 5:1) to give the desired product as a yellow oil (1.5 g, 91%). νmax (film) /cm−1;
2944, 2838, 1700; 1H NMR (500 MHz, CDCl3) δ 7.29 – 7.20 (m, 3H), 7.13 (d, J = 6.7 Hz, 1H), 5.96
(t, J = 4.7 Hz, 1H), 2.93 (t, J = 8.2 Hz, 2H), 2.57 – 2.50 (m, 2H); 13C{1H} NMR (126 MHz, CDCl3)
δ 144.8, 136.3, 128.7, 128.6, 127.8, 126.7, 120.3, 116.3, 114.6 (q, CF3, J = 289 Hz), 30.9, 27.1, 21.9.
1-(2,2,2-Trifluoroacetyl)-1,2-dihydroquinolin-4-yl acetate 16
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 38
Following the general procedure for the synthesis of enol acetates using 1-(2,2,2-trifluoroacetyl)-2,3-
dihydroquinolin-4(1H)-one61 (2.5 g, 10 mmol), isopropenyl acetate (100 mL) and p-toluenesulfonic
acid monohydrate (0.2 g, 0.1 equiv., 1.1 mmol) to give the desired product as yellow oil (1.2 g,
1
2
3
4
5
6
1
41%). νmax (film) /cm−1; 3000, 1755, 1702, 1600, 1484, 1269, 1209; H NMR (500 MHz, CDCl3) δ
7
8
9
8.05 (dd, J = 7.9, 1.6 Hz, 1H), 7.73 (dd, J = 8.5, 1.9 Hz, 1H), 7.63 – 7.56 (m, 1H), 7.39 – 7.32 (m,
1H), 5.44 (dd, J = 9.6, 4.4 Hz, 1H), 4.35 (dd, J = 13.7, 4.4 Hz, 1H), 4.14 (dd, J = 13.8, 9.6 Hz, 1H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
2.13 (s, 3H). C{1H} NMR (126 MHz, CDCl3) δ 188.2, 169.3, 141.4, 135.1, 128.5, 127.4, 125.1,
124.1, 117.3, 116.2 (q, CF3, J = 288 Hz), 70.7, 48.9, 20.4. HMRS (APCI-FTMS) m/z: [M+H]+ calcd
for [C13H10F3NO3+H] 286.0686; Found 286.0685.
(3,4-Dihydronaphthalen-1-yl)oxy)triisopropylsilane 5
The ketone (1.45 g, 5 mmol) and triethylamine (2.09 ml, 9.0 mmol) were dissolved in
dichloromethane (15 ml). Triisopropylsilyl triflate (4 ml, 6.0 mmol) was added and the reaction
mixture stirred overnight. The ethereal solution was concentrated under reduced pressure and the
residue purified by column chromatography on basic alumina using hexane as the eluent to give the
enol ether as yellow oil (1.20 g, 40%), νmax (film) /cm−1: 2943, 2860, 1640, 1256; H NMR (400
1
MHz, CDCl3) δ 7.57 (d, J = 6.3 Hz, 1H), 7.25 – 7.11 (m, 3H), 5.19 (t, J = 4.7 Hz, 1H), 2.82 – 2.73 (t,
J = 8.2 Hz, 2H), 2.37 – 2.27 (m, 2H), 1.36 – 1.26 (m, 3H), 1.16 (d, J = 7.2 Hz, 18H); 13C{1H} NMR
(101 MHz, CDCl3) δ 148.4, 137.1, 133.7, 127.1, 126.8, 126.1, 121.9, 103.8, 28.2, 22.2, 18.1, 12.8.
3,4-Dihydronaphthalen-1-yl diethylphosphonate 10 62
Diisopropylamine (2.94 ml, 21 mmol) was dissolved in anhydrous THF (50 ml) and the solution
cooled to –78 °C. n-BuLi (8.4 ml, 21 mmol, 2.5 M in hexane) was added dropwise. α-Tetralone (2.68
g, 20 mmol) was dissolved in anhydrous THF (10 ml) at –78 °C and the LDA solution was added.
The mixture was stirred under an argon atmosphere for 1 h at –78 °C. Diethylphosphorochloridate
(5.1 g, 30 mmol) was dissolved in anhydrous THF (5 ml), and the solution added dropwise to the
reaction mixture. The mixture was allowed to reach room temperature and stirred for 1 h. The
solvents were removed under reduce pressure, the residue was dissolved in diethyl ether (100 mL),
and the solution washed with saturated NH4Cl (50 mL) and water (50 mL). The organic layer was
dried over anhydrous MgSO4, filtered, and the solvents removed under reduced pressure. The residue
was purified using silica gel column chromatography using petroleum ether-EtOAc (5:1 v/v) as the
eluent to give the enol phosphate as a yellow oil (2.93 g, 69%). νmax (film) /cm−1: 3000, 1240, 1600;
1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 6.2 Hz, 1H), 7.25 – 7.13 (m, 3H), 5.91 (t, J = 4.7 Hz, 1H),
4.28 – 4.19 (m, 4H), 2.83 (t, J = 8.1 Hz, 2H), 2.47 – 2.40 (m, 2H), 1.38 (t, J = 7.1 Hz, 6H); 13C{1H}
NMR (100 MHz, CDCl3): δ 145.4, 137.0, 131.2, 128.3, 127.6, 126.8, 121.9, 111.5, 67.0, 65.9, 26.2,
22.1, 16.8.
22
ACS Paragon Plus Environment

Page 23 of 38
The Journal of Organic Chemistry
1
2
3
3,4-Dihydronaphthalen-1-yl benzoate 12 39
1-Tetralone (2.5 g, 17 mmol) and benzoic anhydride (3.8 g, 16 mmol) were dissolved in hexane (100
mL), and perchloric acid (0.2 mL) added. The mixture was stirred at room temperature for 2 h, and
filtered to remove the solids formed. The filtrate was washed with NaOH (1N, 100 mL), saturated
NaHCO3 (100 mL), and brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified using silica gel column chromatography using n-
pentane/ethylactate (6:2) to afford 3,4-dihydronaphthalen-1-yl benzoate as a colourless liquid (1.09
g, 26%). νmax (film) /cm−1: 3000, 2841, 1736, 1500; 1H NMR (500 MHz, CDCl3) δ 8.25 (dd, J = 8.2,
1.1 Hz, 2H), 7.71 – 7.65 (m, 1H), 7.56 (t, J = 7.7 Hz, 2H), 7.24 – 7.15 (m, 4H), 5.88 (t, J = 4.7 Hz,
1H), 2.97 (t, J = 8.1 Hz, 2H), 2.59 – 2.52 (m, 2H); 13C{1H} NMR (126 MHz, CDCl3) δ 165.0, 145.8,
136.4, 133.5, 130.5, 130.1, 129.5, 128.6, 128.0, 127.6, 126.4, 120.8, 115.7, 27.5, 22.1.
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
tert-Butyl-[(3, 4-dihydronaphthalen-1-yl)oxy]diphenylsilane 8 63
Potassium hexamethyldisilazide (0.7 g, 3.5 mmol) was dissolved in tetrahydrofuran (12 mL), and the
solution cooled to –78 °C. Tetralone (0.3 g, 2.0 mmol) was added dropwise by syringe. The resulting
pale-brown solution was stirred for 20 min at –78 °C. tert-Butylchlorodiphenylsilane (0.75 mL, 2.7
mmol) was added dropwise. The mixture was stirred for 5 min at –78 °C, allowed to reach room
temperature, and stirred for 1 h. The solvents were removed under reduced pressure. The pale yellow
oily residue was dissolved in pentane (20 mL), the solution was filtered through a pad of celite, and
the filtrate was concentrated under reduced pressure. The residue was purified using silica gel
column
chromatography
(hexanes)
to
provide
tert-butyl((3,4-dihydronaphthalen-1-
yl)oxy)diphenylsilane as a colourless solid (0.35 g, 45%). mp = 64-69 °C [Lit.63 mp 69 °C]; νmax
(film) /cm−1: 2937, 2700, 1638, 1250, 1113; 1H NMR (500 MHz, CDCl3) δ 7.72 – 7.69 (m, 4H), 7.35
– 7.02 (m, 10H), 4.69 (t, J = 4.7 Hz, 1H), 2.58 (t, J = 7.9 Hz, 2H), 2.09 – 1.89 (m, 2H), 1.04 (s, 9H);
13C{1H} NMR (126 MHz, CDCl3) δ 145.6, 135.1, 133.3, 131.3, 130.7, 127.6, 125.5, 125.2, 124.9,
124.2, 119.7, 103.6, 25.9, 24.5, 19.9, 17.4.
General Procedure for enol ether/ester oxidation
A. Using MCPBA
NaHCO3 (2 equiv.) was suspended in dichloromethane (2 mL per 100 mg of enol ether/ester) and the
mixture cooled to 0 °C. Meta-chloroperoxybenzoic acid (77% w/w; 1.5 equiv.) was added. The
mixture was stirred for 10 min. The enol ether/ester (0.2 g) was added, and the reaction followed by
TLC until complete consumption of the starting material was observed. Diethyl ether was added (10
mL) and the mixture washed with water (10 mL), aqueous Na2CO3 (3 x 10 mL), and brine (10 mL).
The organic phase was dried over anhydrous Na2SO4, and the solvents removed under reduced
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 38
pressure. The residue was purified using column chromatography on silica gel (eluent: hexanes/ethyl
1
2
3
4
acetate 95:5) to give the desired compound.
B. Using TPPP
5
6
The
catalyst
(0.1
equiv.)
and
the
enol
ether/ester
were
dissolved
in
7
8
9
chloroform/acetonitrile/dichloromethane (2 mL per 100 mg of enol ether/ester), and the mixture was
cooled. TPPP (2 equiv.) was added, and the reaction followed by TLC until complete consumption of
the starting material was observed. Diethyl ether was added (10 mL) and the reaction mixture was
filtered on a pad of celite. The solvents were removed under reduced pressure and the residue
purified using column chromatography on silica gel (eluent: hexanes/ethyl acetate 95:5) to give the
desired compound.
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-[(Triisopropylsilyl)oxy]-3,4-dihydronaphthalen-1(2H)-one 6
Prepared according to the general procedure for enol ether/ester oxidation using ((3,4-
dihydronaphthalen-1-yl)oxy)triisopropylsilane 5 (0.20 g, 0.73 mmol), meta-chloroperoxybenzoic
acid (0.17 g) and sodium bicarbonate (0.10 g, 1.11 mmol) to give 2-((triisopropylsilyl)oxy)-3,4-
1
dihydronaphthalen-1(2H)-one (0.19 g, 89%). νmax (film) /cm−1: 2941, 2865, 1700, 1903, 1295. H
NMR: δH (500 MHz; CDCl3): 7.96 (d, J = 7.8 Hz, 1H), 7.39 (t, J = 7.4 Hz, 1H), 7.18 (dd, J = 16.4,
8.9 Hz, 2H), 4.41 (dd, J = 10.3, 4.4 Hz, 1H), 3.13 – 2.86 (m, 2H), 2.32 – 2.09 (m, 2H), 1.18 – 1.05
13
(m, 3H), 1.03 (d, J = 5.8 Hz, 18H). C{1H} NMR (126 MHz, CDCl3) δ 197.2, 143.5, 133.3, 132.0,
128.6, 127.7, 126.5, 74.7, 32.9, 27.1, 17.9, 12.2.
1-Oxo-2,3-dihydro-1H-inden-2-yl acetate 64
Prepared according to the general procedure for enol ether/ester oxidation using 1H-inden-3-yl
acetate 15 (0.50 g, 2.8 mmol), meta-chloroperoxybenzoic acid (1.40 g) and sodium bicarbonate (0.40
g, 4.7 mmol) to give 1-oxo-2,3-dihydro-1H-inden-2-yl acetate (0.25 g, 46%). νmax (film) /cm−1: 2932,
1
1745, 1726. H NMR (500 MHz, CDCl3) δ 7.82 (d, J = 7.7 Hz, 1H), 7.67 (td, J = 7.6, 1.1 Hz, 1H),
7.50 – 7.41 (m, 2H), 5.45 (dd, J = 8.0, 4.9 Hz, 1H), 3.68 (dd, J = 16.9, 8.0 Hz, 1H), 3.07 (dd, J =
16.9, 4.8 Hz, 1H), 2.21 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 200.6, 170.4, 150.4, 135.9,
134.5, 128.1, 126.6, 124.5, 74.0, 33.4, 20.8.
1-Oxo-1-phenylpropan-2-yl acetate 65
Prepared according to the general procedure for enol ether/ester oxidation using 1-phenylprop-1-en-
1-yl acetate 17 (0.2 g, 1.1 mmol), meta-chloroperoxybenzoic acid (0.3 g) and sodium bicarbonate
(0.2 g, 2.3 mmol) to give 1-oxo-1-phenylpropan-2-yl acetate (0.1 g, 40%). νmax (film) /cm−1: 3004,
1
1764, 1206. H NMR (500 MHz, CDCl3) δ 7.35 – 7.22 (m, 5H), 3.12 (q, J = 5.3 Hz, 1H), 2.07 (s,
3H), 1.40 (d, J = 5.3 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 169.1, 136.1, 128.8, 128.5, 125.5,
24
ACS Paragon Plus Environment

Page 25 of 38
The Journal of Organic Chemistry
84.9, 61.3, 21.0, 13.8.
1
2
3
4
5-Oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl acetate 66
5
6
7
8
Prepared according to the general procedure for enol ether/ester oxidation using 6,7-dihydro-5H-
benzo[7]annulen-9-yl acetate 14 (1 g, 5 mmol), meta-chloroperoxybenzoic acid (1.2 g) and sodium
bicarbonate (0.8 g, 9.5 mmol) to give 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl acetate (0.6
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
1
g, 56%). H NMR (500 MHz, CDCl3) δ 7.72 – 7.68 (m, 1H), 7.19 (dd, J = 5.7, 3.4 Hz, 2H), 7.02 (dd,
J = 5.4, 3.6 Hz, 1H), 3.52 (t, J = 4.7 Hz, 1H), 3.20 – 3.09 (m, 1H), 2.68 – 2.59 (m, 1H), 2.20 – 2.12
(m, 1H), 1.97 (s, 3H), 1.93 – 1.83 (m, 1H), 1.61 – 1.42 (m, 2H).
General procedure for protecting group removal
The substrate was dissolved in methanol (5 mL per 100 mg of starting material) and camphorsulfonic
acid (1.1 equiv) added. The reaction was followed by TLC until complete consumption of the
starting material was observed. The solvents were removed under reduced pressure and residue
purified using column chromatography on silica gel (eluent: hexanes/ethyl acetate 3:1) to give the
corresponding α-hydroxy-carbonyl species.
2-Hydroxy-3,4-dihydronaphthalen-1(2H)-one 7 67
From 2-((triisopropylsilyl)oxy)-3,4-dihydronaphthalen-1(2H)-one
2-((Triisopropylsilyl)oxy)-3,4-dihydronaphthalen-1(2H)-one 6 (0.2 g, 0.6 mmol) was dissolved in
methanol (10 mL), and camphorsulphonic acid (0.16 g, 0.6 mmol) was added. The reaction was
followed by TLC until complete consumption of the starting material was observed. The solvents
were removed under reduced pressure and the residue was purified using column chromatography on
silica gel to give 2-hydroxy-3,4-dihydronaphthalen-1(2H)-one (0.05 g, 50%) νmax (film) /cm−1: 3475,
3066, 1686, 1603. 1H NMR (400 MHz, CDCl3) δ 8.07 (dd, J = 7.8, 1.2 Hz, 1H), 7.55 (td, J = 7.5, 1.4
Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 4.41 (dd, J = 13.5, 5.4 Hz, 1H), 3.24 –
3.00 (m, 2H), 2.62 – 2.50 (m, 1H), 2.15 – 1.98 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 199.6,
144.3, 134.2, 130.4, 128.9, 127.6, 126.9., 73.9, 31.9, 27.8.
Asymmetric oxidation
Prepared according to the general procedure for TPPP enol ether/ester epoxidation, catalyst (0.1
equiv) and the enol ether (1 equiv) to give 2-hydroxy-3,4-dihydronaphthalen-1(2H)-one.
For non-racemic material: []D = +13 (c = 0.03, CHCl3); 88% ee. Literature value:68 []D = +11
20
20
(c = 0.7, CHCl3); 31% ee.
2-Hydroxy-2,3-dihydro-1H-inden-1-one 19 69
Prepared according to the general procedure for protecting group removal using 1-oxo-2,3-dihydro-
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 38
1H-inden-2-yl acetate (0.15 g, 0.8 mmol) and camphorsulphonic acid (0.20 g, 0.9 mmol) to give 2-
1
2
3
1
hydroxy-2,3-dihydro-1H-inden-1-one (0.1 g, 86%). νmax (film) /cm−1: 3414, 2923, 1718, 1609. H
NMR (500 MHz, CDCl3) δ 7.80 (d, J = 7.7 Hz, 1H), 7.67 (td, J = 7.5, 1.2 Hz, 1H), 7.53 – 7.41 (m,
2H), 4.58 (dd, J = 7.9, 5.1 Hz, 1H), 3.62 (dd, J = 16.5, 7.9 Hz, 1H), 3.05 (dd, J = 16.5, 5.1 Hz, 1H).
13C{1H} NMR (126 MHz, CDCl3) δ 206.5, 150.9, 135.9, 134.0, 128.0, 126.8, 124.4, 74.3, 35.1.
4
5
6
7
8
9
20
20
For non-racemic material: []D = –16 (c = 0.04, CHCl3); 78% ee. Literature value:69 []D = +54
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
(c = 1, MeOH); 97% ee.
2-Hydroxy-1-phenylpropan-1-one 21 70
Prepared according to the general procedure for protecting group removal using 1-oxo-1-
phenylpropan-2-yl acetate (0.10 g, 0.5 mmol) and camphorsulphonic acid (0.10 g, 0.5 mmol) to give
2-hydroxy-1-phenylpropan-1-one (0.07 g, 89%). νmax (film) /cm−1: 3459, 2979, 1682. 1H NMR (500
MHz, CDCl3) δ 7.86 (dd, J = 8.3, 1.1 Hz, 2H), 7.58 – 7.53 (m, 1H), 7.44 (t, J = 7.8 Hz, 2H), 5.15 –
5.04 (m, 1H), 1.38 (d, J = 7.0 Hz, 3H). C{1H} NMR (126 MHz, CDCl3) δ 202.4, 134.0, 133.3,
13
20
128.8, 128.6, 69.3, 22.3. For non-racemic material: []D = –25 (c = 0.02, CHCl3); 59% ee.
Literature value:70 []D20 = –64.4 (c = 7.8, CHCl3); >98% ee.
6-Hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one 18 71
Prepared according to the general procedure for protecting group removal using 5-oxo-6,7,8,9-
tetrahydro-5H-benzo[7]annulen-6-yl acetate (0.10 g, 0.5 mmol) and camphorsulphonic acid (0.10 g,
0.5 mmol) to give 6-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (0.06 g, 75%). νmax
(film) /cm−1: 3420, 3055,2998,1635. H NMR (500 MHz, CDCl3) δ 7.66 (dd, J = 7.7, 1.3 Hz, 1H),
1
7.34 (td, J = 7.5, 1.5 Hz, 1H), 7.26 – 7.21 (m, 1H), 7.14 (d, J = 7.6 Hz, 1H), 5.36 (dd, J = 10.7, 5.9
Hz, 1H), 3.02 – 2.86 (m, 2H), 2.21 – 2.11 (m, 2H), 2.00 – 1.89 (m, 1H), 1.82 – 1.70 (m, 1H).
13C{1H} NMR (126 MHz, CDCl3) δ 199.6, 170.2, 141.6, 132.0, 130.0, 129.1, 126.8, 34.1, 29.2, 23.5,
22
20.7. For non-racemic material: []D20 = +28 (c = 0.03, CHCl3); 92% ee. Literature value:71 []D
=
+43.4 (c = 0.23, CHCl3); 98% ee.
3-Hydroxy-1-(2,2,2-trifluoroacetyl)-2,3-dihydroquinolin-4(1H)-one 20
NaHCO3 (0.1 g, 1.1 mmol) was suspended in dichloromethane (4 mL), and the mixture cooled to 0
°C. Meta-chloroperoxybenzoic acid (77% w/w; 0.19 g) was added. The mixture was stirred for 10
min. 1-(2,2,2-Trifluoroacetyl)-1,2-dihydroquinolin-4-yl acetate 16 (0.2 g, 0.7 mmol) was added. The
reaction was followed by TLC until complete consumption of the starting material was observed.
Diethyl ether was added (10 mL) and the mixture was washed with water (10 mL), aqueous Na2CO3
(30 mL), and brine (10 mL). The organic phase was dried over anhydrous Na2SO4 and the solvents
removed under reduced pressure. The residue was purified using column chromatography on silica
26
ACS Paragon Plus Environment

Page 27 of 38
The Journal of Organic Chemistry
gel to give 4-oxo-1-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroquinolin-3-yl acetate (0.1 g, 50%).
4-Oxo-1-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroquinolin-3-yl acetate (0.15 g, 0.5 mmol) was
dissolved in methanol (5 mL), and camphorsulphonic acid (0.1 g, 0.5 mmol) was added. The reaction
was followed by TLC until complete consumption of the starting material was observed. The
solvents were removed under reduced pressure, and the residue was purified using column
chromatography on silica gel to give 3-hydroxy-1-(2,2,2-trifluoroacetyl)-2,3-dihydroquinolin-4(1H)-
one (0.1 g, 78%). νmax (film) /cm−1: 3394, 3000, 1696, 1257. 1H NMR (500 MHz, CDCl3) δ 8.04 (dd,
J = 7.8, 1.6 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.62 – 7.56 (m, 1H), 7.33 (td, J = 7.9, 1.0 Hz, 1H),
1
2
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
13
4.45 (dd, J = 12.4, 5.3 Hz, 1H), 3.73 – 3.63 (m, 2H). C{1H} NMR (126 MHz, CDCl3) δ 194.8,
142.3, 136.2, 135.2, 128.2, 127.2, 124.2, 123.6, 119.0, 116.2 (q, CF3, J = 288 Hz) 71.5. HRMS
(ASAP-TOF) m/z: [M+H]+ calcd for [C11H8F3NO3+H] 260.0529; Found 260.0535. For non-racemic
material: []D20 = –33 (c = 0.3, CHCl3); 67% ee.
1-(2,4,5-Trimethoxyphenyl)propan-1-ol 24 72
2-(2,4,5-Trimethoxyphenyl)acetaldehyde 23 (5.00 g, 25.48 mmol) was dissolved in anhydrous
tetrahydrofuran (135 mL), and the solution cooled to 0 °C. A solution of EtMgBr (17.0 mL, 3 M in
Et2O, 50.97 mmol, 2 equiv.) was added slowly. The mixture was stirred at 0 °C for 30 min and
allowed to stand for 16 h at room temperature. Saturated aqueous NH4Cl (25 mL) was added and the
solvents removed under reduced pressure. Water (50 mL) and diethyl ether (40 mL) were added and
the aqueous phase was extracted with Et2O (2 x 40 mL). The combined organic phases were washed
with water (60 mL) and brine (60 mL), dried (MgSO4), and the solvents removed under reduced
pressure to furnish 1-(2,4,5-trimethoxyphenyl)propan-1-ol as a yellow oil (5.36 g, 93%); mp 71 – 72
°C [lit.69 68 – 70 °C]; νmax (CH2Cl2)/cm-1 3494 (broad), 2962, 2935, 2834, 1509, 1464, 1205, 1038;
1H NMR (500 MHz, CDCl3) δ 0.93 (t, J = 7.4 Hz, 3H), 1.68 – 1.83 (m, 2H), 2.43 (br, 1H), 3.81 (s,
13
3H), 3.83 (s, 3H), 3.87 (s, 3H), 4.77 (dd, J = 7.4, 5.9 Hz, 1H), 6.50 (s, 1H), 6.87 (s, 1H); C{1H}
NMR (126 MHz, CDCl3) δ 10.6, 30.6, 56.3, 56.3, 56.9, 71.6, 97.6, 111.2, 124.3, 143.2, 148.7, 150.8;
HMRS (NSI-FTMS) m/z: [M+Na]+ calcd for [C12H18O4Na] 249.1097; Found 249.1092.
1-(2,4,5-Trimethoxyphenyl)propan-1-one 25 73
1-(2,4,5-Trimethoxyphenyl)propan-1-ol 24 (1.0001 g, 4.42 mmol) was dissolved in dichloromethane
(5 mL), and MnO2 (3.84 g, 44.2 mmol, 10 equiv.) added in one portion. The suspension was heated
using a heating mantle under reflux for 24 hr. After cooling, the reaction mixture was filtered
through a pad of celite, and the solvents were removed under reduced pressure. The residue was
purified by column chromatography on silica gel (eluent: hexanes/ethyl acetate 5:1) to provide 1-
(2,4,5-trimethoxyphenyl)propan-1-one as a colourless solid (0.4596 g, 46%); mp 105 – 107 °C [lit.74
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 38
107 – 108 °C]; νmax(CH2Cl2)/cm-1 2972, 2939, 2916, 2835, 1605, 1472, 1270, 1025; H NMR (400
MHz, CDCl3) δ 1.15 (t, J = 7.2 Hz, 3H), 2.97 (q, J = 7.2 Hz, 2H), 3.86 (s, 3H), 3.90 (s, 3H), 3.93 (s,
3H), 6.49 (s, 1H), 7.42 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 8.7, 37.2, 56.2, 56.3, 56.4, 96.6,
112.8, 119.2, 143.1, 153.6, 155.2, 200.8; HRMS (NSI-FTMS) m/z: [M+Na]+ calcd for [C12H16O4Na]
247.0941; Found 247.0943.
1
1
2
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
(Z)-1-(2,4,5-Trimethoxyphenyl)prop-1-en-1-yl acetate 26
A solution of n-BuLi in n-hexane (1.5 mL, 2.5 M, 3.75 mmol, 1.4 equiv) was added dropwise to a
solution of diisipropylamine (0.62 mL, 4.42 mmol, 1.7 equiv) in anhydrous tetrahydrofuran (16 mL)
at –78 °C. After 30 minutes, a solution of 1-(2,4,5-trimethoxyphenyl)propan-1-one 25 (0.5916 g, 2.6
mmol) in anhydrous tetrahydrofuran (16 mL) was added dropwise. After 45 minutes, acetic
anhydride (0.52 mL, 5.5 mmol, 2.1 equiv.) was added dropwise, and the reaction mixture stirred for
44 hours at room temperature. Saturated aqueous NaHCO3 (75 mL) and diethyl ether (10 mL) were
added. The aqueous phase was extracted with Et2O (2 x 75 mL), and the combined organic phases
were washed with brine (75 mL), dried (Na2SO4), and concentrated under reduced pressure. The
residue was recrystallized twice from isopropanol, and the mother liquors recrystallized. The
resulting solids were re-dissolved in ether (30 mL), washed with aqueous HCl (1M, 15 mL x 2) dried
with sodium sulphate, filtered, and the solvents removed under reduced pressure to provide (Z)-1-
(2,4,5-trimethoxyphenyl)prop-1-en-1-yl acetate as a pale-yellow waxy solid (0.3571 g, 51%); νmax
1
(CH2Cl2)/cm–1 2937, 2847, 1752, 1610, 1509; H NMR (400 MHz, CDCl3) δ 6.84 (s, 1H), 6.51 (s,
1H), 5.80 (q, J = 7.0 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.83 (s, 3H), 2.22 (s, 3H), 1.70 (d, J = 7.0
Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 168.7, 151.5, 149.7, 144.3, 143.0, 116.7, 115.6, 112.7,
98.3, 56.8, 56.7, 56.2, 20.8, 11.8; HRMS (NSI-FTMS) m/z: [M+H]+ calcd for [C14H19O5] 267.1227;
Found 267.1227.
1-Oxo-1-(2,4,5-trimethoxyphenyl)propan-2-yl acetate 27
Racemic oxidation
NaHCO3 (0.315 g, 3.75 mmol, 3 equiv.) and meta-chloroperoxybenzoic acid (77% w/w; 0.315 g)
were added to dichloromethane (6.5 ml), and the mixture cooled to 0 °C. (Z)-1-(2,4,5-
trimethoxyphenyl)prop-1-en-1-yl acetate 26 (0.325 g, 1.219 mmol) was added. The mixture was
stirred for 16 h at room temperature, diethyl ether (10 mL) added, and the mixture washed with water
(10 mL), aqueous Na2CO3 (3 x 10 mL), and brine (10 mL). The organic phase was dried over
anhydrous MgSO4, and the solvents removed under reduced pressure. The residue was purified using
column chromatography on silica gel (eluent: hexanes/ethyl acetate 3:1) to give 1-oxo-1-(2,4,5-
trimethoxyphenyl)propan-2-yl acetate as a colourless solid (0.177 g, 29% over two steps); mp 102 –
104 °C; νmax (CH2Cl2)/cm-1 2939, 2850, 1740, 1605, 1515, 1469, 1404, 1223; H NMR (500 MHz,
1
28
ACS Paragon Plus Environment

Page 29 of 38
The Journal of Organic Chemistry
CDCl3) δ 1.45 (d, J = 6.9 Hz, 3H), 2.14 (s, 3H), 3.87 (s, 3H), 3.93 (s, 3H), 3.96 (s, 3H), 6.00 (q, J =
1
2
3
4
5
6
7
8
13
6.9 Hz, 1H), 6.49 (s, 1H), 7.46 (s, 1H); C{1H} NMR (126 MHz, CDCl3) δ 16.5, 21.0, 56.3, 56.4,
56.4, 75.2, 96.3, 113.2, 116.3, 143.6, 154.8, 155.3, 170.8, 195.7; HRMS (NSI-FTMS): m/z [M+Na]+
Calcd for [C14H18O6Na] 305.0996; Found 305.0988; HPLC (Daicel Chiralpak AD-H) (80:20,
hexane:isopropanol, flow rate: 0.8 mL/min); 12.27 min (49.15%), 15.70 min (50.85%).
Asymmetric oxidation
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
A. Prepared according to the general procedure for TPPP enol ether/ester epoxidation, using catalyst
2 (0.0289 g, 0.041 mmol, 0.1 equiv.), the enol acetate (0.109 g, 0.410 mmol) and TPPP (0.371 g,
0.820 mmol, 2 equiv.) in chloroform (2.2 ml). The reaction was stirred for 72 hours at -45 °C.
Purification by column chromatography on silica gel (eluent: hexanes/ethyl acetate 3:1) afforded 1-
oxo-1-(2,4,5-trimethoxyphenyl)propan-2-yl acetate as a colourless gum (0.012 g, 6% over 2 steps);
HPLC (Daicel Chiralpak AD-H) (80:20, hexane:isopropanol, flow rate: 0.8 mL/min); 12.23 min
(24.76%), 15.63 min (75.24%).
B. Prepared according to the general procedure for TPPP enol epoxidation, using catalyst 2 (0.0224
g, 0.031 mmol, 0.11 equiv.), the repurified enol acetate (0.0763 g, 0.286 mmol) and TPPP (0.264 g,
0.58 mmol, 2 equiv.) in chloroform (1.5 ml). The reaction was stirred for 20 hours at –40 °C, and the
solvents removed under reduced pressure. Purification by column chromatography on silica gel
(eluent: hexanes/ethyl acetate 3:1) afforded 1-oxo-1-(2,4,5-trimethoxyphenyl)propan-2-yl acetate as
a colourless gum (0.0258 g, 32%); HPLC (Daicel Chiralpak AD-H) (80:20, hexane:isopropanol, flow
rate: 0.8 mL/min); 11.98 min (31.41%), 15.30 min (68.59%). [α]D26 = –21.7 (c = 0.6, CHCl3).
Tatarinoid A 22 42
Racemic synthesis
Prepared according to the general procedure for protecting group removal using 1-oxo-1-(2,4,5-
trimethoxyphenyl)propan-2-yl acetate 27 (0.139 g, 5 g, 0.492 mmol) and camphorsulfonic acid
(0.125 g, 0.538 mmol, 1.1 equiv.) in methanol (7 ml). Purification by column chromatography on
silica gel (eluent: hexanes/ethyl acetate 3:2) afforded (±)-tatarinoid A as a colourless gum (0.0876 g,
1
74%). νmax (CH2Cl2)/cm-1 3463, 2936, 2847, 1648, 1603, 1515, 1467, 1271, 1221, 1114, 1025; H
NMR (500 MHz, CDCl3) δ 1.35 (d, J = 6.8 Hz, 3H), 3.89 (s, 3H), 3.93 (s, 3H), 3.97 (s, 3H), 5.14 (q,
13
J = 6.8 Hz, 1H), 6.49 (s, 1H), 7.48 (s, 1H); C{1H} NMR (126 MHz, CDCl3) δ 21.3, 56.2, 56.3,
56.5, 72.9, 96.3, 113.1, 115.1, 143.6, 155.1, 155.6, 201.6; HPLC (Daicel Chiralcel OJ) (70:30,
hexane:isopropanol, flow rate: 0.8 mL/min); 27.67 min (49.52%), 29.20 min (50.48%).
Asymmetric Synthesis
Prepared according to the general procedure for protecting group removal using 1-oxo-1-(2,4,5-
trimethoxyphenyl)propan-2-yl acetate (0.053 g, 0.492 mmol) and camphorsulfonic acid (0.125 g,
0.538 mmol, 1.1 equiv.) in methanol (2.7 ml). Purification by column chromatography on silica gel
29
ACS Paragon Plus Environment