Catalytic enantioselective vinylogous Mukaiyama-Michael addition of 2-silyloxyfurans to cyclic unsaturated oxo esters

Article abstract of DOI:10.1021/jo3020648

The copper-catalyzed asymmetric addition of 2-silyloxyfurans to cyclic unsaturated oxo esters is reported. The reaction proceeds with excellent diastereocontrol (usually dr 99:1) and modest to high enantioselectivity, depending on the nature of the ester group and the substitution of the cyclic oxo ester. We have shown that these substrates can be transformed into a variety of building blocks bearing a γ-butenolide or γ-lactone connected to a cycloalkane or cycoalkene moiety.

Full text of DOI:10.1021/jo3020648

Subscriber access provided by UNIV OF CALIFORNIA SAN DIEGO LIBRARIES
Article
Catalytic Enantioselective Vinylogous Mukaiyama-Michael
Addition of 2-Silyloxyfurans to Cyclic Unsaturated Oxo Esters
Xavier Jusseau, Pascal Retailleau, Laurent Chabaud, and Catherine Guillou
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo3020648 • Publication Date (Web): 14 Feb 2013
Downloaded from http://pubs.acs.org on February 17, 2013
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 39
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Catalytic Enantioselective Vinylogous Mukaiyamaꢀ
Michael Addition of 2ꢀSilyloxyfurans to Cyclic
Unsaturated Oxo Esters
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Xavier Jusseau, Pascal Retailleau, Laurent Chabaud* and Catherine Guillou*
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS. LabEx LERMIT.
1, Avenue de la Terrasse, 91198 GifꢀsurꢀYvette, France.
catherine.guillou@icsn.cnrsꢀgif.fr; laurent.chabaud@icsn.cnrsꢀgif.fr
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 (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
ABSTRACT.
The copperꢀcatalyzed asymmetric addition of 2ꢀsilyloxyfurans to cyclic unsaturated oxo esters is
reported. The reaction proceeds with excellent diastereocontrol (usually dr : 99/1) and modest to high
ACS Paragon Plus Environment
1

The Journal of Organic Chemistry
Page 2 of 39
enantioselectivity, depending on the nature of the ester group and the subtitution of the cyclic oxo ester.
We shown that these substrates can be transformed into a variety of building blocks bearing a γꢀ
butenolide or γꢀlactone connected to a cycloalkane or cycoalkene moiety.
1
2
3
4
5
6
7
8
9
KEYWORDS. asymmetric synthesis · butenolide · copper · homogeneous catalysis · Michael reaction.
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
INTRODUCTION
γꢀButenolides and γꢀlactones represent a subunit of numerous natural products which display a wide
range of biological activities including antitumor, antibiotic, antifungal, neurotoxic properties or are
found in some plant hormones (Figure 1).1 Thus, access to optically active γꢀbutenolides is of great
interest.
Figure 1. Some examples of natural products containing γꢀbutenolide/γꢀlactone connected to a cyclic
framework
The catalytic asymmetric addition of 2ꢀsilyloxyfurans to carbonyl compounds2 and acyclic Michael
acceptors3 is a powerful method to synthesize γꢀbutenolides in a diastereoꢀ and enantioselective manner.
Numerous efforts in the development of Lewis acidꢀ and organoꢀcatalyzed asymmetric reactions of 2ꢀ
silyloxyfurans with α,βꢀunsaturated imides,3aꢀ3f aldehydes,3gꢀ3i and ketones,3jꢀ3n have been reported. To
the best of our knowledge only one study of asymmetric reaction of silyloxyfurans with cyclic Michael
ACS Paragon Plus Environment
2

Page 3 of 39
The Journal of Organic Chemistry
acceptor (benzoquinone) has been reported with low enantioselectivity (33% ee) and using a
stoichiometric amount of copperꢀ(II)ꢀPyBox complex.4
1
2
3
4
5
6
7
8
We recently reported a copperꢀcatalyzed diastereoselective addition of 2ꢀsilyloxyfurans to cyclic
unsaturated oxo esters.5 Herein, we describe a catalytic asymmetric conjugate addition of 2ꢀ
silyloxyfurans to cyclic unsaturated oxo esters that proceeds with high diastereocontrol (usually dr :
99/1) and enantioselectivity up to 96% ee. This approach provides a straightforward access to chiral
butenolides connected to a cycloalkane moiety.
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
RESULTS AND DISCUSSION
The copperꢀcatalyzed addition of silyloxyfurans 1 to cyclic Michael acceptors 2 affords βꢀketoesters 3
with three contiguous stereogenic centers (Scheme 1). We previously observed that the βꢀketoesters
1
products exist as a mixture of ketone and enol forms in solution, leading to complex H NMR spectra.
As expected, this equilibrium prevented the direct determination of the diastereoꢀ and enantioselectivies
of butenolides 3 by chiral HPLC. Thus, all βꢀketoesters 3 were transformed into the corresponding
phosphate 4 prior to HPLC analysis. It is worth mentioning that no epimerization of the allylic hydrogen
atom of the butenolide was observed during the derivatization.
Scheme 1. Copperꢀcatalyzed asymmetric addition of silyloxyfurans to cyclic unsaturated oxo esters
Reaction solvents and ligand survey.
We began our study by using the conditions we previously reported for the diastereoselective
addition of 2ꢀsilyloxyfuran 1a to methyl oxo ester 2a.5 In the presence of Cu(OTf)2 (10 mol %), isoꢀ
propylꢀbis(oxazoline) ligand L1 in CH2Cl2 at ꢀ78°C, we obtained butenolide 3a in poor yield (38%) and
enantiomeric excess (ee = 10%, dr : 95/5). We then undertook a screening of solvents which revealed
that the best results were obtained in a mixture of toluene/THF (v/v = 3/1) at ꢀ78°C.6 Under these
ACS Paragon Plus Environment
3

The Journal of Organic Chemistry
Page 4 of 39
conditions, the Michael adduct 3a was isolated in 73% yield as one diastereomer (dr >99/1) with 69 %
enantiomeric excess (table 1, entry 1). A variety of commercially available bis(oxazoline) (L1-L4) and
Pyꢀbox ligands (L5-L6) were screened to identify a more effective catalytic system (Table 1). We first
observed that all chiral ligands produced butenolide 3a with high diastereocontrol (dr >98/2). However,
the enantiomeric excess was more dependent on the nature of the chiral ligand. When the reaction was
carried out with bis(oxazoline) ligand L2 (R = iPr, entry 2) the ee was slightly improved to 71% though
the isolated yield dropped to 33%. With ligand L4 (R = Bn, entry 4) butenolide 3a was obtained with
77% ee and good yield (68%). The chiral ligand L3 bearing a bulkier R group (R = tBu) dramatically
diminished the enantioselectivity (entry 3, ee = ꢀ3%). The same trend was observed with tridentate Pyꢀ
box ligands L5-L6, resulting in a complete loss of enantioselectivity (ee = 0%) (entries 5ꢀ6).
Table 1. Ligand screening for the enantioselective conjugate addition of 2ꢀsilyloxyfuran 1a to methyl
oxo ester 2a
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
Yield
Entry
ligand
R
dr (ee%)b
3a (%)a
1
2
3
Ph
iPr
tBu
73
>99/1 (69)
>99/1 (71)
>98/2 (ꢀ3)
L1
L2
L3
33
52
ACS Paragon Plus Environment
4

Page 5 of 39
The Journal of Organic Chemistry
4
5
6
ꢀ
ꢀ
ꢀ
68
52
44
98/2 (ꢀ77)
99/1 (0)
99/1 (0)
L4
L5
L6
1
2
3
4
5
6
7
8
9
a Isolated yield. b Determined by chiral HPLC on the corresponding enol phosphate, see supporting
information.
Effect of the ester group on the stereoselectivity
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 effect of the ester group of the Michael acceptor on the enantioselection was then evaluated. Both
ligands L2 (R = iPr, ee = 71%) and L4 (R = Bn, ee = ꢀ77%) were tested on substrates 2b-g having esters
of varying steric hindrance. Although ligand L4 (R = Bn, table 1, entry 4) proved to be more efficient
with the methyl ester 2a, we found that bis(oxazoline) L2 (R = iPr) generally gave better enantiomeric
excess with the other oxo esters (see supporting information). A summary of the results with ligand L2
is shown in table 2.
Table 2. Influence of the ester group size on the enantioselectivity with ligand L2
Product
Oxo
Entry
R1
dr (ee%)b
Yield (%)a
ester
1
2
3
4
5
6
7
8
Me
Et
3a (33)
>99/1 (71)
99/1 (88)
>99/1 (74)
99/1 (85)
95/5 (26)
96/4 (73)
99/1 (95)
99/1 (ꢀ91)c
2a
2b
2c
2d
2e
2f
3b (75)
3c (73)
iBu
iPr
tBu
Ph
3d (74)
3e (36)
3f (76)
Bn
Bn
3g (57)
2g
2g
ent-3g (57)
a Isolated yield. b Determined by chiral HPLC on the corresponding enol phosphate, see supporting
information. cLigand L4 was used.
ACS Paragon Plus Environment
5

The Journal of Organic Chemistry
Page 6 of 39
1
2
3
4
5
6
7
8
9
As shown in entry 2 of table 2, ethyl ester 2b delivered butenolide 3b with improved yield (75%) and
enantioselectivity (ee = 88%) compared to the methyl ester 2a (entry 1).7 Increasing the steric hindrance
using the isoꢀbutyl ester (ie 2c, entry 3) led to lower enantioselectivity, but the isoꢀpropyl group (ie 2d,
entry 4) gave similar results to those obtained with the ethyl ester 2b (entry 2). The more sterically
demanding tertꢀbutyl ester 2e was less reactive and provided butenolide 3e with low selectivity (entry
5). The use of phenyl ester 2f did not improve the stereoselectivity (entry 6), however the benzyl ester
2g furnished butenolide 3g in good yield and with excellent enantioselectivity (95% ee) (entry 7).8
Interestingly, the other enantiomer entꢀ3g could be obtained in good enantiomeric excess using the
commercial ligand L4 (R = Bn) (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
All these results showed the significant role of the ester moiety on the enantioselectivity, a point that
has never been addressed in the copperꢀcatalyzed asymmetric Michael addition on cyclic oxo esters.9,10
Scope of the reaction.
The scope of the reaction was explored with a variety of ethyl oxo esters 2b, 2hꢀ2l, that proved to be
more stable than the corresponding benzyl oxo esters (table 3). All substrates reacted effectively to give
butenolides as one diastereomer, except for the fiveꢀmembered ring (entry 6). We found that further
improvement of the enantioselectivity could be achieved on substrate 2b by carrying out the reaction at ꢀ
95°C instead of ꢀ78°C, giving 3b with 91% ee (table 3, entry 1). The high reactivity of ketoester 2b
even at low temperature allowed us to conduct the reaction with lower catalyst loading (Cu(OTf)2, 5
mol %, L2, 6 mol %) to afford 3b in 60% yield and 92% ee.
The 4ꢀmethylsilyloxyfuran 1b could also be used but a significant decrease in enantioselectivity was
observed (entry 2).11 A gemꢀdimethyl substituent at the 4ꢀ or 5ꢀposition of the oxo ester ring was
tolerated and provided an excellent 96% ee and 90% ee respectively (entries 3ꢀ4). For substrate 2j
having the sterically hindered gemꢀdimethyl group in αꢀposition of the ketone function, the reaction still
proceeded with high diastereoselectivity and low enantiocontrol was observed (entry 5). The fiveꢀ and
ACS Paragon Plus Environment
6

Page 7 of 39
The Journal of Organic Chemistry
sevenꢀmembered rings 2k and 2l also reacted in good yields with silyloxyfuran 1a even at ꢀ95°C. As
shown in entry 6, the fiveꢀmembered ring 2k led to a 78/22 ratio of diastereomers, formed with 84% ee
and 88% ee respectively. The use of the sevenꢀmembered ring 2l allowed the isolation of one
diastereomer with moderate enantioselectivity (entry 7).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
Table 3. Copperꢀcatalyzed enantioselective conjugate addition of 2ꢀsilyloxyfurans to oxo esters
Product
dr
Entry R3
Oxo ester
Product
Yield (%)a
(ee%)b
>99/1
(91)c
1
2
H
81
69
99/1
(59)
Me
2b
>99/1
(96)
3
4
5
H
H
H
74
79
82
>99/1
(90)
99/1
(60)d
ACS Paragon Plus Environment
7

The Journal of Organic Chemistry
Page 8 of 39
1
2
3
4
5
6
7
8
78/22
6
7
H
H
63
72
(84/88) c,e
>99/1c
(79)
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
b
aIsolated yield. Determined by chiral HPLC on the corresponding enol phosphate, see supporting
information.creaction carried out at ꢀ95°C. Determined by chiral HPLC on the pꢀnitrobenzoyl
d
derivative, see supporting information. eThe ee of the major and minor diastereomers, respectively.
Stereochemical model.
The relative and absolute configuration was determined by single crystal Xꢀray analysis of the enol
form of 3b and 3h.13ꢀ14 The sense of asymmetric induction is consistent with an attack of the
silyloxyfuran from the Siꢀface of the coordinated oxo ester.
Evans and coworkers have shown by Xꢀray cristallography that the metal atom in the alkylidene
malonate/copperꢀ(II) complex is in a distorted squareꢀplanar geometry, and the sixꢀmembered ring
formed by the dicarbonyl, alkene carbon, and copper atom adopts a boat conformation.10 On the basis of
these observations, two complexes A and B can be depicted (Figure 2). Complex B might be higher in
energy than complex A because of nonꢀbonding interactions between the ligand and the R2 substituents
(R2 = H or Me). In the complex A, the bottom Reꢀface is shielded by the box ligand, preventing the
approach of the nucleophile. Thus, the attack of the silyloxyfuran occurs on the Siꢀface of complex A
through an exo DielsꢀAlder type transition state (relative to the ketone) that may explain respectively,
the sense of the enantioselectivity and the high level of diastereoselectivity observed in most cases.
Figure 2. Oxo ester/copperꢀ(II) complex geometry and proposed stereochemical model
ACS Paragon Plus Environment
8

Page 9 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
In this model, it is also expected that both faces will be hindered if R2 is a methyl group, resulting in a
poor enantiotopic face differentiation and low e.e. (table 3, entry 5).
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
As shown in table 2 the ester substituent R1 has an influence on the enantioselectivity. Although its
exact role is not clear, it might be possible that the box ligand directs the R1 group towards the opposite
Siꢀface. Thus, for the bulky tertꢀbutyl ester 2e, both faces will be hindered, resulting in low ee (table 2,
entry 5). Unfavorable interactions between the R1 group (and/or the carbonyl of the ester) with the R3
substituent (R3 = Me) might also explain the breakdown in enantioselectivity observed with
silyloxyfuran 1b. However, for these last two examples, an antiperiplanar openꢀTS cannot be ruled
out.5a
Substrate functionalization.
Scheme 2 illustrates some possible functionalizations of the optically active butenolide 3b. For
instance, butenolide 3b was easily Oꢀacylated by treatment with sodium hydride then pꢀ
nitrobenzoylchloride to give compound 5. Alternatively, butenolide 3b reacted with chlorophosphate to
give enol phosphate 4b.15 Upon treatment with sodium hydride and methyl iodide, Cꢀalkylation
occurred diastereoselectively (dr > 95/5) to form 6 bearing a quaternary carbon atom. Interestingly,
further functionnality could be introduced by mean of allylation reaction under TsujiꢀTrost conditions to
give product 7 in 82% (dr : 94/6).
ACS Paragon Plus Environment
9

The Journal of Organic Chemistry
Page 10 of 39
Hydrogenation of butenolide 3b afforded a γꢀlactone which under acidic conditions gave the
1
2
decarboxylated γꢀlactone 8. Interestingly, this decarboxylation product is equivalent to a vinylogous
MukaiyamaꢀMichael addition of silyloxyfuran to cyclohexꢀ2ꢀenꢀ1ꢀone followed by hydrogenation.5a
Scheme 2. Functionalization of butenolide 3b
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
CONCLUSION.
In conclusion, we have developed the first copperꢀcatalyzed asymmetric addition of silyloxyfuran to
cyclic oxo esters. The C2ꢀsymmetric isoꢀpropylꢀbox (L2) copper (II) complex has been found to be an
excellent catalyst for this transformation, providing functionalized butenolide derivatives with high
diastereoꢀ and enantioselectivities. During the course of the optimisation, we examined the role of the
ester group on the reactivity and the enantioselectivity. This point, unexplored in the copperꢀcatalyzed
Michael addition on cyclic oxo esters until now revealed a significant contribution of the ester group
size on the enantioselectivity. Taking advantage of the different functionalities of the Michael adducts,
we have shown that the enantioenriched butenolides can be transformed into a variety of building blocks
ACS Paragon Plus Environment
10

Page 11 of 39
The Journal of Organic Chemistry
bearing a γꢀbutenolide or γꢀlactone connected to a cycloalkane or cycoalkene moiety. Current efforts are
now directed toward the extension of this reaction to different Michael acceptors and nucleophiles.
EXPERIMENTAL SECTION.
1
2
3
4
5
6
7
8
9
General method. All reactions were carried out under argon with dry solvents unless otherwise noted.
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
Reactions were monitored by thinꢀlayer chromatography on silica gel plates (60F ) with a fluorescent
254
indicator. Yields refer to chromatographically or crystalline pure compounds. All commercially
available reagents were used without further purification. CH2Cl2 and THF were dried by activated
alumina. Et2O extra dry 99.5% was purchased. CHCl3 and 1,2ꢀdichloroethane were distilled over CaCl2.
Anhydrous toluene, 99.8%, Active dry, was purchased. All separations were carried out under flash
chromatographic conditions on silica gel prepacked column (230ꢀ400 mesh) at medium pressure
(20psi). All new compounds gave satisfactory spectroscopic analyses (IR, 1H NMR, 13C NMR, HRMS).
NMR spectra were determined on 300 MHz or 500 MHz spectrometers. 1H NMR spectra are reported in
parts per million (δ) relative to residual solvent peak. Data for 1H are reported as follows: chemical shift
(δ ppm), multiplicity (s = singlet, brs = broad singlet, d = doublet, t = triplet, q = quartet, sxt = sextet,
sept = septuplet, dd = doubleꢀdoublet, td = tripleꢀdoublet, dt = doubleꢀtriplet, ddd = double double
13
doublet, m = multiplet), coupling constant in Hz, and integration. C NMR spectra were obtained on
75.5 MHz spectrometer and are reported in parts per million (δ) relative to the residual solvent peak.
HRMS spectra were obtained on an E.S.I. TOF spectrometer. Infrared (IR) (υ, cmꢀ1) spectra were
recorded on a Fourier Spectrum FTꢀIR. Melting points were measured in capillary tubes and are
uncorrected.
Representative procedures.
General procedure A : Copper-catalyzed asymmetric conjugate addition of silyloxyfuran to cyclic
oxo esters. To a cooled solution (ꢀ78°C) of copperꢀ(II) triflate (0.1 eq) and ligand (0.11 eq) in the
appropriate solvent (38 mL/mmol) under argon was added a solution of βꢀketoester 2 in the appropriate
ACS Paragon Plus Environment
11

The Journal of Organic Chemistry
Page 12 of 39
solvent (0.8 mL/mmol). The reaction mixture was stirred for 30 min, then the silyloxyfurane was added
(1.2 eq). The reaction was monitored by TLC until completion. The reaction was quenched with
aqueous saturated ammonium chloride, at ꢀ78°C, then allowed to warm up to 25°C and extracted with
ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered and concentrated in
vacuo. The resulting oil was treated with THF/aqueous hydrochloric acid 1N (v/v: 1/1, 10mL/mmol) at
25°C for 30 min. The reaction mixture was then diluted with water and extracted with ethyl acetate. The
combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The resulting oil
was purified by flash chromatography (Heptane/EtOAc) to afford the title compound. Racemic mixtures
were prepared by the same method, without the use of the chiral ligand.
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
General procedure B : Derivatization of substrates to enol phosphate for NMR and HPLC
analysis. To a cooled suspension (0°C) of sodium hydride (1.2 eq) (Caution : hydrogen gas evolution)
in THF (4.5 mL/mmol) under argon was added a solution of butenolide 3 (1.0 eq) in THF (4.5
mL/mmol). After stirring for 30 min, diphenyl phosphoryl chloride (0.95 eq) was added and the reaction
mixture allowed to warm up slowly to 25°C. The reaction was monitored by TLC. The reaction was
quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate. The combined
organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude mixture was
purified by flash chromatography (heptane/EtOAc) to afford the phosphate 4.
General Procedure C: Synthesis of β-ketoesters.
To a solution of tert-butyl 6ꢀ(1,3ꢀdioxolanꢀ2ꢀyl)ꢀ3ꢀoxohexanoate16 (1.0 eq) in xylene/cyclohexane
(v/v: 1/1; 1.0ꢀ3.0 mL/mmol) was added the corresponding alcohol (1.05 to 6.0 eq) and the mixture was
heated at 135°C until completion was reached. All volatiles were removed by distillation (azeotrope t-
BuOH/cyclohexane) then xylene in vacuo. The resulting oil was purified by flash chromatography
(heptane/EtOAc) to afford the corresponding ester.
A solution of the ester in 50% aqueous acetic acid at 25°C was stirred until the completion was
reached. The mixture was then diluted with water and saturated with NaCl, and extracted with ethyl
ACS Paragon Plus Environment
12

Page 13 of 39
The Journal of Organic Chemistry
acetate. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and
concentrated in vacuo. The traces of acetic acid were azeotroped with toluene. The resulting oil was
purified by flash chromatography or distilled under reduce pressure to afford the title compound.
1
2
3
4
5
6
7
8
9
Iso-butyl 6-oxocyclohex-1-enecarboxylate (2c).
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
Prepared according to general procedure C form tert-butyl 6ꢀ(1,3ꢀdioxolanꢀ2ꢀyl)ꢀ3ꢀoxohexanoate
(1.43 g, 5.54 mmol, 1.0 eq), 2ꢀmethylpropanꢀ1ꢀol (1.54 mL, 16.61 mmol, 3.0 eq), in xylene/cyclohexane
(v/v: 1/1; 20.0 mL) and refluxed for 15 hrs. The crude mixture was purified by flash chromatography
1
(heptane/EtOAc 80/20) to afford the isoꢀbutyl ester C1 as a colorless oil (1.13 g, 79%). H NMR
(CDCl3, 300 MHz) (keto/enol 90/10) δ (ppm): 4.81 (t, J = 4.3 Hz, 1H), 3.98ꢀ3.76 (m, 4H), 3.88 (d, J =
6.7 Hz, 2H), 3.40 (s, 2H), 2.58 (t, J =7.0 Hz, 2H), 1.98ꢀ1.83 (m, J = 6.7 Hz, 1H), 1.78ꢀ1.58 (m, 4H),
0.89 (d, J = 6.7 Hz, 6H). 13C NMR (CDCl3, 75 MHz) δ (ppm): 202.5 (Cq), 167.4 (Cq), 104.3 (CH), 71.6
(CH2), 65.0 (2xCH2), 49.4 (CH2), 42.8 (CH2), 33.1 (CH2), 27.8 (CH), 19.2 (2xCH3), 18.0 (CH2). I.R υ
(neat): 2961, 2878, 1739, 1714, 1233, 1137 cmꢀ1. M.S. (ESI, m/z) 257.1 [MꢀH]ꢀ, 281.1 [M+Na]+.
H.R.M.S. (ESI, m/z) Calcd for C13H22O5Na : 281.1365, found: 281.1360.
Isoꢀbutyl 6ꢀ(1,3ꢀdioxolanꢀ2ꢀyl)ꢀ3ꢀoxohexanoate C1 (1.13 g, 4.375 mmol, 1.0 eq), in 50% aqueous
acetic acid (57.0 mL) was stirred for 30 hrs. The crude mixture was purified by flash chromatography
(heptane/AcOEt 80/20) to afford compound 2c as a colorless oil (207 mg, 24%). 1H NMR (CDCl3, 300
MHz) keto/enol 82/18 δ (ppm): 7.64 (t, J = 4.3 Hz, 1H), 3.97 (d, J = 6.7 Hz, 2H), 2.55ꢀ2.46 (m, 4H),
13
2.10ꢀ1.91 (m, 3H), 0.95 (d, J = 6.7 Hz, 6H). C NMR (CDCl3, 75 MHz) δ (ppm): 194.5 (Cq), 164.8
(Cq), 155.7 (CH), 133.4 (Cq), 71.2 (CH2), 38.7 (CH2), 27.7 (CH), 26.1 (CH2), 22.2 (CH2), 19.1
(2xCH3). I.R υ (neat): 2961, 1736, 1712, 1647, 1265, 1220 cmꢀ1. M.S. (ESI, m/z) 195.1 [MꢀH]ꢀ, 197.1
[M+H]+, 219.1 [M+Na]+, 260.1 [M+CH3CN+Na]+. H.R.M.S. (ESI, m/z) Calcd for C11H16O3Na :
219.0997, found: 219.0998.
Iso-propyl 6-oxocyclohex-1-enecarboxylate (2d).
ACS Paragon Plus Environment
13

The Journal of Organic Chemistry
Page 14 of 39
Prepared according to general procedure C from tert-butyl 6ꢀ(1,3ꢀdioxolanꢀ2ꢀyl)ꢀ3ꢀoxohexanoate (100
mg, 0.387 mmol, 1.0 eq), propanꢀ2ꢀol (70 mg, 1.161 mmol, 3.0 eq), in xylene/cyclohexane (v/v: 1/1; 2.0
mL) and refluxed for 3 days. The crude mixture was purified by flash chromatography (heptane/EtOAc
1
2
3
4
5
6
7
8
1
70/30) to afford the isoꢀpropyl ester C2 as a colorless oil (54 mg, 57%). H NMR (CDCl3, 300 MHz) δ
9
(ppm): 5.03 (sept, J = 6.3 Hz, 1H), 4.82 (t, J = 4.3 Hz, 1H), 3.98ꢀ3.76 (m, 4H), 3.37 (s, 2H), 2.58 (t, J =
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
7.0 Hz, 2H), 1.78ꢀ1.60 (m, 4H), 1.23 (d, J = 6.3 Hz, 6H). C NMR (CDCl3, 75 MHz) δ (ppm): 202.5
(Cq), 166.8 (Cq), 104.2 (CH), 69.0 (CH), 64.9 (2xCH2), 49.7 (CH2), 42.5 (CH2), 32.8 (CH2), 21.7
(2xCH3), 17.8 (CH2). I.R υ (neat): 2989, 2882, 1736, 1713, 1141, 1103 cmꢀ1. M.S. (ESI, m/z) 245.1
[M+H]+, 262.2 [M+NH4]+. H.R.M.S. (ESI, m/z) Calcd for C12H21O5: 245.1389, found: 245.1393.
Isoꢀpropyl 6ꢀ(1,3ꢀdioxolanꢀ2ꢀyl)ꢀ3ꢀoxohexanoate C2 (1.3 g, 5.322 mmol, 1.0 eq), in 50% aqueous
acetic acid (70.0 mL) was stirred for 24 hrs. The crude mixture was purified by flash chromatography
(heptane/MTBE 50/50) to afford compound 2d as a colorless oil (420 mg, 43%). 1H NMR (CDCl3, 300
MHz) keto/enol 82/18 δ (ppm): 7.57 (t, J = 4.2 Hz, 1H), 5.14 (sept, J = 6.3 Hz, 1H), 2.52ꢀ2.44 (m, 4H),
13
2.09ꢀ1.97 (m, 2H), 1.27 (d, J = 6.3 Hz, 6H). C NMR (CDCl3, 75 MHz) δ (ppm): 194.4 (Cq), 164.2
(Cq), 154.9 (CH), 133.7 (Cq), 68.6 (CH), 38.7 (CH2), 26.1 (CH2), 22.2 (CH2), 21.7 (2xCH3). I.R. υ
(neat): 2981, 1732, 1709, 1710, 1682, 1373, 1268 cmꢀ1. M.S. (ESI, m/z) 183.1 [M+H]+, 205.1 [M+Na]+.
H.R.M.S. (ESI, m/z) Calcd for C10H15O3: 183.1021, found: 183.1016.
Phenyl 6-oxocyclohex-1-enecarboxylate (2f).
Prepared according to general procedure C from tert-butyl 6ꢀ(1,3ꢀdioxolanꢀ2ꢀyl)ꢀ3ꢀoxohexanoate 2.0
g, 7.743 mmol, 1.0 eq), phenol (3.64 g, 38.72 mmol, 5.0 eq), in xylene/yclohexane (v/v: 1/1; 40.0 mL)
and refluxed for 3.5 days. The crude mixture was purified by flash chromatography (heptane/EtOAc
1
70/30) to afford the phenyl ester C3 as a colorless oil (1.11 g, 52%). H NMR (CDCl3, 300 MHz)
(keto/enol 90/10) δ (ppm): 7.41 (t, J = 7.6 Hz, 2H), 7.26 (t, J = 7.6 Hz, 1H), 7.15 (d, J = 7.6 Hz, 2H),
4.88 (t, J = 4.6 Hz, 1H), 4.03ꢀ3.83 (m, 4H), 3.70 (s, 2H), 2.73 (t, J =7.1 Hz, 2H), 1.87ꢀ1.66 (m, 4H). 13C
ACS Paragon Plus Environment
14

Page 15 of 39
The Journal of Organic Chemistry
NMR (CDCl3, 75 MHz) δ (ppm): 201.9 (Cq), 165.9 (Cq), 150.5 (Cq), 129.5 (2xCH), 126.2 (CH), 121.5
(2xCH), 104.2 (CH), 64.9 (2xCH2), 49.2 (CH2), 42.7 (CH2), 32.7 (CH2), 17.8 (CH2). I.R υ (neat): 2953,
2885, 1741, 1714, 1139 cmꢀ1. M.S. (ESI, m/z) 279.1 [M+H]+ , 296.2 [M+NH4]+. H.R.M.S. (ESI, m/z)
Calcd for C15H19O5 : 279.1232, found: 279.1241.
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
Phenyl 6ꢀ(1,3ꢀdioxolanꢀ2ꢀyl)ꢀ3ꢀoxohexanoate C3 (1.11 g, 3.990 mmol, 1.0 eq), in 50% aqueous acetic
acid (50.0 mL) was stirred for 24 hrs. The crude mixture was purified by recrystallization in MTBE to
afford the title compound 2f as white solid (725 mg, 84%). 1H NMR (CDCl3, 300 MHz) keto/enol 82/18
δ (ppm): 7.88 (t, J = 4.1 Hz, 1H), 7.37 (t, J = 7.9 Hz, 2H), 7.22 (t, J = 7.9 Hz, 1H), 7.14 (d, J = 7.9 Hz,
2H), 2.65ꢀ2.52 (m, 4H), 2.16ꢀ2.04 (m, 2H). 13C NMR (CDCl3, 75 MHz) δ (ppm): 194.0 (Cq), 163.0
(Cq), 157.4 (CH), 150.6 (Cq), 132.7 (Cq), 129.4 (2xCH), 126.0 (CH), 121.6 (2xCH), 38.7 (CH2), 26.4
(CH2), 22.1 (CH2). I.R υ (neat): 1737, 1677, 1262, 1181 cmꢀ1. M.S. (ESI, m/z) 217.1 [M+H]+.
H.R.M.S. (ESI, m/z) Calcd for C13H13O3 : 217.0865, found: 217.0870. mp : 70ꢀ72°C.
Benzyl 6-oxocyclohex-1-enecarboxylate (2g).
Prepared according to general procedure C from tert-butyl 6ꢀ(1,3ꢀdioxolanꢀ2ꢀyl)ꢀ3ꢀoxohexanoate (2.0
g, 7.743 mmol, 1.0 eq), benzyl alcohol (4.8 mL, 46.46 mmol, 6.0 eq), in xylene/cyclohexane (v/v: 1/1;
40.0 mL) and refluxed for 3.5 days. The crude mixture was purified by flash chromatography
(heptane/EtOAc 70/30) to afford the benzyl ester C4 as a colorless oil (2.07 g, 92%). 1H NMR (CDCl3,
300 MHz) (keto/enol 90/10) δ (ppm): 7.36ꢀ7.31 (m, 5H), 5.15 (s, 2H), 4.81 (t, J = 4.4 Hz, 1H), 3.98ꢀ
13
3.75 (m, 4H), 3.46 (s, 2H), 2.57 (t, J =7.1 Hz, 2H), 1.77ꢀ1.58 (m, 4H). C NMR (CDCl3, 75 MHz) δ
(ppm): 202.1 (Cq), 167.1 (Cq), 135.3 (Cq), 128.6 (2xCH), 128.5 (CH), 128.4 (2xCH), 104.2 (CH), 67.1
(CH2), 64.9 (2xCH2), 49.3 (CH2), 42.6 (CH2), 32.7 (CH2), 17.8 (CH2). I.R υ (neat): 2953, 2885, 1741,
1714, 1139 cmꢀ1. M.S. (ESI, m/z) 293.1 [M+H]+, 310.2 [M+NH4]+. H.R.M.S. (ESI, m/z) Calcd for
C16H21O5: 293.1389, found: 293.1381.
ACS Paragon Plus Environment
15

The Journal of Organic Chemistry
Page 16 of 39
Benzyl 6ꢀ(1,3ꢀdioxolanꢀ2ꢀyl)ꢀ3ꢀoxohexanoate C4 (1.57 g, 5.371 mmol, 1.0 eq), in 50% aqueous acetic
acid (70.0 mL) was stirred for 24 hrs. The crude mixture was purified by distillation under reduce
pressure (P = 0.54 mbar, bp = 150ꢀ165°C) to afford 2g as a yellow oil (850 mg, 69%). 1H NMR (CDCl3,
300 MHz) keto/enol 88/12 δ (ppm): 7.74 (t, J = 4.2 Hz, 1H), 7.48ꢀ7.34 (m, 5H), 5.29 (s, 2H), 2.59ꢀ2.50
1
2
3
4
5
6
7
8
9
13
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
(m, 4H), 2.15ꢀ2.03 (m, 2H). C NMR (CDCl3, 75 MHz) δ (ppm): 194.3 (Cq), 164.4 (Cq), 156.4 (CH),
135.7 (Cq), 133.0 (Cq), 128.6 (2xCH), 128.3 (CH), 128.2 (2xCH), 66.8 (CH2), 38.8 (CH2), 26.2 (CH2),
22.1 (CH2). I.R υ (neat): 2949, 1734, 1645, 1253, 1215 cmꢀ1. M.S. (ESI, m/z) 231.1 [M+H]+, 253.1
[M+Na]+, 294.1 [M+CH3CN+Na]+. H.R.M.S. (ESI, m/z) Calcd for C14H14O3Na: 253.0841, found:
253.0833.
(6S)-methyl 2-oxo-6-((R)-5-oxo-2,5-dihydrofuran-2-yl)cyclohexanecarboxylate (3a). Prepared
according to general procedure A from methyl 6ꢀoxocyclohexꢀ1ꢀenecarboxylate 2a (30.0 mg, 0.195
mmol, 1.0 eq), copperꢀ(II) triflate (7.2 mg, 0.020 mmol, 0.1 eq), 2,2ꢀBis((4S)ꢀ(–)ꢀ4ꢀ
isopropyloxazoline)propane (5.7 mg, 0.022 mmol, 0.11 eq), 2ꢀ(trimethylsiloxy)furan (40 ꢀL, 0.234
mmol, 1.2 eq), in toluene/THF (v/v: 3/1) and stirred for 3 days at ꢀ78°C. The crude mixture was purified
1
by flash chromatography (heptane/EtOAc 50/50) to afford 3a as a colorless oil (15.3 mg, 33%). H
NMR (CDCl3, 300 MHz) keto/enol 44/56 δ (ppm): 12.66 (s, 1H, OH enol), 7.48 (dd, J = 5.7 1.6 Hz, 1H,
enol), 7.40 (dd, J = 5.8, 1.7 Hz, 1H, keto), 6.11 (m, 2H, enol+keto), 5.37 (td, J = 4.7, 1.9 Hz, 1H, enol),
5.10 (td, J = 3.4, 1.7 Hz, 1H, keto), 3.83 (s, 3H, enol), 3.73 (s, 3H, keto), 3.33 (m, 1H, enol), 3.29 (d, J =
11.4 Hz, 1H, keto), 2.87 (m, 1H, keto), 2.55 (m, 1H, keto), 2.44ꢀ2.28 (m, 3H, keto+enol), 2.24ꢀ1.52 (m,
13
8H, keto+enol). C NMR (CDCl3, 75 MHz) δ (ppm): 204.3 (Cq), 178.7 (Cq), 176.3 (Cq), 173.1 (Cq),
170.1 (Cq), 155.4 (CH), 154.3 (CH), 121.6 (CH), 121.5 (CH), 95.6 (Cq), 85.2 (CH), 84.7 (CH), 56.7
(CH), 52.3 (CH3), 51.7 (CH3), 42.9 (CH), 40.8 (CH2), 34.6 (CH), 28.7 (CH2), 27.3 (CH2), 24.1 (CH2),
22.3 (CH2), 18.9 (CH2). IR υ (neat): 2950, 1743, 1711 cm–1. M.S. (ESI, m/z) 261 [M+Na]+. HRMS
(ESI, m/z) calcd. for C12H14NaO5: 261.0739 ; found: 261.0742.
ACS Paragon Plus Environment
16

Page 17 of 39
The Journal of Organic Chemistry
(S)-methyl
2-((diphenoxyphosphoryl)oxy)-6-((R)-5-oxo-2,5-dihydrofuran-2-yl)cyclohex-1-
1
2
3
4
5
6
7
8
9
enecarboxylate (4a). Prepared according to general procedure B from methyl 2ꢀoxoꢀ6ꢀ(5ꢀoxoꢀ2,5ꢀ
dihydrofuranꢀ2ꢀyl)cyclohexanecarboxylate 3a (24 mg, 0.101 mmol, 1.0 eq), sodium hydride (60%, 4.9
mg, 0.121 mmol, 1.2 eq), diphenylphosphoryl chloride (20 ꢀL, 0.096 mmol, 0.95 eq). The crude
mixture was purified by flash chromatography (heptane/EtOAc 40/60) to afford compound 4a as a
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
colorless oil (34.4 mg, 76%). (Rf = 0.2 heptane/EtOAc 50/50). H NMR (CDCl3, 500 MHz) δ (ppm):
7.36 (dd, J = 5.7, 1.2 Hz, 1H), 7.31ꢀ7.25 (m, 4H), 7.20ꢀ7.11 (m, 6H), 5.98 (dd, J = 5.7, 1.8 Hz, 1H), 5.09
13
(m, 1H), 3.47 (s, 3H), 3.30 (brs, 1H), 2.36 (m, 2H), 1.73ꢀ1.52 (m, 4H). C NMR (CDCl3, 75 MHz) δ
(ppm): 172.7 (Cq), 166.6 (Cq), 154.9 (CH), 154.8 (d, JP-C = 8.2 Hz, Cq), 150.5 (d, JP-C = 7.7 Hz, 2xCq),
130.1 (4xCH), 125.8 (2xCH), 122.1 (CH), 120.2 (d, JP-C = 1.1 Hz, 2xCH), 120.0 (d, JP-C = 1.1 Hz,
2xCH), 115.4 (d, JP-C = 8.2 Hz, Cq), 84.9 (d, JP-C = 2.2 Hz, CH), 52.1 (CH3), 38.1 (CH), 28.7 (d, JP-C
=
1.1 Hz, CH2), 23.0 (CH2), 19.7 (CH2). I.R υ (neat): 2944, 1754, 1717, 1589, 1487, 1434, 1364, 1295,
1184, 1159, 1129, 940. M.S. (ESI, m/z) 471.1 [M+H]+. H.R.M.S. (ESI, m/z) Calculated for
25
C24H23O8PNa: 493.1028 ; found: 493.1035. [α]D +32.6 (c = 0.973, CHCl3, 71% ee). HPLC analysis:
chiralcel OJꢀH, hexane/EtOH (v/v: 80/20).
(6S)-ethyl 2-oxo-6-((R)-5-oxo-2,5-dihydrofuran-2-yl)cyclohexanecarboxylate (3b). Prepared
according to general procedure A from ethyl 6ꢀoxocyclohexꢀ1ꢀenecarboxylate 2b (35.0 mg, 0.208
mmol, 1.0 eq), copperꢀ(II) triflate (7.6 mg, 0.021 mmol, 0.1 eq), 2,2ꢀBis((4S)ꢀ(–)ꢀ4ꢀ
isopropyloxazoline)propane (6.2 mg, 0.023 mmol, 0.11 eq), 2ꢀ(trimethylsiloxy)furan (42 ꢀL, 0.250
mmol, 1.2 eq), in toluene/THF (v/v: 3/1) and stirred for 2.5 hrs at ꢀ78°C. The crude mixture was purified
1
by flash chromatography (heptane/EtOAc 50/50) to afford 3b as a colorless oil (39.4 mg, 75%). H
NMR (CDCl3, 500 MHz) keto/enol 56/44 δ (ppm): 12.70 (s, 1H, OH enol), 7.44 (dd, J = 5.7 1.5 Hz, 1H,
enol), 7.36 (dd, J = 5.8, 1.6 Hz, 1H, keto), 6.07 (dd, J = 5.8, 2.2 Hz, 1H, enol), 6.03 (dd, J = 5.8, 2.2 Hz,
1H, keto), 5.33 (ddd, J = 4.8, 2.1, 1.6 Hz, 1H, enol), 5.05 (ddd, J = 3.2, 2.0, 1.6 Hz, 1H, keto), 4.35ꢀ4.03
(m, 4H, keto+enol), 3.28 (m, 1H, enol), 3.21 (d, J = 11.5 Hz, 1H, keto), 2.82 (m, 1H, keto), 2.48 (m, 1H,
ACS Paragon Plus Environment
17

The Journal of Organic Chemistry
Page 18 of 39
keto), 2.39ꢀ2.22 (m, 3H, keto+enol), 2.18ꢀ1.47 (m, 8H, keto+enol), 1.30 (t, J = 7.1 Hz, 3H, enol), 1.24
(t, J = 7.1 Hz, 3H, keto). 13C NMR (CDCl3, 75 MHz) δ (ppm): 204.4 (Cq), 176.2 (Cq), 173.1 (Cq),
172.2 (Cq), 171.9 (Cq), 169.6 (Cq), 155.4 (CH), 154.4 (CH), 121.7 (CH), 121.5 (CH), 95.2 (Cq), 85.2
(CH), 84.8 (CH), 61.4 (CH2), 60.8 (CH2), 56.9 (CH), 42.8 (CH), 40.8 (CH2), 34.5 (CH), 28.7 (CH2),
27.2 (CH2), 24.1 (CH2), 22.4 (CH2), 18.9 (CH2), 14.2 (CH3), 14.0 (CH3). IR υ (neat): 2940, 1745, 1711,
1641, 1613, 1220, 818 cm–1. M.S. (ESI, m/z) 275 [M+Na]+. HRMS (ESI, m/z) calcd. for C13H16NaO5
275.0895; found 275.0899.
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
(S)-ethyl-2-((diphenoxyphosphoryl)oxy)-6-((R)-5-oxo-2,5-dihydrofuran-2-yl)cyclohex-1-
enecarboxylate (4b). Prepared according to general procedure B from ethyl 2ꢀoxoꢀ6ꢀ(5ꢀoxoꢀ2,5ꢀ
dihydrofuranꢀ2ꢀyl)cyclohexanecarboxylate 3b (39.4 mg, 0.156 mmol, 1.0 eq), sodium hydride (60%, 6.3
mg, 0.187 mmol, 1.2 eq), diphenylphosphoryl chloride (31 ꢀL, 0.148 mmol, 0.95 eq). The crude
mixture was purified by flash chromatography (heptane/EtOAc 40/60) to afford compound 4b as a
colorless oil (57.4 mg, 76%). 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.45 (dd, J = 5.7, 1.6 Hz, 1H), 7.39ꢀ
7.30 (m, 4H), 7.26ꢀ7.16 (m, 6H), 6.07 (dd, J = 5.7, 2.4 Hz, 1H), 5.17 (m, 1H), 4.19 (m, 2H), 3.39 (m,
13
1H), 2.46 (m, 2H), 1.87ꢀ1.53 (m, 4H), 1.19 (t, J = 7.2 Hz, 3H). C NMR (CDCl3, 75 MHz) δ (ppm):
172.5 (Cq), 165.9 (d, JP-C = 1.7 Hz, Cq), 154.7 (CH), 154.0 (d, JP-C = 8.0 Hz, Cq), 150.3 (d, JP-C = 7.6
Hz, 2xCq), 129.8 (CH, 4xCH), 125.6 (CH, 2xCH), 122.0 (CH), 120.0 (d, JP-C = 2.0 Hz, 2xCH), 119.9
(d, JP-C = 2.0 Hz, 2xCH), 115.6 (d, JP-C = 7.6 Hz, Cq), 84.7 (d, JP-C = 1.7 Hz, CH), 61.2 (CH2), 37.9
(CH), 28.4 (CH2), 22.7 (CH2), 19.5 (CH2), 13.9 (CH3). I.R υ (neat): 2942, 1753, 1713, 1487, 1434,
1296, 948. M.S. (ESI, m/z) 507.1 [M+Na]+. H.R.M.S. (ESI, m/z) Calcd for C25H25O8PNa: 507.1185,
25
found: 507.1200. [α]D +47.2 (c = 0.992, CHCl3, 88% ee). HPLC analysis: chiralcel OJꢀH,
hexane/EtOH (v/v: 80/20).
(6S)-iso-butyl 2-oxo-6-((R)-5-oxo-2,5-dihydrofuran-2-yl)cyclohexanecarboxylate (3c). Prepared
according to general procedure A from isoꢀbutyl 6ꢀoxocyclohexꢀ1ꢀenecarboxylate 2c (35.0 mg, 0.178
ACS Paragon Plus Environment
18

Page 19 of 39
The Journal of Organic Chemistry
mmol, 1.0 eq), copperꢀ(II) triflate (6.5 mg, 0.018 mmol, 0.1 eq), 2,2ꢀBis((4S)ꢀ(–)ꢀ4ꢀ
isopropyloxazoline)propane (5.3 mg, 0.020 mmol, 0.11 eq), 2ꢀ(trimethylsiloxy)furan (36 ꢀL, 0.214
mmol, 1.2 eq), in toluene/THF (v/v : 3/1) and stirred for 24 hrs at ꢀ78°C. The crude mixture was purified
1
2
3
4
5
6
7
8
1
by flash chromatography (heptane/EtOAc 50/50) to afford 3c as a colorless oil (36.3 mg, 74%). H
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
NMR (CDCl3, 300 MHz) keto/enol 40/60 δ (ppm): 12.65 (s, 1H, OH enol), 7.41 (dd, J = 5.7, 1.6 Hz,
1H, enol), 7.31 (dd, J = 5.8, 1.6 Hz, 1H, keto), 6.01 (dd, J = 5.7, 2.0 Hz, 1H, enol), 5.98 (dd, J = 5.7, 2.2
Hz, 1H, keto), 5.32 (td, J = 4.7, 1.6 Hz, 1H, enol), 5.01 (td, J = 3.3, 1.9 Hz, 1H, keto), 3.86 (m, 4H,
keto+enol), 3.26 (m, 1H, enol), 3.19 (d, J = 11.5 Hz, 1H keto), 2.78 (m, 1H, keto), 2.50ꢀ1.40 (m, 14H,
13
keto+enol), 0.90 (dd, J = 6.7, 0.6 Hz, 6H, enol), 0.85 (d, J = 6.7 Hz, 6H, keto). C NMR (CDCl3, 75
MHz) δ (ppm): 204.4 (Cq), 176.7 (Cq), 173.1 (Cq), 172.2 (Cq), 172.0 (Cq), 169.7 (Cq), 155.3 (CH),
154.4 (CH), 121.6 (CH), 95.3 (Cq), 85.1 (CH), 84.8 (CH), 71.6 (CH2), 70.9 (CH2), 56.8 (CH), 42.3
(CH), 40.8 (CH2), 34.6 (CH), 28.7 (CH2), 27.7 (CH), 27.5 (CH), 27.3 (CH2), 24.1 (CH2), 21.8 (CH2),
19.23 (CH3), 19.21 (CH3), 19.1 (CH3), 19.01 (CH3), 18.99 (CH2). IR υ (neat): 2960, 1750, 1713, 1644,
1610, 1222, 1157 cm–1. M.S. (ESI, m/z) 344.1 [M+NH4]+. HRMS (ESI, m/z) calcd. for C15H24NO5:
298.1654 ; found: 298.1662.
(6S)-iso-butyl-2-((diphenoxyphosphoryl)oxy)-6-((R)-5-oxo-2,5-dihydrofuran-2-yl)cyclohex-1-
enecarboxylate (4c). Prepared according to general procedure B from iso-butyl 2ꢀoxoꢀ6ꢀ(5ꢀoxoꢀ2,5ꢀ
dihydrofuranꢀ2ꢀyl)cyclohexanecarboxylate 3c (36.3 mg, 0.129 mmol, 1.0 eq), sodium hydride (60%, 6.2
mg, 0.155 mmol, 1.2 eq), diphenylphosphoryl chloride (25 ꢀL, 0.123 mmol, 0.95 eq). The crude
mixture was purified by flash chromatography (heptane/AcOEt 40/60) to afford compound 4c as a
colorless oil (45.0 mg, 72%). 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.49 (dd, J = 5.8, 1.6 Hz, 1H), 7.43ꢀ
7.32 (m, 4H), 7.31ꢀ7.19 (m, 6H), 6.12 (dd, J = 5.7, 2.1 Hz, 1H), 5.20 (m, 1H), 3.85 (m, 2H), 3.44 (brs,
13
1H), 2.51 (m, 2H), 1,91 (m, 1H), 1.86ꢀ1.57 (m, 4H), 0.92 (d, J = 6.7 Hz, 6H). C NMR (CDCl3, 75
MHz) δ (ppm): 172.6 (Cq), 166.1 (Cq), 154.7 (CH), 154.0 (d, JP-C = 7.7 Hz, Cq), 150.4 (d, JP-C = 7.1
Hz, 2xCq), 129.9 (4xCH), 125.6 (2xCH), 122.1 (CH), 120.09 (d, JP-C = 4.9 Hz, 2xCH), 120.04 (d, JP-C
=
ACS Paragon Plus Environment
19

The Journal of Organic Chemistry
Page 20 of 39
4.9 Hz, 2xCH), 115.6 (d, JP-C = 8.2 Hz, Cq), 84.8 (d, JP-C = 2.0 Hz, CH), 71.5 (CH2), 37.9 (CH), 28.5
(CH2), 27.5 (CH), 22.7 (CH2), 19.6 (CH2), 19.20 (CH3), 19.19 (CH3). I.R υ (neat): 2964, 1778, 1757,
1714, 1487, 1304, 1140, 953 cmꢀ1. M.S. (ESI, m/z) 511.1 [MꢀH]ꢀ, 547.1 [M+Cl]ꢀ, 530.2 [M+NH4]+.
1
2
3
4
5
6
7
8
25
H.R.M.S. (ESI, m/z) Calcd for C27H29O8PNa : 535.1498, found: 535.1490. [α]D +30.9 (c = 1.607,
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
CHCl3, 74% ee). HPLC analysis: chiralcel OJꢀH, hexane/EtOH (v/v: 80/20).
(6S)-iso-propyl 2-oxo-6-((R)-5-oxo-2,5-dihydrofuran-2-yl)cyclohexanecarboxylate (3d). Prepared
according to general procedure A from isoꢀpropyl 6ꢀoxocyclohexꢀ1ꢀenecarboxylate 2d (35.0 mg, 0.192
mmol, 1.0 eq), copperꢀ(II) triflate (7.4 mg, 0.019 mmol, 0.1 eq), 2,2ꢀBis((4S)ꢀ(–)ꢀ4ꢀ
isopropyloxazoline)propane (5.6 mg, 0.021 mmol, 0.11 eq), 2ꢀ(trimethylsiloxy)furan (39 ꢀL, 0.230
mmol, 1.2 eq), in toluene/THF (v/v: 3/1) and stirred for 3 hrs at ꢀ78°C. The crude mixture was purified
1
by flash chromatography (heptane/EtOAc 50/50) to afford 3d as a colorless oil (37.6 mg, 74%). H
NMR (CDCl3, 300 MHz) keto/enol 50/50 δ (ppm): 12.74 (s, 1H, OH enol), 7.40 (dd, J = 5.8 1.6 Hz, 1H,
enol), 7.32 (dd, J = 5.8, 1.6 Hz, 1H, keto), 6.02 (dd, J = 5.7, 2.2 Hz, 1H, enol), 5.98 (dd, J = 5.8, 2.2 Hz,
1H, keto), 5.27 (ddd, J = 4.7, 2.2, 1.6 Hz, 1H, enol), 5.12ꢀ4.91 (m, 3H, keto+enol), 3.23 (m, 1H, enol),
3.12 (d, J = 11.5 Hz, 1H, keto), 2.78 (m, 1H, keto), 2.43 (m, 1H, keto), 2.30ꢀ2.19 (m, 2H, keto+enol),
2.07 (m, 1H, keto), 1.97 (m, 1H, keto), 1.80 (m, 1H, keto), 1.46ꢀ1.73 (m, 5H, keto+enol), 1.29ꢀ1.12 (m,
12H, keto). 13C NMR (CDCl3, 75 MHz) δ (ppm): 204.5 (Cq), 176.1 (Cq), 173.1 (Cq), 172.2 (Cq), 171.5
(Cq), 169.2 (Cq), 155.5 (CH), 154.5 (CH), 121.8 (CH), 121.5 (CH), 95.4 (Cq), 85.3 (CH), 84.8 (CH),
69.2 (CH), 68.6 (CH), 56.9 (CH), 42.7 (CH), 40.9 (CH2), 34.5 (CH), 29.7 (CH), 28.7 (CH), 27.2 (CH),
24.1 (CH2), 22.3 (CH2), 22.0 (CH3), 21.8 (CH3), 21.7 (CH3), 21.8 (CH3), 18.9 (CH2). IR υ (neat): 2938,
1754, 1713, 1638, 1226, 1106 cm–1. M.S. (ESI, m/z) 284.1 [M+NH4]+. HRMS (ESI, m/z) calcd. for
C14H22NO5: 284.1498 ; found: 284.1491.
(S)-iso-propyl-2-((diphenoxyphosphoryl)oxy)-6-((R)-5-oxo-2,5-dihydrofuran-2-yl)cyclohex-1-
enecarboxylate (4d). Prepared according to general procedure B from iso-propyl 2ꢀoxoꢀ6ꢀ(5ꢀoxoꢀ2,5ꢀ
dihydrofuranꢀ2ꢀyl)cyclohexanecarboxylate 3d (37.6 mg, 0.141 mmol, 1.0 eq), sodium hydride (60%, 6.8
ACS Paragon Plus Environment
20

Page 21 of 39
The Journal of Organic Chemistry
mg, 0.169 mmol, 1.2 eq), diphenylphosphoryl chloride (28 ꢀL, 0.134 mmol, 0.95 eq). The crude
mixture was purified by flash chromatography (heptane/EtOAc 40/60) to afford compound 4d as a
white solid (49.7 mg, 74%). 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.39 (dd, J = 5.7, 1.6 Hz, 1H), 7.32ꢀ
7.22 (m, 4H), 7.19ꢀ7.09 (m, 6H), 6.02 (dd, J = 5.8, 2.2 Hz, 1H), 5.10 (m, 1H), 4.97 (sept, 1H), 3.33 (brs,
1
2
3
4
5
6
7
8
9
13
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), 2.41 (m, 2H), 1.78ꢀ1.43 (m, 4H), 1.16 (d, J = 5.1 Hz, 3H), 1.14 (d, J = 5.1 Hz, 3H). C NMR
(CDCl3, 75 MHz) δ (ppm): 172.6 (Cq), 165.6 (Cq), 154.7 (CH), 153.6 (d, JP-C = 7.7 Hz, Cq), 150.3 (d,
JP-C = 7.1 Hz, 2xCq), 129.9 (d, JP-C = 1.7 Hz, 4xCH), 125.6 (2xCH), 122.2 (CH), 120.1 (d, JP-C = 5.1 Hz,
2xCH), 120.0 (d, JP-C = 5.1 Hz, 2xCH), 116.1 (d, JP-C = 8.7 Hz, Cq), 84.7 (d, JP-C = 1.7 Hz, CH), 69.2
(CH), 38.0 (CH), 28.4 (CH2), 22.7 (CH2), 21.7 (CH3), 21.6 (CH3), 19.6 (CH2). I.R υ (neat): 2980, 1757,
1708, 1486, 1301, 953 cmꢀ1. M.S. (ESI, m/z) 497.1 [MꢀH]ꢀ, 533.1 [M+Cl]ꢀ, 516.2 [M+NH4]+. H.R.M.S.
(ESI, m/z) Calcd for C26H27O8PNa: 521.1341, found: 521.1343. mp : 136ꢀ138°C. [α]D25 +47.6 (c = 1.40,
CHCl3, 85% ee). HPLC analysis: chiralcel OJꢀH, hexane/EtOH (v/v: 80/20).
(6S)-tert-butyl 2-oxo-6-((R)-5-oxo-2,5-dihydrofuran-2-yl)cyclohexanecarboxylate (3e). Prepared
according to general procedure A from tert-butyl 6ꢀoxocyclohexꢀ1ꢀenecarboxylate 2e (35.0 mg, 0.178
mmol, 1.0 eq), copperꢀ(II) triflate (6.5 mg, 0.018 mmol, 0.1 eq), 2,2ꢀBis((4S)ꢀ(–)ꢀ4ꢀ
isopropyloxazoline)propane (5.9 mg, 0.020 mmol, 0.11 eq), 2ꢀ(trimethylsiloxy)furan (36 ꢀL, 0.214
mmol, 1.2 eq), in toluene/THF (v/v: 3/1) and stirred for 2 days at ꢀ78°C. The crude mixture was purified
1
by flash chromatography (heptane/EtOAc 50/50) to afford 3e as a colorless oil (18.2 mg, 36%). H
NMR (CDCl3, 300 MHz) keto/enol 50/50 δ (ppm): 12.80 (s, 1H, OH enol), 7.42 (dd, J = 5.7, 1.6 Hz,
1H, enol), 7.35 (dd, J = 5.7, 1.6 Hz, 1H, keto), 6.03 (dd, J = 5.6, 2.1 Hz, 1H, enol), 6.00 (dd, J = 5.6, 2.1
Hz, 1H, keto), 5.25 (m, 1H, enol), 5.01 (m, 3H, keto), 3.15 (m, 1H, enol), 3.01 (d, J = 11.4 Hz, 1H,
keto), 2.74 (m, 1H, keto), 2.40 (m, 1H, keto), 2.29ꢀ2.18 (m, 2H, keto+enol), 2.05 (m, 1H, keto), 1.96 (m,
13
1H, keto), 1.79 (m, 1H, keto), 1.72ꢀ1.42 (m, 5H, keto+enol), 1.46 (s, 9H, keto), 1.39 (s, 9H, keto). C
NMR (CDCl3, 75 MHz) δ (ppm): 205.0 (Cq), 175.4 (Cq), 173.2 (Cq), 172.3 (Cq), 171.7 (Cq), 168.8
(Cq), 155.5 (CH), 154.7 (CH), 121.7 (CH), 121.5 (CH), 96.4 (Cq), 85.4 (CH), 84.9 (CH), 57.4 (CH),
ACS Paragon Plus Environment
21

The Journal of Organic Chemistry
Page 22 of 39
42.7 (CH), 41.0 (CH2), 34.9 (CH), 28.7 (CH2), 28.3 (CH3), 28.0 (CH3), 27.1 (CH2), 24.1 (CH2), 22.4
(CH2), 18.9 (CH2). IR υ (neat): 2938, 1753, 1711, 1638, 1228, 1143 cm–1. M.S. (ESI, m/z) 298.2
[M+NH4]+. HRMS (ESI, m/z) calcd. for C15H24NO5: 298.1654 ; found: 298.1663.
1
2
3
4
5
6
7
8
9
(6S)-tert-butyl-2-((diphenoxyphosphoryl)oxy)-6-((R)-5-oxo-2,5-dihydrofuran-2-yl)cyclohex-1-
enecarboxylate (4e). Prepared according to general procedure B from tertꢀbutyl 2ꢀoxoꢀ6ꢀ(5ꢀoxoꢀ2,5ꢀ
dihydrofuranꢀ2ꢀyl)cyclohexanecarboxylate 3e (33.2 mg, 0.118 mmol, 1.0 eq), sodium hydride (60%, 5.7
mg, 0.142 mmol, 1.2 eq), diphenylphosphoryl chloride (23.0 ꢀL, 0.112 mmol, 0.95 eq). The crude
mixture was purified by flash chromatography (heptane/EtOAc 40/60) to afford compound 4e as a
colorless oil (42.4 mg, 74%). 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.52 (dd, J = 5.7, 1.6 Hz, 1H), 7.32ꢀ
7.22 (m, 4H), 7.19ꢀ7.09 (m, 6H), 6.14 (dd, J = 5.7, 2.1 Hz, 1H), 5.21 (m, 1H), 3.40 (brs, 1H), 2.51ꢀ2.46
(m, 2H), 1.88ꢀ1.52 (m, 4H), 1.49 (s, 9H). 13C NMR (CDCl3, 75 MHz) δ (ppm): 172.6 (Cq), 165.2 (d, JP-
C = 1.7 Hz, Cq), 154.8 (CH), 152.6 (d, JP-C = 7.7 Hz, Cq), 150.8 (d, JP-C = 7.1 Hz, 2xCq), 129.7 (4xCH),
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
125.6 (2xCH), 122.2 (CH), 120.1 (2xCH), 120.0 (2xCH), 117.1 (d, JP-C = 9.1 Hz, Cq), 84.7 (d, JP-C
=
2.0 Hz, CH), 82.4 (Cq), 38.0 (CH), 28.2 (CH2), 28.0 (3xCH3), 22.5 (CH2), 19.7 (CH2). I.R υ (neat):
2978, 1755, 1703, 1488, 1298, 1184, 1154, 1129, 950 cmꢀ1. M.S. (ESI, m/z) 530.2 [M+NH4]+, 547.1
25
[M+Cl]ꢀ. H.R.M.S. (ESI, m/z) Calcd for C27H29O8PNa: 535.1498, found: 535.1494. [α]D +14.4 (c =
0.927, CHCl3, 26% ee). HPLC analysis: chiralcel OJꢀH, hexane/EtOH (v/v: 80/20).
(6S)-phenyl 2-oxo-6-((R)-5-oxo-2,5-dihydrofuran-2-yl)cyclohexanecarboxylate (3f). Prepared
according to general procedure A from phenyl 6ꢀoxocyclohexꢀ1ꢀenecarboxylate 2f (40.0 mg, 0.185
mmol, 1.0 eq), copperꢀ(II) triflate (7.0 mg, 0.019 mmol, 0.1 eq), 2,2ꢀBis((4S)ꢀ(–)ꢀ4ꢀ
isopropyloxazoline)propane (5.4 mg, 0.020 mmol, 0.11 eq), 2ꢀ(trimethylsiloxy)furan (37 ꢀL, 0.232
mmol, 1.2 eq), in toluene/THF (v/v : 3/1) and stirred for 2 hrs at ꢀ78°C. The crude mixture was purified
1
by flash chromatography (heptane/EtOAc 50/50) to afford 3f as a colorless oil (42.3 mg, 76%). H
NMR (CDCl3, 300 MHz) keto/enol 63/37 δ (ppm): 12.35 (s, 1H, OH enol), 7.49 (dd, J = 5.7, 1.7 Hz,
ACS Paragon Plus Environment
22

Page 23 of 39
The Journal of Organic Chemistry
1H, enol), 7.38ꢀ7.28 (m, 5H, keto+enol), 7.23ꢀ7.11 (m, 2H, keto+enol), 7.09ꢀ7.00 (m, 4H, keto+enol),
6.09ꢀ6.05 (m, 2H, keto+enol), 5.32 (m, 1H, enol), 5.06 (m, 1H, keto), 3.43 (d, J = 11.7 Hz, 1H, keto),
3.39 (m, 1H, enol), 2.83 (m, 1H, keto), 2.51 (m, 1H, keto), 2.40ꢀ2.29 (m, 3H, keto+enol), 2.12 (m, 1H,
keto), 2.03 (m, 1H, keto), 1.90 (m, 1H, keto), 1.78ꢀ1.56 (m, 5H, keto+enol). 13C NMR (CDCl3, 75 MHz)
δ (ppm): 204.1 (Cq), 178.3 (Cq), 173.0 (Cq), 172.1 (Cq), 170.7 (Cq), 168.6 (Cq), 155.5 (CH), 154.8
(CH), 150.4 (Cq), 149.9 (Cq), 129.6 (CH), 129.5 (CH), 126.3 (CH), 126.2 (CH), 121.8 (CH), 121.6
(CH), 121.4 (CH), 94.8 (Cq), 85.7 (CH), 84.9 (CH), 56.9 (CH), 43.0 (CH), 41.0 (CH2), 34.8 (CH), 28.8
(CH2), 27.5 (CH2), 24.2 (CH2), 23.6 (CH2), 18.5 (CH2). IR υ (neat): 2949, 1751, 1713, 1593, 1185,
1160, 733 cm–1. M.S. (ESI, m/z) 318.1 [M+NH4]+. HRMS (ESI, m/z) calcd. for C17H20NO5: 318.1341 ;
found: 318.1326.
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
(6S)-phenyl
2-((diphenoxyphosphoryl)oxy)-6-((R)-5-oxo-2,5-dihydrofuran-2-yl)cyclohex-1-
enecarboxylate (4f). Prepared according to general procedure B from phenyl 2ꢀoxoꢀ6ꢀ(5ꢀoxoꢀ2,5ꢀ
dihydrofuranꢀ2ꢀyl)cyclohexanecarboxylate 3f (44.5 mg, 0.148 mmol, 1.0 eq), sodium hydride (60%, 7.1
mg, 0.178 mmol, 1.2 eq), diphenylphosphoryl chloride (29 ꢀL, 0.141 mmol, 0.95 eq). The crude
mixture was purified by flash chromatography (heptane/EtOAc 40/60) to afford compound 4f as a white
1
solid (60.0 mg, 80%). H NMR (CDCl3, 500 MHz) δ (ppm): 7.54 (dd, J = 5.7, 1.6 Hz, 1H), 7.39ꢀ7.05
(m, 15H), 6.17 (dd, J = 5.8, 2.2 Hz, 1H), 5.26 (m, 1H), 3.49 (brs, 1H), 2.62 (m, 2H), 2.04ꢀ1.75 (m, 4H).
13C NMR (CDCl3, 75 MHz) δ (ppm): 172.4 (Cq), 164.7 (d, JP-C = 1.9 Hz, Cq), 155.7 (d, JP-C = 7.7 Hz,
Cq), 154.8 (CH), 150.4 (Cq), 150.2 (d, JP-C = 7.2 Hz, 2xCq), 129.89 (2xCH), 129.85 (2xCH), 129.4
(2xCH), 125.9 (CH), 125.7 (2xCH), 122.1 (CH), 121.6 (2xCH), 120.1 (d, JP-C = 5.0 Hz, 4xCH), 115.0
(d, JP-C = 8.5 Hz, Cq), 85.2 (d, JP-C = 2.0 Hz, CH), 38.3 (CH), 28.7 (CH2), 23.6 (CH2), 19.6 (CH2). I.R υ
(neat): 2949, 1752, 1487, 1297, 1184, 1159, 948.cmꢀ1. M.S. (ESI, m/z) 531.1 [MꢀH]ꢀ , 567.1 [M+Cl]ꢀ,
550.2 [M+NH4]+. H.R.M.S. (ESI, m/z) Calcd for C29H25O8PNa : 555.1185, found: 555.1176. mp : 145ꢀ
25
147 °C. [α]D +3.2 (c = 0.700, CHCl3, 95% ee). HPLC analysis: chiralcel IC, hexane/EtOH (v/v:
85/15).
ACS Paragon Plus Environment
23

The Journal of Organic Chemistry
Page 24 of 39
(6S)-benzyl 2-oxo-6-((R)-5-oxo-2,5-dihydrofuran-2-yl)cyclohexanecarboxylate (3g). Prepared
according to general procedure A from benzyl 6ꢀoxocyclohexꢀ1ꢀenecarboxylate 2g (40.0 mg, 0.174
mmol, 1.0 eq), copperꢀ(II) triflate (6.2 mg, 0.017 mmol, 0.1 eq), 2,2ꢀBis((4S)ꢀ(–)ꢀ4ꢀ
isopropyloxazoline)propane (5.1 mg, 0.019 mmol, 0.11 eq), 2ꢀ(trimethylsiloxy)furan (35 ꢀL, 0.209
mmol, 1.2 eq), in toluene/THF (v/v: 3/1) and stirred for 2.5 hrs at ꢀ78°C. The crude mixture was purified
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
1
by flash chromatography (heptane/EtOAc 50/50) to afford 3g as a colorless oil (31.2 mg, 57%). H
NMR (CDCl3, 300 MHz) keto/eno 37/63 δ (ppm): 12.57 (s, 1H, OH enol), 7.36ꢀ7.23 (m, 11H,
keto+enol), 7.13 (dd, J = 5.6, 1.7 Hz, 1H, keto), 5.90 (dd, J = 5.7, 2.1 Hz, 1H, enol), 5.57 (dd, J = 5.7,
2.1 Hz, 1H, keto), 5.22 (m, 1H, enol), 5.16 (s, 2H, enol), 5.12 (d, J = 12.2 Hz, 1H, keto), 5.03 (d, J =
12.2 Hz, 1H, keto), 4.94 (m, 1H, keto), 3.25 (m, 1H, enol), 3.19 (d, J = 11.4 Hz, 1H, keto), 2.77 (m, 1H,
keto), 2.44 (m, 1H, keto), 2.32ꢀ2.32 (m, 3H, keto+enol), 2.06 (m, 1H, keto), 1.95 (m, 1H, keto), 1.90ꢀ
1.43 (m, 6H, keto+enol). 13C NMR (CDCl3, 75 MHz) δ (ppm): 204.3 (Cq), 176.8 (Cq), 173.1 (Cq),
172.1 (Cq), 171.6 (Cq), 169.5 (Cq), 155.5 (CH), 154.3 (CH), 135.2 (Cq), 135.1 (Cq), 128.9 (CH), 128.8
(CH), 128.61 (CH), 128.59 (CH), 128.5 (CH), 128.4 (CH), 121.6 (CH), 121.3 (CH), 121.4 (CH), 94.89
(Cq), 85.3 (CH), 84.7 (CH), 67.2 (CH2), 66.5 (CH2), 56.8 (CH), 43.0 (CH), 40.9 (CH2), 34.5 (CH), 28.7
(CH2), 27.4 (CH2), 24.1 (CH2), 22.8 (CH2), 18.8 (CH2). IR υ (neat): 2948, 1748, 1713, 1643, 1602,
1267, 1219, 1158, 818 cm–1. M.S. (ESI, m/z) 332.1 [M+NH4]+. HRMS (ESI, m/z) calcd. for C18H22NO5:
332.1498 ; found: 332.1497.
(S)-benzyl
2-((diphenoxyphosphoryl)oxy)-6-((R)-5-oxo-2,5-dihydrofuran-2-yl)cyclohex-1-
enecarboxylate (4g). Prepared according to general procedure B from benzyl 2ꢀoxoꢀ6ꢀ(5ꢀoxoꢀ2,5ꢀ
dihydrofuranꢀ2ꢀyl)cyclohexanecarboxylate 3g (27.4 mg, 0.087 mmol, 1.0 eq), sodium hydride (60%, 4.2
mg, 0.104 mmol, 1.2 eq), diphenylphosphoryl chloride (18 ꢀL, 0.083 mmol, 0.95 eq). The crude
mixture was purified by flash chromatography (heptane/EtOAc 40/60) to afford compound 4g as a
1
colorless oil (23.0 mg, 51%). H NMR (CDCl3, 500 MHz) δ (ppm): 7.36ꢀ7.11 (m, 16H), 5.80 (dd, J =
5.7, 2.1 Hz, 1H), 5.14 (d, J = 12.0 Hz, 1H), 5.06 (dt, J = 4.6, 1.8 Hz, 1H), 4.88 (d, J = 12.0 Hz, 1H),
ACS Paragon Plus Environment
24

Page 25 of 39
The Journal of Organic Chemistry
3.33 (brs, 1H), 2.49ꢀ2.40 (m, 2H), 1.89ꢀ1.53 (m, 4H). 13C NMR (CDCl3, 75 MHz) δ (ppm): 172.6 (Cq),
165.8 (Cq), 154.7 (d, JP-C = 5.0 Hz, Cq), 154.6 (CH), 150.3 (d, JP-C = 4.4 Hz, 2xCq), 135.3 (Cq), 129.9
(2xCH), 129.8 (2xCH), 128.8 (2xCH), 128.5 (2xCH), 128.4 (CH), 125.7 (2xCH), 121.9 (CH), 120.1 (d,
JP-C = 2.0 Hz, 2xCH), 120.0 (d, JP-C = 2.0 Hz, 2xCH), 115.1 (d, JP-C = 5.0 Hz, Cq), 84.8 (d, JP-C = 2.0
Hz, CH), 67.0 (CH2), 38.0 (CH), 28.5 (CH2), 23.1 (CH2), 19.5 (CH2). I.R υ (neat): 2953, 1755, 1720,
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
1488, 1297, 1185, 1160, 1131, 952 cmꢀ1. M.S. (ESI, m/z) 545.1 [MꢀH]ꢀ, 581.1 [M+Cl]ꢀ, 564.2
[M+NH4]+. H.R.M.S. (ESI, m/z) Calcd for C30H27O8PNa: 569.1341, found: 569.1334. [α]D25 +36.9 (c =
1.540, CHCl3, 95% ee). HPLC analysis: chiralcel OJꢀH, hexane/EtOH (v/v: 60/40).
(2S)-ethyl 2-((S)-4-methyl-5-oxo-2,5-dihydrofuran-2-yl)-6-oxocyclohexanecarboxylate (3b’).
Prepared according to general procedure A from ethyl 6ꢀoxocyclohexꢀ1ꢀenecarboxylate 2b (35.0 mg,
0.208 mmol, 1.0 eq), copperꢀ(II) triflate (7.6 mg, 0.021 mmol, 0.1 eq), 2,2ꢀBis((4S)ꢀ(–)ꢀ4ꢀ
isopropyloxazoline)propane (6.2 mg, 0.023 mmol, 0.11 eq), 2 trimethyl((3ꢀmethylfuranꢀ2ꢀyl)oxy)silane
(43 mg, 0.250 mmol, 1.2 eq), in toluene/THF (v/v: 3/1) and stirred for 2 hrs at ꢀ78°C. The crude mixture
was purified by flash chromatography (heptane/EtOAc 50/50) to afford 3b' as a colorless oil (38.2 mg,
1
69%). H NMR (CDCl3, 300 MHz) keto (d.r. 60/40)/enol 65/35 δ (ppm): 12.72 (s, 1H, OH enol), 7.04
(t, J = 1.0 Hz, 1H, enol), 6.97 (t, J = 0.9 Hz, 1H, keto dia.1), 6.95 (t, J = 1.2 Hz, 1H, keto dia.2), 5.44
(m, 1H, keto dia.1), 5.22 (m, 1H, enol), 4.95 (m, 1H, keto dia.2), 4.37ꢀ4.04 (m, 6H, keto dia.1+ keto
dia.2+enol), 3.66 (d, J = 2.7 Hz, 1H, keto dia.1), 3.26 (m, 1H, enol), 3.19 (d, J = 11.4 Hz, 1H, keto
dia.2), 3.08 (m, 1H, enol), 2.86ꢀ2.46 (m, 5H, keto dia.1+ keto dia.2+enol), 2.38ꢀ2.27 (m, 3H, keto
dia.1+keto dia.2), 2.23ꢀ1.52 (m, 20H, keto dia.1+ keto dia.2+enol), 1.40ꢀ1.22 (m, 9H, keto dia.1+ keto
dia.2+enol). 13C NMR (CDCl3, 75 MHz) keto A/keto B/enol δ (ppm): 208.1 (Cq), 204.7 (Cq), 175.9
(Cq), 175.0 (Cq), 172.0 (Cq), 169.8 (Cq), 147.8 (CH), 146.7 (CH), 146.6 (CH), 130.5 (Cq), 129.8 (Cq),
95.5 (Cq), 83.0 (CH), 82.8 (CH), 82.5 (CH), 61.4 (CH2), 60.8 (CH2), 60.7 (CH2), 56.7 (CH) 48.9 (CH),
42.9 (CH), 40.9 (CH2), 36.7 (CH2), 34.5 (CH), 28.7 (CH2), 27.2 (CH2), 26.8 (CH2), 24.1 (CH2), 22.8
(CH2), 22.3 (CH2), 18.9 (CH2), 14.4 (CH3), 14.3 (CH3), 14.1 (CH3), 10.7 (CH3), 10.6 (CH3), 10.5 (CH3).
ACS Paragon Plus Environment
25

The Journal of Organic Chemistry
Page 26 of 39
IR υ (neat): 2930, 1755, 1715, 1646, 1616, 1248, 1225, 1060, 734 cm–1. M.S. (ESI, m/z) 284.1
1
2
3
[M+NH4]+. HRMS (ESI, m/z) calcd. for C14H22NO5: 284.1498 ; found: 284.1487.
4
5
6
7
8
9
(S)-ethyl 2-((diphenoxyphosphoryl)oxy)-6-((R)-4-methyl-5-oxo-2,5-dihydrofuran-2-yl)cyclohex-
1-enecarboxylate (4b’). Prepared according to general procedure B from ethyl 2ꢀoxoꢀ6ꢀ(4ꢀmethylꢀ5ꢀ
oxoꢀ2,5ꢀdihydrofuranꢀ2ꢀyl)cyclohexanecarboxylate 3b' (35.0 mg, 0.131 mmol, 1.0 eq), sodium hydride
(60%, 6.3 mg, 0.157 mmol, 1.2 eq), diphenylphosphoryl chloride (26 ꢀL, 0.124 mmol, 0.95 eq). The
crude mixture was purified by flash chromatography (heptane/EtOAc 40/60) to afford compound 4b’ as
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
a colorless oil (15.0 mg, 24%). H NMR (CDCl3, 300 MHz) δ (ppm): 7.43ꢀ7.34 (m, 4H), 7.31ꢀ7.19 (m,
6H), 7.04 (m, 1H), 5.07ꢀ5.01 (m, 1H), 4.22ꢀ4.01 (m, 2H), 3.33 (brs, 1H), 2.54ꢀ2.45 (m, 2H), 1,92 (t, J =
13
1.9 Hz, 3H), 1.90ꢀ1.68 (m, 4H), 1.23 (t, J = 7.1 Hz, 3H). C NMR (CDCl3, 75 MHz) δ (ppm): 173.7
(Cq), 166.2 (Cq), 153.7 (d, JP-C = 7.9 Hz, Cq), 150.4 (d, JP-C = 7.3 Hz, 2xCq), 147.0 (CH), 130.6 (Cq),
129.9 (2xCH), 129.8 (2xCH), 125.6 (d, JP-C = 2.8 Hz, 2xCH), 120.1 (d, JP-C = 2.7 Hz, 2xCH), 120.0 (d,
JP-C = 2.7 Hz, 2xCH), 115.9 (d, JP-C = 8.2 Hz, Cq), 82.6 (d, JP-C = 2.0 Hz, CH), 61.3 (CH2), 38.1 (CH),
28.4 (CH2), 23.0 (CH2), 19.6 (CH2), 14.0 (CH3), 10.7 (CH3). I.R υ (neat): 2928, 1756, 1714, 1488, 1297,
1185, 952 cmꢀ1. M.S. (ESI, m/z) 499.2 [M+H]+, 516.2 [M+NH4]+, 521.1 [M+Na]+, 497.1 [MꢀH]ꢀ, 533.1
25
[M+Cl]ꢀ. H.R.M.S. (ESI, m/z) Calcd for C26H28O8P: 499.1522, found: 499.1507. [α]D +15.5 (c =
0.917, CHCl3, 59% ee). HPLC analysis: chiralcel OJꢀH, hexane/EtOH (v/v: 80/20).
(2R)-ethyl 3,3-dimethyl-6-oxo-2-((R)-5-oxo-2,5-dihydrofuran-2-yl)cyclohexanecarboxylate (3h).
Prepared according to general procedure A from ethyl 3,3ꢀdimethylꢀ6ꢀoxocyclohexꢀ1ꢀenecarboxylate 2h
(40.0 mg, 0.204 mmol, 1.0 eq), copperꢀ(II) triflate (7.2 mg, 0.020 mmol, 0.1 eq), 2,2ꢀBis((4S)ꢀ(–)ꢀ4ꢀ
isopropyloxazoline)propane (5.9 mg, 0.022 mmol, 0.11 eq), 2ꢀ(trimethylsiloxy)furan (42 ꢀL, 0.245
mmol, 1.2 eq), in toluene/THF (v/v: 3/1) and stirred for 2 hrs at ꢀ78°C. The crude mixture was purified
1
by flash chromatography (heptane/EtOAc 50/50) to afford 3h as a solid (42.0 mg, 74%). H NMR
(CDCl3, 300 MHz) keto/enol 10/90 δ (ppm): 12.46 (s, 1H, OH enol), 7.37 (dd, J = 5.7, 1.7 Hz, 1H,
ACS Paragon Plus Environment
26

Page 27 of 39
The Journal of Organic Chemistry
enol), 7.25 (dd, J = 5.7, 1.7 Hz, 1H, keto), 5.90ꢀ5.85 (m, 2H, keto+enol), 5.28ꢀ5.24 (m, 2H, keto+enol),
4.22ꢀ4.00 (m, 4H, keto+enol), 3.33 (d, J = 11.5 Hz, 1H, keto), 2.66 (t, J = 2.1 Hz, 1H enol), 2.55ꢀ2.00
(m, 6H, keto+enol), 1.33ꢀ1.15 (m, 8H, keto+enol), 1.13 (s, 6H, keto+enol), 0.93 (s, 6H, keto+enol).13C
NMR (CDCl3, 75 MHz) δ (ppm): 205.1 (Cq), 176.3 (Cq), 173.2 (Cq), 171.8 (Cq), 157.1 (CH), 157.0
(CH), 120.3 (CH), 120.1 (CH), 92.7 (Cq), 82.8 (CH), 81.2 (CH), 61.3 (CH2), 60.4 (CH2), 53.2 (CH),
50.1 (CH), 45.4 (CH), 39.2 (CH), 37.2 (CH), 32.6 (Cq), 30.7 (CH2), 29.6 (CH3), 28.4 (CH3), 27.7 (CH3),
26.2 (CH2), 22.1 (CH3), 14.2 (CH3), 13.9 (CH3). IR υ (neat): 2965, 1752, 1714, 1636, 1604, 1284, 1218,
812 cm–1. M.S. (ESI, m/z) 298.2 [M+NH4]+. HRMS (ESI, m/z) calcd. for C15H24NO5: 298.1654 ; found:
298.1645. mp = 109ꢀ112 °C.
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
(S)-ethyl
2-((diphenoxyphosphoryl)oxy)-5,5-dimethyl-6-((R)-5-oxo-2,5-dihydrofuran-2-
yl)cyclohex-1-enecarboxylate (4h). Prepared according to general procedure B from ethyl 3,3ꢀ
dimethylꢀ6ꢀoxoꢀ2ꢀ(5ꢀoxoꢀ2,5ꢀdihydrofuranꢀ2ꢀyl)cyclohexanecarboxylate 3h (20.0 mg, 0.071 mmol, 1.0
eq), sodium hydride (60%, 3.4 mg, 0.086 mmol, 1.2 eq), diphenylphosphoryl chloride (14 ꢀL, 0.068
mmol, 0.95 eq). The crude mixture was purified by flash chromatography (heptane/EtOAc 40/60) to
afford compound 4h as a colorless oil (15.0 mg, 44%). 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.38ꢀ7.26
(m, 5H), 7.22ꢀ7.12 (m, 6H), 5.92 (dd, J = 5.7, 2.2 Hz, 1H), 5.31 (m, 1H), 4.12ꢀ3.83 (m, 2H), 3.00 (brs,
1H), 2.54ꢀ2.43 (m, 2H), 2.16 (m, 1H), 1.34 (m, 1H), 1.19 (s, 3H), 1.12 (t, J = 7.2, Hz, 3H), 1.02 (s, 3H).
13C NMR (CDCl3, 75 MHz) δ (ppm): 172.6 (Cq), 166.1 (d, JP-C = 1.7 Hz, Cq), 156.3 (CH), 155.6 (d, JP-
C = 8.8 Hz, Cq), 150.4 (d, JP-C = 7.1 Hz, Cq), 150.3 (d, JP-C = 7.1 Hz, Cq), 129.9 (2xCH), 129.8 (2xCH),
125.6 (d, JP-C = 1.1 Hz, CH), 125.5 (d, JP-C = 1.1 Hz, CH), 121.0 (CH), 120.1 (d, JP-C = 5.2 Hz, 2xCH),
120.0 (d, JP-C = 5.2 Hz, 2xCH), 112.6 (d, JP-C = 8.2 Hz, Cq), 82.2 (d, JP-C = 2.2 Hz, CH), 61.2 (CH2),
48.3 (CH), 32.0 (Cq), 31.4 (CH2), 27.8 (CH3), 27.2 (CH3), 26.7 (CH2), 14.0 (CH3). I.R υ (neat): 2962,
1756, 1703, 1488, 1296, 1186, 946 cmꢀ1. M.S. (ESI, m/z) 511.1 [MꢀH]ꢀ, 513.2 [M+H]+, 530.2
[M+NH4]+, 535.1 [M+Na]+. H.R.M.S. (ESI, m/z) Calcd for C27H29O8PNa: 535.1498, found:
ACS Paragon Plus Environment
27

The Journal of Organic Chemistry
Page 28 of 39
535.1475. [α]D25 +42.0 (c = 0.808, CHCl3, 96% ee). HPLC analysis: chiralcel OJꢀH, hexane/EtOH (v/v:
1
2
3
90/10).
4
5
(6S)-ethyl 4,4-dimethyl-2-oxo-6-((R)-5-oxo-2,5-dihydrofuran-2-yl)cyclohexanecarboxylate (3i).
Prepared according to general procedure A from ethyl 4,4ꢀdimethylꢀ6ꢀoxocyclohexꢀ1ꢀenecarboxylate 2i
(40.0 mg, 0.204 mmol, 1.0 eq), copperꢀ(II) triflate (7.2 mg, 0.020 mmol, 0.1 eq), 2,2ꢀBis((4S)ꢀ(–)ꢀ4ꢀ
isopropyloxazoline)propane (5.9 mg, 0.022 mmol, 0.11 eq), 2ꢀ(trimethylsiloxy)furan (42 ꢀL, 0.245
mmol, 1.2 eq), in toluene/THF (v/v: 3/1) and stirred for 2 hrs at ꢀ78°C. The crude mixture was purified
by flash chromatography (heptane/EtOAc 50/50) to afford 3i as a colorless oil (45.0 mg, 79%). 1H NMR
(CDCl3, 300 MHz) keto/enol 90/10 δ (ppm): 12.57 (s, 1H, OH enol), 7.34 (m, 1H, enol), 7.31 (dd, J =
5.8, 1.7 Hz, 1H, enol), 6.11 (m, 1H, enol), 5.98 (dd, J = 5.8, 2.1 Hz, 1H, keto), 5.02 (m, 1H, enol), 4.98
(m, 1H, keto), 4.30ꢀ3.98 (m, 4H, keto+enol), 3.30 (m, 1H, enol), 3.05 (d, J = 11.8 Hz, 1H, keto), 2.91
(m, 1H, keto), 2.24ꢀ2.08 (m, 2H, keto+enol), 1.85 (t, J = 13.2 Hz, 1H, keto), 1.66 (s, 1H, keto), 1.55ꢀ
1.14 (m, 7H, enol), 1.19 (t, J = 7.2 Hz, 3H, keto), 1.05 (s, 3H, keto), 0.99 (s, 3H, enol), 0.91 (s, 3H,
enol), 0.88 (s, 3H, keto). 13C NMR (CDCl3, 75 MHz) δ (ppm): 204.6 (Cq), 172.2 (Cq), 169.9 (Cq),
154.6 (CH), 121.6 (CH), 84.8 (CH), 61.4 (CH2), 55.6 (CH), 53.7 (CH2), 40.6 (CH2), 39.3 (CH), 34.4
(Cq), 31.6 (CH3), 25.0 (CH3), 14.0 (CH3). IR υ (neat): 2964, 1752, 1713, 1636, 1604, 1284, 1218, 812
cm–1. M.S. (ESI, m/z) 298.2 [M+NH4]+. HRMS (ESI, m/z) calcd. for C15H24NO5: 298.1654 ; found:
298.1653.
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
(S)-ethyl
2-((diphenoxyphosphoryl)oxy)-4,4-dimethyl-6-((R)-5-oxo-2,5-dihydrofuran-2-
yl)cyclohex-1-enecarboxylate (4i). Prepared according to general procedure B from ethyl 4,4ꢀdimethylꢀ
2ꢀoxoꢀ6ꢀ(5ꢀoxoꢀ2,5ꢀdihydrofuranꢀ2ꢀyl)cyclohexanecarboxylate 3i (45.0 mg, 0.161 mmol, 1.0 eq),
sodium hydride (60%, 7.7 mg, 0.193 mmol, 1.2 eq), diphenylphosphoryl chloride (32 ꢀL, 0.153 mmol,
0.95 eq). The crude mixture was purified by flash chromatography (heptane/EtOAc 40/60) to afford
1
compound 4i as a colorless oil (62.5 mg, 80%). H NMR (CDCl3, 300 MHz) δ (ppm): 7.35ꢀ7.25 (m,
5H), 7.20ꢀ7.09 (m, 6H), 6.05 (dd, J = 5.8, 2.2 Hz, 1H), 5.20 (dt, J = 5.2, 1.9 Hz, 1H), 4.14ꢀ3.94 (m, 2H),
ACS Paragon Plus Environment
28

Page 29 of 39
The Journal of Organic Chemistry
3.28 (m, 1H), 2.26ꢀ2.02 (m, 2H), 1.43 (ddd, J = 13.5, 5.8, 2.3 Hz, 1H), 1.13 (t, J = 7.1 Hz, 3H), 0.98ꢀ
0.89 (m, 1H), 0.91 (s, 3H), 0.88 (s, 3H). 13C NMR (CDCl3, 75 MHz) δ (ppm): 172.5 (Cq), 166.0 (d, JP-C
= 1.6 Hz, Cq), 154.3 (CH), 151.1 (d, JP-C = 7.7 Hz, Cq), 150.4 (d, JP-C = 5.2 Hz, Cq), 150.3 (d, JP-C = 5.2
Hz, Cq), 129.9 (4xCH), 125.7 (2xCH), 122.8 (CH), 120.1 (2xCH), 120.0 (2xCH), 115.8 (d, JP-C = 8.9
Hz, Cq), 83.8 (d, JP-C = 1.7 Hz, CH), 61.4 (CH2), 41.8 (CH2), 37.0 (CH), 34.6 (CH2), 30.8 (CH3), 30.4
(Cq), 24.6 (CH3), 14.0 (CH3). I.R υ (neat): 2960, 1756, 1722, 1590, 1488, 1297, 1186, 950 cmꢀ1. M.S.
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
(ESI, m/z) 511.1 [MꢀH]ꢀ, 547.1 [M+Cl]ꢀ, 530.2 [M+NH4]+, 535.1 [M+Na]+. H.R.M.S. (ESI, m/z)
25
Calcd for C27H30O8P: 513.1678, found: 513.1665. [α]D +80.7 (c = 1.225, CHCl3, 90% ee). HPLC
analysis: chiralcel OJꢀH, hexane/EtOH (v/v: 90/10).
(6S)-ethyl 3,3-dimethyl-2-oxo-6-((R)-5-oxo-2,5-dihydrofuran-2-yl)cyclohexanecarboxylate (3j).
Prepared according to general procedure A from ethyl 3,3ꢀdimethylꢀ6ꢀoxocyclohexꢀ1ꢀenecarboxylate 2j
(30.0 mg, 0.153 mmol, 1.0 eq), copperꢀ(II) triflate (5.5 mg, 0.015 mmol, 0.1 eq), 2,2ꢀBis((4S)ꢀ(–)ꢀ4ꢀ
isopropyloxazoline)propane (4.5 mg, 0.017 mmol, 0.11 eq), 2ꢀ(trimethylsiloxy)furan (31 ꢀL, 0.183
mmol, 1.2 eq), in toluene/THF (v/v: 3/1) and stirred for 2 hrs at ꢀ78°C. The crude mixture was purified
1
by flash chromatography (heptane/EtOAc 50/50) to afford 3j as a colorless oil (35.0 mg, 82%). H
NMR (CDCl3, 300 MHz) keto/enol 50/50 δ (ppm): 12.95 (s, 1H, OH enol), 7.38 (dd, J = 5.7, 1.5 Hz,
1H, enol), 7.30 (dd, J = 5.8, 1.8 Hz, 1H, keto), 6.03 (dd, J = 5.7, 2.1 Hz, 1H, enol), 5.97 (dd, J = 5.8, 2.1
Hz, 1H, keto), 5.27 (ddd, J = 1.8, 2.1, 4.8 Hz, 1H, enol), 5.00 (m, 1H, keto), 4.24ꢀ3.98 (m, 4H,
keto+enol), 3.38 (d, J = 12.2 Hz, 1H, keto), 3.23 (m, 1H, enol), 2.76 (m, 1H, enol), 2.00 (m, 1H, keto),
1.84ꢀ1.30 (m, 7H, keto+enol), 1.26 (t, J = 7.1, 3H, enol), 1.20 (t, J = 7.1, 3H, keto), 1.14 (s, 3H, keto),
13
1.12 (s, 3H, enol), 1.11 (s, 3H, enol), 1.01 (s, 3H, keto). C NMR (CDCl3, 75 MHz) δ (ppm): 209.1
(Cq), 182.2 (Cq), 173.1 (Cq), 172.5 (Cq), 172.3 (Cq), 170.3 (Cq), 155.4 (CH), 154.5 (CH), 121.5 (CH),
121.4 (CH), 93.6 (Cq), 85.0 (CH), 84.9 (CH), 61.4 (CH2), 60.9 (CH2), 53.0 (CH), 44.7 (Cq), 43.1 (CH2),
38.0 (CH), 35.8 (Cq), 35.3 (CH2), 35.0 (Cq), 27.1 (CH2), 26.9 (CH3), 24.9 (CH2), 24.4 (CH3), 23.5
(CH3), 18.9 (CH3), 14.2 (CH3), 14.1 (CH3). IR υ (neat): 2977, 1751, 1707, 1642, 1601, 1259, 1080,
ACS Paragon Plus Environment
29