Organocatalytic Enantioselective Conjugate Addition of Azlactones to Enolizable Linear and Cyclic Enones

Article abstract of DOI:10.1021/acs.joc.6b01356

Highly diastereo- and enantioselective conjugate additions of azlactones to enolizable cyclic and linear enones were conducted by employing proline aryl sulfonamide as the organocatalyst in trifluorotoluene. The conjugate adducts bearing contiguous quaternary and tertiary stereocenters were obtained in moderate to good yields with excellent diastereoselectivities and moderate to good enantioselectivities. This developed protocol filled in the substrate gap for the organocatalytic conjugate addition of azlactone to enones.

Full text of DOI:10.1021/acs.joc.6b01356

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Note
Organocatalytic Enantioselective Conjugate Addition
of Azlactones to Enolizable Linear and Cyclic Enones
Chao-Ming Wang, Jun-An Xiao, Jing Wang, Sha-Sha Wang, Zhao-Xu Deng, and Hua Yang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01356 • Publication Date (Web): 27 Jul 2016
Downloaded from http://pubs.acs.org on August 2, 2016
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Organocatalytic Enantioselective Conjugate Addition of
Azlactones to Enolizable Linear and Cyclic Enones
ChaoꢀMing Wang, JunꢀAn Xiao, Jing Wang, ShaꢀSha Wang, ZhaoꢀXu
Deng,† Hua Yang*
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College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, P. R.
China
eꢀmail: hyangchem@csu.edu.cn
ABSTRACT: Highly diastereoꢀ and enantioselective conjugate additions of azlactones
with enolizable cyclic and linear enones were realized by employing proline aryl
sulfonamide as the organocatalyst in trifluorotoluene. The conjugate adducts bearing
contiguous quaternary and tertiary stereocenters were obtained in moderate to good
yields with excellent diastereoselectivities and moderate to good enantioselectivities.
This developed protocol filled in the substrate gap for the organocatalytic conjugate
addition of azlactone to enones.
α,αꢀDisubstituted αꢀamino acids are nonproteinogenic modified amino acids, in
which αꢀsubstituents could severely restrict the conformational freedom of peptides
containing such residues. As a consequence, these amino acids are frequently being
used as probes to investigate the biologically active conformation and clarify the
secondary structure of peptides.1 Moreover, α,αꢀdisubstituted αꢀamino acids are present
in many biologically active compounds such as (+)ꢀLYꢀ354740,2 altemicidin,3
kaitocephalin,4 and sphingofungin5. Given the biological importance of
α,αꢀdisubstituted αꢀamino acids, considerable synthetic interests have been attracted to
develop stereoselective accesses to diverse α,αꢀdisubstituted αꢀamino acids.6 As the
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intrinsic hurdle arises from the demanding steric effect of quaternary stereocenter, the
enantioselective synthesis of α,αꢀdisubstituted αꢀamino acid is still an everꢀstanding
challenge in synthetic and medicinal chemistry.7
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As well known, azlactone, as a class of versatile building blocks for the masked
amino acid, can serve as a facile Micheal donor.8 Among all the established
methodologies accessing α,αꢀdisubstituted αꢀamino acids, the organocatalytic
conjugate addition of azlactone to α,βꢀunsaturated enone or enal proved to be quite
straightforward, atomꢀeconomic, and operationally accessible, which has progressively
occupied the mainstream in the synthetic efforts of α,αꢀdisubstituted αꢀamino acids.9
Wang and coꢀworkers reported an elegant enantioselective conjugate additions of
azlactone to α,βꢀunsaturated trichloromethyl ketones catalyzed by quinineꢀderived
thiourea. However, the more reactive trichloromethyl ketone was prerequisite and the
replacement of methyl or phenyl ketone proved inactive.10 Zhang et al. employed
quinineꢀderived thioureas catalysts to realize the conjugate addition between azlactone
and chalcone, in which only oꢀhydroxyl chalcone was the competent substrate to
furnish the regioselective Cꢀ2 attack product.11 Very recently, Ye and coꢀworkers
demonstrated 1,6ꢀconjugate addition of azlactones to cyclic dienones catalyzed by
primary amine catalysts with excellent enantioꢀ and diastereoselectivities.12
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Scheme 1. Synthetic Profiles of Organocatalytic Conjugate Addition of Azlactone
Unfortunately, despite these encouraging advances, the unmodified and enolizable
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benzalacetones and cyclohexenones with less electrophilicity still remained elusive and
unsuccessful for the organocatalytic enantioselective conjugate addition of azlactones.
It can be rationalized that these enolizable enones could readily undergo the enolization
under the organocatalytic conditions, leading to the reduction in the electrophilicity and
the decrease in the efficacy of activating enones as Micheal acceptor. Amarante group
described a conjugate addition of azlactone to benzalacetone catalyzed by
(±)ꢀcamphorsulfonic acid, resulting in racemic Micheal adduct.13 It is worth noting that
only single success of the enantioselective conjugate addition of azlactone to
benzalacetone was achieved by Peters and coꢀworkers with the employment of chiral
mono or bisꢀpalladacycle as the organometallic catalyst.14 Our continuous interests in
the organocatalyzed enone chemistry15 stimulated us to face this challenge filling in the
substrate gap with the enolizable enones. Herein, we describe the enantioselective
conjugate addition of azlactones to cyclic enones and linear enones catalyzed by
prolinosulphonamide organocatalyst (Hua Cat), in which water was found to show
beneficial effect on the enantioselectivity as depicted in the working mode in Scheme 1.
Certainly, this reported approach would address the drawback of the existing
organocatalytic conjugate addition of azlactone leading to α, αꢀdisubstituted αꢀamino
acid.
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Table 1. Organocatalyst Screeninga
Initially, the conjugate addition between cyclohexenone (1a) and azlactone 2a
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was used as a model reaction to screen the reaction parameters. Based on our previous
success on the organocatalytic enone chemistry, we speculated that amino acid
sulphonamide should effectively activate enone through the formation of iminium ion
to promote this reaction. Accordingly, various sulphonamides 3aꢀ3e derived from
secondary amino acids were evaluated respectively. Gratifyingly, the desired product
4a could be obtained in 70% yield along with 15:1 dr and 67.5:32.5 er upon using 20
mol% of pꢀdodecylꢀNꢀarylsulphoprolinamide (3a) in DCM at room temperature (Table
1). The employment of TBSꢀ4ꢀhydroxyprolinamide 3b and trimethyl analogues (3c and
3d) all gave slightly lower enantioselectivity. The introduction of electronꢀwithdrawing
group onto the phenyl moiety (3e) remarkably slowed down the reaction without
affecting the level of enantioselectivity. On the other hand, primary amine catalyst 3f
afforded poor yield, possibly due to the decomposition of azlactone promoted by the
primary amino group.16 As a consequence, prolinasulphonamide 3a was chosen as the
optimum catalyst for this transformation.
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Subsequently, other reaction parameters including reaction medium and additive
were further optimized by using 3a as the organocatalyst. The results are summarized in
Table 2. Firstly, various commonly used solvents were screened and the less polar
solvent was appropriate for this reaction (Table 2, entries 1ꢀ10). In view of both
reactivity and enantioselectivity, trifluorotoluene proved to be the optimal reaction
medium (entry 8). Then, a series of additives was investigated. The addition of base
such as trimethylamine or K2CO3 dramatically lowered the levels of chemical yield and
enantioselectivity (Table 2, entries 11ꢀ12). However, the acidic additives including
PhCO2H or NH4Cl did not obviously affect this transformation (entries 13 & 14).
Interestingly, removal of water by adding 4Å MS significantly decreased the
enantioselectivity and diastereoselectivity, suggesting that water is crucial to the
enantioselectivity in this reaction. However, the addition of water (1 equiv. or 10 equiv.)
was unable to further enhance the diastereoselectivity and enantioselectivity (entries
15ꢀ17). Interestingly, the addition neutral inorganic salt could slightly enhance
enantioselectivity (entries 18ꢀ21). Ultimately, adding 10 mol% of NaCl afforded 93:7
er with good yield (80%) (Table 2, entry 18). As a result, the optimal conditions were
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finalized as 20 mol% of 3a with 10 mol% NaCl in trifluorotoluene at room temperature.
Table 2. Optimization of Reaction Conditionsa
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Entry
solvent
Additive
Yield
(%)
70
62
74
63
77
22
90
86
25
46
31
35
77
76
20
90
86
80
76
72
65
er
dr
(10 mol%)
1
2
THF
ꢀ
87.5:12.5
62:38
12:1
>20:1
5:1
DMF
ꢀ
3
DMSO
ꢀ
64:36
4
2ꢀMeꢀTHF
ꢀ
ꢀ
88.5:11.5
89:11
>20:1
15:1
5
Toluene
6
Et2O
ꢀ
87.5:12.5
86:14
15:1
7
Dioxane
ꢀ
>20:1
>20:1
15:1
8
Trifluorotoluene
MeOH
ꢀ
90:10
9
ꢀ
67.5:32.5
78:22
10
11
12
13
14
15b
16c
17d
18
19
20
21
CH3CN
ꢀ
10:1
Trifluorotoluene
Trifluorotoluene
Trifluorotoluene
Trifluorotoluene
Trifluorotoluene
Trifluorotoluene
Trifluorotoluene
Trifluorotoluene
Trifluorotoluene
Trifluorotoluene
Trifluorotoluene
Et3N
K2CO3
PhCOOH
NH4Cl
4Å MS
H2O
H2O
NaCl
KCl
NaBr
NaI
53.5:46.5
67.5:32.5
87.5:12.5
86.5:13.5
65:35
>20:1
5:1
>20:1
15:1
5:1
90:10
>20:1
>20:1
90:10
93:7
>20:1
91:9
>20:1
>20:1
>20:1
91:5:8.5
87.5:12.5
a Unless otherwise noted, the reaction was carried out at 0.2 mmol scale in CH2Cl2 (1 mL) with a molar
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ratio of 1a/2a = 5:1 at RT for 24 h.
b 100 mg 4
Å
MS was added.
c H2O (1 equiv.) was added.
d H2O (10 equiv.) was added.
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Having established the optimized reaction conditions, we next studied the substrate
scope of the title reaction and the results are summarized in Table 3. Firstly, the
substituent effects on R2 were evaluated and it was found that the orthoꢀ and
metaꢀsubstituted azlactones provided the comparable levels of chemical yield and
enantioselectivity (4b and 4c) while the presence of paraꢀsubstituent slightly lowered
the enantioselectivity (4d and 4e). Pleasingly, various R1 substituting groups (Me, Et,
nꢀPr, iꢀPr and iꢀBu, 4fꢀ4j) were well tolerated, in which isoꢀbutyl analogue afforded the
superior level of enantioselectivity (94:6 er, 4j). Lastly, the cyclic enone was extended
to cyclopentenone and the chemical yield and enantioselectivity of the corresponding
adduct 4k were dramatically eroded (67% yield, 61.5:38.5 er), whose structure was
unambiguously assigned by single crystal Xꢀray diffraction.
Table 3. Substrate Scope for the Conjugate Addition of Cyclic Enonesa
O
O
O
3a (20 mol%)
R2 NaCl (10 mol%)
O
N
R1
n
+
O
R1
N
C6H5CF3, RT
n
O
1a n = 1
1b n = 0
2
4
R2
x-ray structure of 4k
O
O
O
O
O
O
Bn
N
CH3
Bn
N
Bn
Bn
Bn
N
O
O
O
O
O
O
N
N
N
O
O
O
O
O
Cl
O
Cl
Cl
O
4b, 77%
92:8 er
>20:1 dr
4c, 64%
93.5:6.5 er
>20:1 dr
4d, 72%
87:13 er
>20:1 dr
4a, 80%
93:7 er
>20:1 dr
4e, 80%
85.5:14.5 er
>20:1 dr
4f, 74%
92:8 er
>20:1 dr
O
O
O
O
n-Pr
i-Pr
i-Bu
Bn
Et
O
O
O
O
O
O
O
N
N
N
N
N
O
O
O
4g, 67%
84.5:15.5 er
>20:1 dr
4h, 72%
90:10 er
>20:1 dr
4i, 71%
91:9 er
>20:1 dr
4j, 68%
94:6 er
>20:1 dr
4k, 67%
61.5:38.5 er
>20:1 dr
a Unless otherwise noted, the reaction was carried out at 0.2 mmol scale in C6H5CF3 (1 mL) with a molar
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ratio of 1/2 = 5:1 at RT for 48 h.
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Subsequently, we moved forward to extend this protocol to the unmodified linear α,
βꢀunsaturated enone ꢀꢀ 4ꢀphenylꢀ3ꢀbutenꢀ2ꢀone, less reactive Micheal acceptor (Table
4). Encouragingly, the conjugate addition of azlactone 2 to 4ꢀphenylꢀ3ꢀbutenꢀ2ꢀone did
proceed to afford the corresponding adduct 6a in 65% yield with moderate
enantioselectivity and excellent diastereoselectivity (90:10 er and >20:1 dr) at 30°C.
Furthermore, at higher temperature, the level of enantioselectivity was severely eroded
although the chemical yield was improved. Differently, the addition of NaCl did not
show any beneficial effect on the enantioselectivity. Thereafter, the reliability and
feasibility of the linear substrates were also evaluated. As shown in Table 4, the
metaꢀsubstitution slightly decreased the level enantioselectivity (6c) while orthoꢀ and
paraꢀsubstitution patterns showed negligible effect on the enantioselectivity (6b and
6d). However, the diastereoselectivity was obviously affected by the orthoꢀsubstituent
(6b). The introduction of electronꢀdonating group obviously reduced the level of
enantioselectivity (6e). Variation of R3 (6gꢀ6k) demonstrated that isoꢀpropyl group
gave the superior level of enantioselectivity (97.5:2.5 er). At last, the electronꢀrich
4ꢀ(thienyl)ꢀ3ꢀbutenꢀ2ꢀone also furnished the corresponding product 6l in moderate
yield albeit with lower enantioselectivity. The absolute configuration of 6a was
established through the comparison of its specific rotation with the reported data in the
literature.14a
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Table 4. Extension of the Conjugate Addition of Azlactone to Linear Enonesa
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a Unless otherwise noted, the reaction was carried out at 0.2 mmol scale in C6H5CF3 (1 mL) with a molar
ratio of 5/2 = 5:1 at 30°C for 72 h.
b Performed at 30°C for 96 h.
Finally, largeꢀscale reaction of this transformation was performed by using 1 mmol
of 2a and the corresponding adduct 4a was obtained in good yield (81%) and good
stereoselectivity (92:8 er and >20:1 dr) (Scheme 2). Pleasingly, the level of
enantiopurity for 4a was readily enhanced to >99.5:0.5 er via single recrystallization.
To demonstrate the utility of this methodology, further transformation of the obtained
adduct was subsequently proceeded and 4a, 4b, and 4j were treated with concentrated
hydrochloric acid at room temperature respectively, furnishing the corresponding
αꢀcyclohexanoneꢀsubstituted αꢀamino acid 7aꢀ7c in good yield and stereoselectivity.
Scheme 2. Largeꢀscale Experiment and Synthetic Transformation of Adduct 4
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In summary, we developed organocatalytic asymmetric conjugate additions of
azlactones to enolizable α,βꢀunsaturated cyclic and linear enones in good yields and
stereoselectivities employing proline aryl sulfonamide as the catalyst. The resulting
adducts bearing two contiguous quaternary and tertiary stereocenters were efficiently
constructed, which could serve as the precursors for α,αꢀdisubstituted αꢀamino acids.
Noticeably, the less reactive enones towards organocatalytic conjugate addition of
azlactone were finally tackled, which would significantly complement the versatility of
this methodology.
EXPERIMENTAL SECTION
General Experimental Methods. Unless otherwise noted, all the reagents were purchased from
commercial suppliers and used without further purification. 1H NMR spectra were recorded at 400
MHz or 500 MHz. The chemical shifts were recorded in ppm relative to tetramethylsilane and with
the solvent resonance as the internal standard. Data were reported as follows: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants (Hz),
integration. 13C NMR data were collected at 100 MHz with complete proton decoupling. Chemical
shifts were reported in ppm from the tetramethylsilane with the solvent resonance as internal
standard. Infrared spectra (IR) were measured by FTꢀIR apparatus. High resolution mass
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spectroscopy (HRMS) was recorded on TOF MS ES+ mass spectrometer and acetonitrile was used
to dissolve the sample. Column chromatography was carried out on silica gel (200ꢀ300 mesh).
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8
9
Catalyst 3a 17a
,
3bꢀ , ,
3d 15b 3e 17b azlactone 2,14a, 17c and α, βꢀunsaturated enone 517d were prepared
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according to the reported protocol.
Preparation of catalyst 3f. A solution of pꢀdodecylbenzenesulfonyl chloride (1.72 g. 5.0 mmol, 1
equiv, sold as mixture of isomers) in anhydrous THF (25 mL) was added dropwise to the mixture of
(1R, 2R)ꢀ1,2ꢀcyclohexaneꢀ1,2ꢀdiamine (0.57 g, 5.0 mmol, 1equiv) and triethylamine (1.02 g, 10.0
mmol, 2 equiv) in THF (10 mL) with iceꢀcooling. After the addition, the mixture was warmed to
room temperature and stirred overnight. The result solution was concentrated in vacuo. And the
residue was purified via flash silica gel chromatography (MeOH/DCM = 1/19) to give
sulphonamide 3f as colorless oil (1.72 g, 4.1 mmol, yield 82%); [α]D20 = +27.6 (c = 1 in CH2Cl2); IR
(KBr) ν 3568, 3268, 2927, 1595, 1458, 1326, 1160, 833 cmꢀ1; 1H NMR (CDCl3, 400 MHz, major
isomer) δ 7.82 (d, J = 8.0 Hz, 2H), 7.26ꢀ7.32 (m, 2H), 2.65ꢀ2.74 (m, 1H), 2.53ꢀ2.60 (m, 1H), 2.40 (td,
J = 10.4, 3.6 Hz, 1H), 1.94 (d, J = 12.4 Hz, 1H), 1.52ꢀ1.71 (m, 7H), 1.03ꢀ1.31 (m, 20H), 0.72ꢀ0.87
(m, 6H); 13C NMR (CDCl3, 100 MHz, major isomer) δ 151.8, 138.3, 128.4, 128.3, 127.7, 127.0,
60.6, 54.8, 46.1, 36.8, 35.3, 32.6, 31.7, 29.6, 29.2, 27.1, 25.0, 24.8, 22.6, 20.6, 14.0; HRMS
(TOFꢀES+) m/z: [M+H]+ calcd for C24H43N2O2S 423.3045, found 423.3036;
General procedures for synthesis of compound 4aꢀ4k.
Azlactone (0.2 mmol, 1 equiv), cyclic enone (1.0 mmol, 5 equiv), NaCl (1.17 mg, 0.02 mmol, 0.1
equiv) and catalyst (0.04 mmol, 0.2 equiv) were dissolved in trifluorotoluene (1.0 mL) at room
temperature. After completion of the reaction (monitored by TLC), organic solvent was removed in
vacuo. Then the residue was purified via flash chromatography (petroleum ether/ethyl acetate =
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19/1ꢀ9/1) to yield the corresponding product.
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General procedures for the synthesis of compound 6aꢀ6l.
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Azlactone (0.2 mmol, 1 equiv), linear enone (1.0 mmol, 5 equiv) and catalyst (0.04 mmol, 0.2 equiv)
were dissolved in trifluorotoluene (1.0 mL) at 30°C. After completion of the reaction (monitored by
TLC), organic solvent was removed in vacuo. Then the residue was purified via flash
chromatography (petroleum ether/ethyl acetate = 19/1ꢀ9/1) to yield the corresponding product.
Characterization Data for the Micheal Adducts 4a−4k and 6aꢀ6l.
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(R)ꢀ4ꢀbenzylꢀ4ꢀ((S)ꢀ3ꢀoxocyclohexyl)ꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone 4a
White solid (55.6 mg, 0.160 mmol, yield 80%, > 20:1 dr, 93:7 er); m.p. 137ꢀ138°C; [α]D20 = +106.8
(c = 1 in CH2Cl2); IR (KBr) ν 2937, 1816, 1710, 1656, 1450, 1320, 961, 880 cmꢀ1; 1H NMR (CDCl3,
400 MHz) δ 7.81ꢀ7.83 (m, 2H), 7.52ꢀ7.56 (m, 1H), 7.41ꢀ7.45 (m, 2H), 7.10ꢀ7.18 (m, 5H), 3.28 (d, J
= 13.2 Hz, 1H), 3.15 (d, J = 13.2 Hz, 1H), 2.41ꢀ2.54 (m, 4H), 2.25ꢀ2.34 (m, 1H), 2.13ꢀ2.21 (m, 2H),
1.60ꢀ1.73 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 209.6, 178.6, 160.5, 133.8, 132.8, 130.2, 128.7,
128.2, 127.9, 127.4, 125.3, 44.5, 42.3, 41.0, 40.9, 25.6, 24.4; HRMS (TOFꢀES+) m/z: [M+Na]+
calcd for C22H21NO3Na 370.1419, found 370.1405; HPLC analysis: (CHIRALCEL ODꢀH, 10%
iꢀpropanol/hexanes, 1.0 mL/min, UV: 254 nm), tR = 10.4 min (major), 18.5 min (minor).
(R)ꢀ4ꢀbenzylꢀ2ꢀ(2ꢀchlorophenyl)ꢀ4ꢀ((S)ꢀ3ꢀoxocyclohexyl)oxazolꢀ5(4H)ꢀone 4b
White solid (58.8 mg, 0.154 mmol, yield 77%, > 20:1 dr, 92:8 er); m.p. 106ꢀ107°C; [α]D20 = +103.2
(c = 0.5 in CH2Cl2); IR (KBr) ν 3031, 2952, 1814, 1711, 1667, 1479, 1305, 1083, 957, 877 cmꢀ1; 1H
NMR (CDCl3, 400 MHz) δ 7.40ꢀ7.46 (m, 2H), 7.17ꢀ7.32 (m, 7H), 3.31 (d, J = 12.8 Hz, 1H), 3.19 (d,
J = 13.2 Hz, 1H), 2.50ꢀ2.56 (m, 3H), 2.42ꢀ2.46 (m, 1H), 2.27ꢀ2.34 (m, 1H), 2.20ꢀ2.22 (m, 2H),
1.61ꢀ1.74 (m, 2H);13C NMR (CDCl3, 100 MHz) δ 209.3, 178.2, 159.4, 133.7, 133.5, 132.7, 131.0,
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130.8, 130.3, 128.3, 127.5, 126.8, 125.3, 58.4, 44.2, 42.3, 41.0, 40.9, 25.6, 24.4, 18.4; HRMS
(TOFꢀES+) m/z: [M+Na]+ calcd for C22H20NO3NaCl 404.1029, found 404.1013; HPLC analysis:
(CHIRALCEL ODꢀH, 10% iꢀpropanol/hexanes, 1.0 mL/min, UV: 254 nm), tR = 5.6 min (major), 8.2
min (minor).
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(R)ꢀ4ꢀbenzylꢀ2ꢀ(3ꢀchlorophenyl)ꢀ4ꢀ((S)ꢀ3ꢀoxocyclohexyl)oxazolꢀ5(4H)ꢀone 4c
Colorless oil (48.9 mg, 0.128 mmol, yield 64%, > 20:1 dr, 93.5:6.5 er); [α]D20 = +100.2 (c = 1 in
1
CH2Cl2); IR (KBr) ν 3620, 2950, 1817, 1712, 1654, 1293, 1048, 891 cmꢀ1; H NMR (CDCl3, 400
MHz) δ 7.84 (s, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.48ꢀ7.58 (m, 1H), 7.29ꢀ7.39 (m, 2H), 7.10ꢀ7.17 (m,
5H), 3.28 (d, J = 13.2 Hz, 1H), 3.15 (d, J = 13.2 Hz, 1H), 2.38ꢀ2.52 (m, 4H), 2.26ꢀ2.34 (m, 1H),
2.09ꢀ2.20 (m, 1H), 1.61ꢀ1.72 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 209.5, 178.1, 159.5, 134.9,
133.6, 132.9, 130.2, 130.1, 128.3, 127.8, 127.5, 127.0, 126.0, 44.4, 42.3, 41.0, 40.9, 25.6, 24.4;
HRMS (TOFꢀES+) m/z: [M+Na]+ calcd for C22H20NO3NaCl 404.1029, found 404.1011; HPLC
analysis: (CHIRALCEL ADꢀH, 10% iꢀpropanol/hexanes, 1.0 mL/min, UV: 254 nm), tR = 8.8 min
(minor), 13.3 min (major).
(R)ꢀ4ꢀbenzylꢀ2ꢀ(4ꢀchlorophenyl)ꢀ4ꢀ((S)ꢀ3ꢀoxocyclohexyl)oxazolꢀ5(4H)ꢀone 4d
White solid (55.0 mg, 0.144 mmol, yield 72%, > 20:1 dr, 87:13 er); m.p. 133ꢀ134°C; [α]D20 = +95.4
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(c = 0.5 in CH2Cl2); IR (KBr) ν 2943, 1817, 1712, 1653, 1312, 1091, 960，876 cmꢀ1; H NMR
(CDCl3, 400 MHz) δ 7.75 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.10ꢀ7.16 (m, 5H), 3.27 (d,
J = 13.2 Hz, 1H), 3.14 (d, J = 13.2 Hz, 1H), 2.41ꢀ2.53 (m, 4H), 2.26ꢀ2.32 (m, 1H), 2.12ꢀ2.20 (m,
2H), 1.60ꢀ1.72 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 209.3, 178.2, 159.7, 139.2, 133.7, 130.2,
129.2, 129.1, 128.2, 127.4, 123.7, 44.4, 44.3, 40.97, 40.93, 25.6, 24.4, 18.5; HRMS (TOFꢀES+) m/z:
[M+Na]+ calcd for C22H20NO3NaCl 404.1029, found 404.1012; HPLC analysis: (CHIRALCEL
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(major).
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(R)ꢀ4ꢀbenzylꢀ4ꢀ((S)ꢀ3ꢀoxocyclohexyl)ꢀ2ꢀ(pꢀtolyl)oxazolꢀ5(4H)ꢀone 4e
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White solid (57.8 mg, 0.160 mmol, yield 80%, > 20:1 dr, 85.5:14.5 er); m.p. 142ꢀ143 °C; [α]D
=
+90.2 (c = 0.5 in CH2Cl2); IR (KBr) ν 3404, 2962, 1814, 1710, 1656, 1444, 1178, 1045, 957, 879
cmꢀ1; 1H NMR (CDCl3, 400 MHz) δ 7.71 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.11ꢀ7.17 (m,
5H), 3.26 (d, J = 13.2 Hz, 1H), 3.13 (d, J = 13.2 Hz, 1H), 2.43ꢀ2.55 (m, 3H), 2.40 (s, 3H), 2.12ꢀ2.18
(m, 2H), 1.62ꢀ1.71 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 209.8, 178.7, 160.6, 143.5, 133.9,
130.2, 129.5, 128.2, 127.8, 127.3, 122.5, 44.5, 42.3, 41.0, 40.9, 25.6, 24.4, 21.7; HRMS (TOFꢀES+)
m/z: [M+Na]+ calcd for C23H23NO3Na 384.1576, found 384.1579; HPLC analysis: (CHIRALCEL
ADꢀH, 10% iꢀpropanol/hexanes, 1.0 mL/min, UV: 254 nm), tR = 8.9 min (minor), 14.9 min (major).
(R)ꢀ4ꢀmethylꢀ4ꢀ((S)ꢀ3ꢀoxocyclohexyl)ꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone 4f
White solid (40.2 mg, 0.148 mmol, yield 74%, > 20:1 dr, 92:8 er); m.p. 106ꢀ108°C; [α]D20 = +110.2
(c = 0.5 in CH2Cl2); IR (KBr) ν 3743, 2946, 1818, 1710, 1653, 1452, 1003, 881 cmꢀ1; H NMR
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(CDCl3, 400 MHz) δ 7.99ꢀ8.01 (m, 2H), 7.58ꢀ7.62 (m, 1H), 7.49ꢀ7.52 (m, 2H), 2.35ꢀ2.45 (m, 5H),
2.22ꢀ2.32 (m, 1H), 2.05ꢀ2.17 (m, 1H), 1.46ꢀ1.69 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ 209.7,
179.7, 160.6, 133.0, 128.9, 128.0, 125.5, 71.3, 44.9, 42.0, 40.9, 25.2, 24.4, 21.5; HRMS (TOFꢀES+)
m/z: [M+H]+ calcd for C16H18NO3 272.1287, found 272.1283; HPLC analysis: (CHIRALCEL
ASꢀH, 3.0% iꢀpropanol/hexanes, 1.0 mL/min, UV: 254 nm), tR = 17.0 min (minor), 22.7 min
(major).
(R)ꢀ4ꢀethylꢀ4ꢀ((S)ꢀ3ꢀoxocyclohexyl)ꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone 4g
Colorless oil (38.3 mg, 0.134 mmol, yield 67%, > 20:1 dr, 84.5:15.5 er); [α]D20 = +85.2 (c = 0.5 in
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CH2Cl2); IR (KBr) ν 2932, 1815, 1713, 1655, 1451, 1291, 1017 cmꢀ1; 1H NMR (CDCl3, 500 MHz):
δ 8.03 (d, J = 8.0 Hz, 2H), 7.62 (t, J = 8.0 Hz, 1H), 7.52 (t, J = 7.5 Hz, 2H), 2.34ꢀ2.45 (m, 3H),
2.32ꢀ2.44 (m, 1H), 2.11ꢀ2.16 (m, 1H), 1.91ꢀ2.06 (m, 3H), 1.49ꢀ1.68 (m, 2H), 1.30ꢀ1.35 (m, 1H),
0.86 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 209.7, 179.3, 160.8, 132.9, 128.9, 128.0,
125.4, 76.0, 44.0, 42.1, 41.0, 27.8, 25.4, 24.4, 8.0; HRMS (TOFꢀES+) m/z: [M+Na]+ calcd for
C17H19NO3Na 308.1263, found 308.1270; HPLC analysis: (CHIRALCEL ODꢀH, 10%
iꢀpropanol/hexanes, 1.0 mL/min, UV: 254 nm), tR = 6.6 min (major), 10.5 min (minor).
(R)ꢀ4ꢀ((S)ꢀ3ꢀoxocyclohexyl)ꢀ2ꢀphenylꢀ4ꢀpropyloxazolꢀ5(4H)ꢀone 4h
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Colorless oil (43.1 mg, 0.144 mmol, yield 72%, > 20:1 dr, 90:10 er); [α]D20 = +109.2 (c = 0.5 in
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CH2Cl2); IR (KBr) ν 2959, 1810, 1714, 1654, 1291, 1021, 945, 881 cmꢀ1; H NMR (CDCl3, 500
MHz) δ 8.02 (d, J = 7.5 Hz, 2H), 7.59 (t, J = 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 2H), 2.63ꢀ2.67 (m,
1H), 2.38ꢀ2.44 (m, 2H), 2.21ꢀ2.33 (m, 2H), 2.03ꢀ2.08 (m, 1H), 1.90 (td, J = 13.0, 4.5 Hz, 1H),
1.74ꢀ1.84 (m, 2H), 1.58ꢀ1.67 (m, 1H), 1.43ꢀ1.51 (m, 1H), 1.10ꢀ1.29 (m, 4H), 0.89 (t, J = 8.0 Hz,,
3H);13C NMR (CDCl3, 100 MHz) δ 210.0, 179.7, 160.6, 132.9, 128.9, 128.0, 125.5, 76.0, 44.3, 42.2,
41.1, 36.7, 25.7, 24.3, 17.0, 13.8; HRMS (TOFꢀES+) m/z: [M+Na]+ calcd for C18H21NO3Na
322.1419, found 322.1404; HPLC analysis: (CHIRALCEL ODꢀH, 10% iꢀpropanol/hexanes, 1.0
mL/min, UV: 254 nm), tR = 6.0 min (major), 9.3 min (minor).
(R)ꢀ4ꢀisopropylꢀ4ꢀ((S)ꢀ3ꢀoxocyclohexyl)ꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone 4i
Colorless oil (42.5 mg, 0.142 mmol, yield 71%, > 20:1 dr, 91:9 er); [α]D20 = +105.8 (c = 0.5 in
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CH2Cl2); IR (KBr) ν 2967, 1810, 1714, 1655, 1451, 1321, 1291, 1042, 937, 881 cmꢀ1; H NMR
(CDCl3, 500 MHz): δ 8.01ꢀ8.04 (m, 2H), 7.58ꢀ7.62 (m, 1H), 7.53ꢀ7.50 (m, 2H), 2.67ꢀ2.63 (m, 4H),
2.44ꢀ2.38 (m, 2H), 2.33ꢀ2.01 (m, 1H), 1.90 (td, J = 13, 4.5 Hz, 1H), 1.84ꢀ1.74 (m, 2H), 1.67ꢀ1.58 (m,
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1H), 1.51ꢀ1.43 (m, 1H), 1.46ꢀ1.36 (m, 1H), 1.03 (d, J = 6.8 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H);13C
NMR (CDCl3, 100 MHz) δ 210.0, 179.2, 160.8, 132.9, 128.9, 128.0, 125.4, 78.4, 41.4, 41.3, 41.1,
31.4, 25.5, 24.5, 16.6, 16.5; HRMS (TOFꢀES+) m/z: [M+Na]+ calcd for 322.1419, found 322.1407;
HPLC analysis: (CHIRALCEL ADꢀH, 10% iꢀpropanol/hexanes, 1.0 mL/min, UV: 254 nm), tR = 8.3
min (major), 13.7 min (minor).
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(R)ꢀ4ꢀisobutylꢀ4ꢀ((S)ꢀ3ꢀoxocyclohexyl)ꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone 4j
Colorless oil (42.6 mg, 0.136 mmol, yield 68%, > 20:1 dr, 94:6 er); [α]D20 = +106.2 (c = 0.5 in
CH2Cl2); IR (KBr) ν 3364, 2957, 1811, 1714, 1653, 1454, 1291, 1041, 952 cmꢀ1; 1H NMR (CDCl3,
400 MHz) δ 8.01ꢀ8.03 (m, 2H), 7.60 (td, J = 7.2, 1.2 Hz, 1H), 7.49ꢀ7.53 (m, 2H), 2.36ꢀ2.50 (m, 3H),
2.20ꢀ2.31 (m, 2H), 2.06ꢀ2.13 (m, 1H), 1.97ꢀ2.04 (m, 2H), 1.78 (dd, J = 7.2 Hz, 1H), 1.52ꢀ1.64 (m,
2H), 1.37ꢀ1.47 (m, 1H), 0.90 (d, J = 8.0 Hz, 3H), 0.85 (d, J = 8.0 Hz, 3H); 13C NMR (CDCl3, 100
MHz) δ 209.8, 179.8, 160.3, 132.9, 128.9, 128.0, 125.5, 74.8, 45.5,43.5, 41.7, 41.0, 25.3, 24.8, 24.4,
24.2, 23.1; HRMS (TOFꢀES+) m/z: [M+Na]+ calcd for C19H23NO3Na 336.1576, found 336.1585;
HPLC analysis: (CHIRALCEL ODꢀH, 10% iꢀpropanol/hexanes, 1.0 mL/min, UV: 254 nm), tR =
13.2 min (major), 14.7min (minor).
(R)ꢀ4ꢀbenzylꢀ4ꢀ((S)ꢀ3ꢀoxocyclopentyl)ꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone 4k
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White solid (44.6 mg, 0.134 mmol, yield 67%, > 20:1 dr, 61.5:38.5 er); m.p. 116ꢀ117°C; [α]D
=
+56.5 (c = 1 in CH2Cl2); IR (KBr) ν 2963, 1817, 1738, 1651, 1494, 1452, 976, 884 cmꢀ1; 1H NMR
(CDCl3, 400 MHz) δ 7.82ꢀ7.84 (m, 2H), 7.52ꢀ7.56 (m, 1H), 7.41ꢀ7.45 (m, 2H), 7.13ꢀ7.17 (m, 5H),
3.34 (d, J = 13.2 Hz, 1H), 3.16 (d, J = 13.2 Hz, 1H), 2.85ꢀ2.94 (m, 1H), 2.12ꢀ2.47 (m, 5H),
1.94ꢀ2.04 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 216.2, 178.7, 160.7, 133.9, 132.9, 130.1, 128.7,
128.2, 127.9, 127.4, 125.2, 75.9, 43.1, 41.8, 39.4, 38.2, 24.3; HRMS (TOFꢀES+) m/z: [M+Na]+
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calcd for C21H19NO3Na 356.1263, found 356.1251; HPLC analysis: (CHIRALCEL ADꢀH, 10%
iꢀpropanol/hexanes, 1.0 mL/min, UV: 254 nm), tR = 8.6 min (minor), 10.7 min (major).
(R)ꢀ4ꢀbenzylꢀ4ꢀ((R)ꢀ3ꢀoxoꢀ1ꢀphenylbutyl)ꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone 6a14a
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White solid (51.7 mg, yield 65%, > 20:1 dr, 90:10 er); m.p. 115ꢀ116°C; [α]D20 = ꢀ19.6 (c = 1 in
CH2Cl2); 1H NMR (CDCl3, 400 MHz) δ 7.69 (dd, J = 7.2, 1.2 Hz, 2H), 7.48ꢀ7.52 (m, 1H), 7.40ꢀ7.46
(m, 2H), 7.08ꢀ7.23 (m, 10H), 3.98 (dd, J = 8.4, 5.6 Hz, 1H), 3.26ꢀ3.31 (m, 3H), 3.18 (d, J = 13.2 Hz,
1H), 2.10 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 206.2, 177.9, 160.5, 138.1, 134.0, 132.6, 130.3,
129.2, 128.7, 128.3, 128.2, 127.7, 127.3, 125.5, 78.2, 46.7, 44.5, 41.9, 30.7; HPLC analysis:
(CHIRALCEL ADꢀH, 10% iꢀpropanol/hexanes, 1.0 mL/min, UV: 254 nm), tR = 8.1 min (minor),
9.9 min (major).
(R)ꢀ4ꢀbenzylꢀ2ꢀ(2ꢀchlorophenyl)ꢀ4ꢀ((R)ꢀ3ꢀoxoꢀ1ꢀphenylbutyl)oxazolꢀ5(4H)ꢀone 6b
White solid (51.8 mg, 0.120 mmol, yield 60%, 9:1 dr, 89.5:10.5 er); m.p. 116ꢀ117°C; [α]D20 = ꢀ14.4
(c = 0.5 in CH2Cl2); IR (KBr) ν 3031, 2935, 1823, 1718, 1651, 1474, 1321, 1097, 1036, 963, 888,
764 cmꢀ1; 1H NMR (CDCl3, 400 MHz) δ 7.76 (dd, J = 7.2, 1.2 Hz, 2H), 7.53 (td, J = 7.6, 1.2 Hz, 1H),
7.39ꢀ7.43 (m, 3H), 7.31 (dd, J = 7.6, 1.6 Hz, 1H), 7.06ꢀ7.16 (m, 7H), 4.73 (q, J = 4.8 Hz, 1H), 3.21
(d, J = 13.2 Hz, 1H), 3.09ꢀ3.21 (m, 3H), 2.07 (s, 3H);13C NMR (CDCl3, 100 MHz) δ 205.4, 177.3,
160.7, 136.1, 133.8, 132.7, 130.4, 130.2, 128.8, 128.7, 128.1, 127.8, 127.3, 126.7, 125.4, 45.2, 41.7,
41.3, 30.2, 30.1, 29.7; HRMS (TOFꢀES+) m/z: [M+Na]+ calcd for C26H22NO3NaCl 454.1186, found
454.1166; HPLC analysis: (CHIRALCEL ADꢀH, 10% iꢀpropanol/hexanes, 1.0 mL/min, UV:
254nm), tR = 8.1 min (minor), 14.8 min (major).
(R)ꢀ4ꢀbenzylꢀ2ꢀ(3ꢀchlorophenyl)ꢀ4ꢀ((R)ꢀ3ꢀoxoꢀ1ꢀphenylbutyl)oxazolꢀ5(4H)ꢀone 6c
Yellow oil (44.8 mg, 0.104 mmol, yield 52%, > 20:1 dr, 78.5:21.5 er); [α]D20 = ꢀ9.6 (c = 0.5 in
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CH2Cl2); IR (KBr) ν 2928, 1815, 1716, 1654, 1293, 1095, 970, 891 cmꢀ1; H NMR (CDCl3, 400
MHz) δ 7.69 (dd, J = 7.2, 1.2 Hz, 2H), 7.50 (td, J = 7.6, 1.2 Hz, 1H), 7.38 (d, J = 7.6 Hz, 2H),
7.22ꢀ7.25 (m, 1H), 7.09ꢀ7.14 (m, 8H), 3.96 (q, J = 4.4 Hz, 1H), 3.12ꢀ3.32 (m, 4H), 2.12 (s, 3H); 13C
NMR (CDCl3, 100 MHz) δ 205.6, 177.7, 160.8, 140.4, 134.0, 133.8, 132.7, 130.3, 129.6, 129.3,
128.7, 128.2, 127.9, 127.7, 127.6, 127.4, 125.3, 77.9, 46.3, 44.4, 41.8, 30.7; HRMS (TOFꢀES+) m/z:
[M+Na]+ calcd for C26H22NO3NaCl 454.1186, found 454.1174; HPLC analysis: (CHIRALCEL
ADꢀH, 10% iꢀpropanol/hexanes, 1.0 mL/min, UV: 254 nm), tR = 7.8 min (minor), 9.3 min (major).
(R)ꢀ4ꢀbenzylꢀ2ꢀ(4ꢀchlorophenyl)ꢀ4ꢀ((R)ꢀ3ꢀoxoꢀ1ꢀphenylbutyl)oxazolꢀ5(4H)ꢀone 6d
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Yellow oil (49.2 mg, 0.114 mmol, yield 57%, > 20:1 dr, 94:6 er); [α]D20 = ꢀ17.4 (c = 0.5 in CH2Cl2);
IR (KBr) ν 2925, 1815, 1712, 1650, 1493, 1319, 1095, 969, 870 cmꢀ1; 1H NMR (CDCl3, 400 MHz)
δ 7.72ꢀ7.74 (m, 2H), 7.52ꢀ7.56 (m, 1H), 7.41 (t, J = 7.6 Hz, 2H), 7.16ꢀ7.21 (m, 4H), 7.11ꢀ7.15 (m,
5H), 3.98 (q, J = 4.4 Hz, 1H), 3.16ꢀ3.34 (m, 4H), 2.13 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 205.7,
177.7, 160.7, 136.8, 133.8, 133.6, 132.7, 130.6, 130.2, 128.7, 128.5, 128.2, 127.7, 127.4, 125.3,
78.0, 46.0, 44.4, 41.9, 30.6; HRMS (TOFꢀES+) m/z: [M+Na]+ calcd for C26H22NO3NaCl 454.1186,
found 454.1182; HPLC analysis: (CHIRALCEL ADꢀH, 10% iꢀpropanol/hexanes, 1.0 mL/min, UV:
254 nm), tR = 8.2 min (minor), 11.5 min (major).
(R)ꢀ4ꢀbenzylꢀ4ꢀ((R)ꢀ3ꢀoxoꢀ1ꢀphenylbutyl)ꢀ2ꢀ(pꢀtolyl)oxazolꢀ5(4H)ꢀone 6e
20
white solid (45.2 mg, 0.110 mmol, yield 55%, > 20:1 dr, 72.5:27.5 er); m.p. 127ꢀ129°C; [α]D
=
ꢀ16.0 (c = 0.5 in CH2Cl2); IR (KBr) ν 3032, 1812, 1716, 1659, 1496, 1296, 969, 890, 772 cmꢀ1; 1H
NMR (CDCl3, 500 MHz) δ 7.73ꢀ7.74 (m, 2H), 7.51ꢀ7.54 (m, 1H), 7.39ꢀ7.43 (m, 2H), 7.11ꢀ7.16 (m,
7H), 6.98ꢀ7.00 (d, J = 8.0 Hz, 2H), 3.96 (dd, J = 8.0, 6.0 Hz, 1H), 3.18ꢀ3.33 (m, 4H), 2.24 (s, 3H),
2.11 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 206.2, 177.9, 160.5, 137.3, 135.0, 134.1, 132.5, 130.3,
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129.0, 128.6, 128.1, 127.7, 127.2, 125.6, 78.3, 46.5, 44.6, 42.0, 30.7, 21.0; HRMS (TOFꢀES+) m/z:
[M+H]+ calcd for C27H26NO3 412.1913, found 412.1897; HPLC analysis: (CHIRALCEL ADꢀH,
10% iꢀpropanol/hexanes, 1.0 mL/min, UV: 254nm), tR = 8.2 min (minor), 10.0 min (major).
(R)ꢀ4ꢀbenzylꢀ2ꢀ(4ꢀfluorophenyl)ꢀ4ꢀ((R)ꢀ3ꢀoxoꢀ1ꢀphenylbutyl)oxazolꢀ5(4H)ꢀone 6f
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Yellow oil (44.8 mg, 0.108 mmol, yield 54%, > 20:1 dr, 79.5:20.5 er); [α]D20 = ꢀ7.2 (c = 0.5 in
1
CH2Cl2); IR (KBr) ν 2923, 1811, 1714, 1658, 1510, 1229, 1160, 968, 837 cmꢀ1; H NMR (CDCl3,
400 MHz) δ 7.70 (dd, J = 7.2, 1.2 Hz, 2H), 7.48ꢀ7.52 (m, 1H), 7.36ꢀ7.40 (m, 2H), 7.17ꢀ7.21 (m, 2H),
7.08ꢀ7.12 (m, 5H), 6.81ꢀ6.87 (m, 2H), 3.97 (q, J = 4.4 Hz, 1H), 3.13ꢀ3.31 (m, 4H), 2.10 (s, 3H); 13C
NMR (CDCl3, 100 MHz) δ 205.9, 177.8, 162.1 (d, 1JCꢀF = 245 Hz), 160.7, 134.0, 133.9, 132.7, 130.8
(3J CꢀF= 8 Hz ), 130.2, 128.7, 128.2, 127.7, 127.3, 125.4, 115.2(d, 2JCꢀF = 21 Hz), 78.2, 45.9, 44.5,
41.9, 30.6, 29.7; HRMS (TOFꢀES+) m/z: [M+Na]+ calcd for C26H22NO3FNa 438.1481, found
438.1463; HPLC analysis: (CHIRALCEL ADꢀH, 10% iꢀpropanol/hexanes, 1.0 mL/min, UV: 254
nm), tR = 7.8 min (minor), 10.7 min (major).
(R)ꢀ4ꢀMethylꢀ4ꢀ((R)ꢀ3ꢀoxoꢀ1ꢀphenylbutyl)ꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone 6g14a
white solid (36.0 mg, 0.112 mmol, yield 56%, > 20:1 dr, 75.5:24.5 er); m.p. 93ꢀ94°C; [α]D20 = ꢀ84.0
(c = 0.5 in CH2Cl2); 1H NMR (CDCl3, 500 MHz) δ 7.89ꢀ7.90 (m, 2H), 7.56ꢀ7.59 (m, 1 H), 7.45ꢀ7.49
(m, 2H), 7.13ꢀ7.20 (m, 5 H), 3.81 (dd, J = 7.5, 6.5 Hz, 1H), 3.18ꢀ3.20 (m, 2H), 2.10 (s, 3 H,), 1.58 (s,
3 H); HPLC analysis: (CHIRALCEL ADꢀH, 10% iꢀpropanol/hexanes, 1.0 mL/min, UV: 254 nm), tR
= 5.9 min (minor), 7.1 min (major).
(R)ꢀ4ꢀethylꢀ4ꢀ((R)ꢀ3ꢀoxoꢀ1ꢀphenylbutyl)ꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone 6h14b
Colorless oil (45.5 mg, 0.136 mmol, yield 68%, > 20:1 dr, 86:14 er); [α]D20 = ꢀ97.2 (c = 0.5 in
CH2Cl2); 1H NMR (CDCl3, 400 MHz) δ 7.88ꢀ7.90 (m, 2 H), 7.55ꢀ7.56 (m, 1 H), 7.44ꢀ7.48 (m, 2H),
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7.13ꢀ7.19 (m, 5 H), 3.81 (t, J = 6.8 Hz, 1H), 3.15 (d, J = 6.8 Hz, 2H), 2.06 (s, 3 H), 2.00 (q, J = 7.6
Hz, 2H), 0.82 (t, J = 7.6 Hz, 3H); HPLC analysis: (CHIRALCEL ADꢀH, 10% iꢀpropanol/hexanes,
1.0 mL/min, UV: 254 nm), tR = 5.4 min (minor), 6.6 min (major).
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(R)ꢀ4ꢀ((R)ꢀ3ꢀoxoꢀ1ꢀphenylbutyl)ꢀ2ꢀphenylꢀ4ꢀpropyloxazolꢀ5(4H)ꢀone 6i14b
Colorless oil (41.8 mg, 0.120 mmol, yield 60%, > 20:1 dr, 90.5:9.5 er); [α]D20 = ꢀ120.0 (c = 0.5 in
CH2Cl2); 1H NMR (CDCl3, 400 MHz) δ 7.89ꢀ7.92 (m, 2 H), 7.56ꢀ7.61 (m, 1 H), 7.46ꢀ7.50 (m, 2H),
7.15ꢀ7.20 (m, 5 H), 3.81 (dd, J = 7.6, 6.0 Hz, 1 H), 3.17ꢀ3.19 (m, 2 H), 2.08 (s, 3 H), 1.93ꢀ1.97 (m, 2
H), 1.14ꢀ1.28 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H); HPLC analysis: (CHIRALCEL ADꢀH, 10%
iꢀpropanol/hexanes, 1.0 mL/min, UV: 254nm), tR = 5.0 min (minor), 6.2 min (major).
(R)ꢀ4ꢀisopropylꢀ4ꢀ((R)ꢀ3ꢀoxoꢀ1ꢀphenylbutyl)ꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone 6j
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white solid (39.8 mg, 0.114 mmol, yield 57%, > 20:1 dr, 97.5:2.5 er); m.p. 113ꢀ114°C; [α]D
=
ꢀ145.2 (c = 0.5 in CH2Cl2); IR (KBr) ν 2968, 1813, 1724, 1654, 1450, 1289, 923, 881 cmꢀ1; 1H NMR
(CDCl3, 500 MHz) δ 7.89ꢀ7.91 (m, 2H), 7.57ꢀ7.60 (m, 1H), 7.46ꢀ7.49 (m, 2H), 7.22ꢀ7.24 (m, 2H),
7.12ꢀ7.17 (m, 3H), 3.99 (dd, J = 11.0, 3.5 Hz, 1H), 3.28 (dd, J = 17.0, 11.5 Hz, 1H), 2.96 (dd, J =
17.0, 3.5 Hz, 1H), 2.30ꢀ2.37 (m, 1H), 2.04 (s, 3H), 1.28 (d, J = 6.5 Hz, 3H), 0.92 (d, J = 7.0 Hz, 3H);
13C NMR (CDCl3, 100 MHz) δ 206.3, 177.7, 160.6, 137.7, 132.6, 129.4, 128.7, 128.1, 127.8, 127.6,
125.6, 79.5, 44.3, 43.5, 32.1, 30.8, 17.6, 15.6; HRMS (TOFꢀES+) m/z: [M+Na]+ calcd for
C22H23NO3Na 372.1576, found 372.1563; HPLC analysis: (CHIRALCEL ADꢀH, 10%
iꢀpropanol/hexanes, 1.0 mL/min, UV: 254 nm), tR = 4.6 min (minor), 5.4 min (major).
(R)ꢀ4ꢀisobutylꢀ4ꢀ((R)ꢀ3ꢀoxoꢀ1ꢀphenylbutyl)ꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone 6k14b
Colorless oil (42.9 mg, 0.118 mmol, yield 59%, > 20:1 dr, 77:23 er); [α]D20 = ꢀ44.4 (c = 0.5 in
CH2Cl2); 1H NMR (CDCl3, 400 MHz) δ 7.89ꢀ7.92 (m, 2H), 7.57ꢀ7.61 (m, 1H), 7.47ꢀ7.51 (m, 2H),
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7.14ꢀ7.18 (m, 5H), 3.75 (dd, J = 8.0, 5.6 Hz, 1H), 3.16ꢀ3.18 (m, 2H), 2.07 (s, 3H), 2.01 (dd, J = 14.0,
6.4 Hz, 1H), 1.92 (dd, J = 14.0, 6.0 Hz, 1H), 1.48ꢀ1.58 (m, 1H), 0.88 (d, J = 6.4 Hz, 3H), 0.87 (d, J
= 6.4 Hz, 3H); HPLC analysis: (CHIRALCEL ADꢀH, 3.0% iꢀpropanol/hexanes, 1.0 mL/min, UV:
254 nm), tR = 7.5 min (minor), 9.8 min (major).
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(R)ꢀ4ꢀbenzylꢀ4ꢀ((S)ꢀ3ꢀoxoꢀ1ꢀ(thiophenꢀ2ꢀyl)butyl)ꢀ2ꢀphenyloxazolꢀ5(4H)ꢀone 6l
white solid (40.3 mg, 0.100 mmol, yield 50%, > 20:1 dr, 72:28 er); m.p. 118ꢀ119°C; [α]D20 = ꢀ6.0 (c
1
= 0.5 in CH2Cl2); IR (KBr) ν 3036, 1811, 1714, 1657, 1451, 1294, 1095, 971, 890, 775 cmꢀ1; H
NMR (CDCl3, 400 MHz) δ 7.74ꢀ7.76 (m, 1H), 7.52 (t, J = 7.2 Hz, 1H), 7.40 (t, J = 8.0 Hz, 2H),
7.10ꢀ7.14 (m, 5H), 7.06 (d, J = 4.8 Hz, 1H), 6.93 (dd, J = 3.6, 0.8 Hz, 1H), 6.83 (dd, J = 5.2, 3.6 Hz,
1H), 4.33 (q, J = 4.4 Hz, 1H), 3.17ꢀ3.30 (m, 4H), 2,12 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 205.7,
177.6, 161.4, 140.7, 133.9, 132.6, 130.2, 128.7, 128.2, 127.9, 127.4, 127.3, 126.6, 125.6, 125.3,
78.1, 45.9, 42.4, 41.7, 30.7; HRMS (TOFꢀES+) m/z: [M+Na]+ calcd for C24H21NO3SNa 426.1140,
found 426.1152; HPLC analysis: (CHIRALCEL ODꢀH, 10% iꢀpropanol/hexanes, 1.0 mL/min, UV:
254 nm), tR = 7.1 min (minor), 9.1 min (major).
General Procedure for Azlactone Opening
To a solution of the Michael adduct 4 (1eq) in CH3CN (0.1 M) was added conc. HCl (2.5 eq). Then
the stirring was maintained at room temperature until consumption of the starting material. The
solvent was removed in vacuo. And the resulting residue was purified via flash chromatography
(MeOH/DCM = 1/19) to yield the corresponding product 7.
Product 7a was prepared according to general procedure using 4a (69.4 mg, 0.2 mmol) afforded 7a
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as white solid (70.8 mg, 0.194 mmol, yield 97%, > 20:1 dr, > 99.5:0.5 er); m.p. 155ꢀ157°C; [α]D
=
+40.2 (c = 0.5 in CH2Cl2); IR (KBr) ν 3369, 2925, 2534, 1704, 1618, 1524, 1214, 1100, 886, 796
cmꢀ1; 1H NMR (DMSOꢀd6, 400 MHz) δ 7.67ꢀ7.73 (m, 3H), 7.54 (t, J = 7.6 Hz, 1H), 7.45ꢀ7.49 (m,
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2H), 7.14ꢀ7.22 (m, 3H), 7.08ꢀ7.10 (m, 2H), 3.59 (d, J = 13.6 Hz, 1H), 3.38 (d, J = 13.6 Hz, 1H),
2.44ꢀ2.60 (m, 2H), 2.32ꢀ2.40 (m, 1H), 2.16ꢀ2.20 (m, 1H), 2.10ꢀ2.11 (m, 1H), 1.99ꢀ2.03 (m, 1H),
1.40ꢀ1.48 (m, 2H), 1.23 (s, 1H); 13C NMR (DMSOꢀd6, 100 MHz) δ 210.4, 173.2, 166.6, 137.2,
135.5, 131.8, 130.3, 129.0, 128.5, 127.4, 127.0, 66.7, 44.0, 42.4, 41.1, 36.3, 26.7, 25.0; HRMS
(TOFꢀES+) m/z: [M+H]+ calcd for C22H23NO4Na 388.1525, found 388.1511; HPLC analysis:
(CHIRALCEL ADꢀH, 15% iꢀpropanol/hexanes, 1.0 mL/min, UV: 254 nm), tR = 5.8 min (major), 6.2
min (minor).
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Product 7b was prepared according to general procedure using 4b (76.2 mg, 0.2 mmol) afforded 7b
as white solid (73.6 mg, 0.184 mmol, yield 92%, > 20:1 dr, 92:8 er); m.p. 149ꢀ151°C; [α]D20 = +72.4
1
(c = 0.5 in CH2Cl2); IR (KBr) ν 3377, 2930, 2861, 1712, 1631, 1514, 1238, 868 cmꢀ1; H NMR
(DMSOꢀd6, 400 MHz) δ 7.75 (s, 1H), 7.35ꢀ7.49 (m, 3H), 7.20ꢀ7.27 (m, 5H), 3.55 (d, J = 13.2 Hz,
1H), 3.36 (d, J = 12.8 Hz, 1H), 2.55ꢀ2.61 (m, 2H), 2.29ꢀ2.38 (m, 1H), 2.15ꢀ2.20 (m, 2H), 2.00ꢀ2.02
(m, 1H), 1.40ꢀ1.42 (m, 2H), 1.24ꢀ1.28 (m, 1H); 13C NMR (DMSOꢀd6, 100 MHz) δ 211.2, 172.8,
165.3, 138.2, 137.3, 131.4, 130.5, 130.3, 130.1, 129.1, 128.2, 127.6, 126.7, 67.6, 44.3, 43.3, 41.3,
37.4, 27.0, 25.1; HRMS (TOFꢀES+) m/z: [M+H]+ calcd for C22H23NO4Cl 400.1316, found
400.1301; HPLC analysis: (CHIRALCEL ASꢀH, 25% iꢀpropanol/hexanes, 1.0 mL/min, UV: 254
nm), tR = 8.7 min (major), 10.4 min (minor).
Product 7c was prepared according to general procedure using 4j (47.0 mg, 0.15 mmol) afforded 7c
as colorless oil (47.3 mg, 0.143 mmol, yield 95%, > 20:1 dr, > 99.5:0.5 er); [α]D20 = +67.2 (c = 0.1 in
1
CH2Cl2); IR (KBr) ν 3427, 2925, 2364, 1632, 1525, 1232, 1080 cmꢀ1; H NMR (DMSOꢀd6, 500
MHz) δ 7.78ꢀ7.80 (m, 3H), 7.54ꢀ7.57 (m, 1H), 7.48ꢀ7.51 (m, 2H), 2.59ꢀ2.64 (m, 1H), 2.28ꢀ2.42 (m,
4H), 2.14ꢀ2.17 (m, 1H), 1.97ꢀ2.04 (m, 2H), 1.86 (q, J = 7.5 Hz, 1H), 1.51ꢀ1.58 (m, 1H), 1.39ꢀ1.45
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(m, 1H), 1.28ꢀ1.36 (m, 1H), 0.86 (d, J = 7.0 Hz, 3H), 0.82 (d, J = 7.0 Hz, 3H); 13C NMR (DMSOꢀd6,
100 MHz) δ 210.5, 174.5, 165.8, 135.4, 131.8, 129.0, 127.3, 79.6, 65.5, 43.5, 41.1, 26.6, 24.9, 24.6,
24.5, 23.1; HRMS (TOFꢀES+) m/z: [M+Na]+ calcd for C19H25NO4Na 354.1681, found 354.1678;
HPLC analysis: (CHIRALCEL ADꢀH, 15% iꢀpropanol/hexanes, 1.0 mL/min, UV: 254 nm), tR = 7.3
min (major), 8.0 min (minor).
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ASSOCIATED CONTENT
Supporting Information
This material is available free of charge via the internet at http://pubs.acs.org.
1H NMR and 13C NMR spectra for compounds 3f, 4aꢀ4k, 6aꢀ6l and 7aꢀ7c;
HPLC traces for compound 4aꢀ4k, 6aꢀ6l and 7aꢀ7c.
Crystallographic data of 4k in CIF format.
AUTHOR INFORMATION
Corresponding author
*Tel.: +86ꢀ731ꢀ88830833; eꢀmail: hyangchem@csu.edu.cn
†
Current address: Changjun Bilingual School, Changsha 410013, P. R. China
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge the financial support from National Natural Science Foundation of
China (21576296), and Central South University.
References:
(1) (a) Venkatraman, J.; Shankaramma, S. C.; Balaram, P. Chem. Rev. 2001, 101, 3131ꢀ3152. (b)
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Tanaka, M. Chem. Pharm. Bull. 2007, 55, 349ꢀ358.
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(2) Monn, J. A.; Valli, M. J.; Massey, S. M.; Wright, R. A.; Salhoff, C. R.; Johnson, B. G.; Howe, T.;
Alt, C. A.; Rhodes, G. A.; Robey, R. L.; Griffey, K. R.; Tizzano, J. P.; Kallman, M. J.; Helton, D. R.;
Schoepp, D. D. J. Med. Chem. 1997, 40, 528ꢀ537.
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