Palladium-catalyzed regio-, diastereo-, and enantioselective allylation of nitroalkanes with monosubstituted allylic substrates

Article abstract of DOI:10.1021/jo400663d

Pd-catalyzed asymmetric allylic alkylation of nitroalkanes and monosubstituted allylic substrates was performed to afford products with two adjacent chiral centers and with excellent regio-, diastereo-, and enantioselectivities. The usefulness of the protocol in organic synthesis was demonstrated by transformation of the product to an optically active homoallylamine, a 2,3-disubstituted tetrahydropyridine, and an α,β-disubstituted amino acid derivative.

Full text of DOI:10.1021/jo400663d

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Article
Palladium-Catalyzed Regio-, Diastereo-, and Enantio-selective
Allylation of Nitroalkanes with Monosubstituted Allylic Substrates
Xiao-Fei Yang, Wei-Hua Yu, Chang-Hua Ding, Qiu-Ping Ding,
Shi-Li Wan, Xue-Long Hou, Li-Xin Dai, and Pin-Jie Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400663d • Publication Date (Web): 06 Jun 2013
Downloaded from http://pubs.acs.org on June 11, 2013
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Palladium-Catalyzed Regio-, Diastereo-, and Enantio-selective Allylation of
Nitroalkanes with Monosubstituted Allylic Substrates
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Xiao-Fei Yang,† Wei-Hua Yu,§ Chang-Hua Ding,† Qiu-Ping Ding,§ Shi-Li Wan,†
Xue-Long Hou,*,†,‡ Li-Xin Dai,† and Pin-Jie Wang†
‡
†State Key Laboratory of Organometallic Chemistry, Shanghai–Hong Kong Joint
Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 345 Lingling Road, Shanghai 200032, China,
§College of Chemistry and Chemical Engineering, Jiangxi Normal University, 99
Ziyang Road, Nanchang 330022, China
xlhou@sioc.ac.cn
Table of Contents Graphic
ABSTRACT: Pd-catalyzed asymmetric allylic alkylation of nitroalkanes and
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monosubstituted allylic substrates was performed to afford products with two adjacent
chiral centers, with excellent regio-, diastereo-, and enantio-selectivities. The
usefulness of the protocol in organic synthesis was demonstrated by transformation of
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the product to an optically active homoallylamine,
a
2,3-disubstituted
tetrahydropyridine, and an α,β-disubstituted amino acid derivative.
INTRODUCTION
Nitroalkanes are important in organic synthesis because they are readily available, and
nitro groups can be easily transformed into various other functionalities.1 To date,
many strategies have been documented for the synthesis of chiral nitro compounds
with one or two chiral centers,2 but there is still a need to develop protocols for the
synthesis of chiral nitro compounds with different functional groups. Pd-catalyzed
asymmetric allylic alkylation (AAA) is one of the most important reactions in
asymmetric catalysis because one or two chiral centers can be easily installed in
products, with high functionality tolerance.3 This reaction has also been used for the
reaction of nitroalkanes with allylic substrates.4,5a However, these reactions have
some limitations: symmetrically 1,3-disubstituted cyclic allylic substrates are usually
used in the reactions4b–h and there have been few reports of the use of monosubstituted
allylic substrates; there have been even fewer reports of the successful construction of
two chiral centers in the products, with control of diastereoselectivity.4d Regio-,
diastereo-, and enantio-selective transition-metal-catalyzed allylic alkylations of
nitroalkanes with monosubstituted allylic substrates therefore remain to be explored.
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Recently, we achieved regio- and enantio-selective Pd-catalyzed allylic alkylation of
nitromethane in the presence of a ferrocene-based chiral ligand, SIOCPhox.6h Based
on this and other results that we have obtained,6 we describe here Pd-catalyzed
enantioselective allylic alkylation of nitroalkanes with monosubstituted allylic
substrates, furnishing the desired nitro compounds containing two vicinal stereogenic
centers with high regio-, diastereo-, and enantio-selectivities. The usefulness of the
protocol in organic synthesis is also revealed by transformation of the product to
homoallylamine, β-amino acid, and disubstituted tetrahydropyridine derivatives with
two chiral centers.
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Results and discussion
Our initial studies focused on the reaction of nitroethane with cinnamyl carbonate.
Using DABCO as the base and (Sc,Rphos,Ra)-L1 as the ligand, the reaction in
dichloromethane after 8 h gave branched and linear products in a ratio of 95:5.
Although the diastereomeric ratio (dr) of 2a was low, namely 75:25, the
enantioselectivity was excellent. Encouraged by this result, an investigation of the
impact of various parameters on the reaction was conducted (Table 1). The dr
changed from 75:25 to 81:19, whereas the enantioselectivity was unchanged, when
the reaction was run in THF (entry 2). The dr value increased further to 91:9 when the
reaction temperature was lowered from rt to 0 °C (entry 3). The reaction hardly
proceeded at −20 °C (entry 4). The reaction was accelerated significantly by addition
of a small amount of a polar solvent, DMSO (0.1 mL). The reaction was complete in
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10 h, and provided the products in high yields with excellent regio-, diastereo-, and
enantio-selectivities [94% yield, 2a/3a ratio 93/7, dr 94/6 with 98% enantiomeric
excess (ee) for 2a; entry 5]. Other organic bases, such as diisopropylethylamine
(DIPEA), triethylamine (TEA), and DMAP, were screened in a mixed solvent,
THF/DMSO, but gave inferior results (entries 6–8). Other SIOCPhox ligands, shown
in Figure 1, were tested. The reaction with the ligand (Rphos,Ra)-L2 gave with a lower
dr than that obtained with (Sc,Rphos,Ra)-L1, suggesting an important role of the central
chirality on the oxazoline ring in controlling the diastereoselectivity (entry 9 vs entry
5). The configuration at the phosphorus atom controls the configuration of the product,
since product 2a, with the opposite configuration, was afforded when (Sphos,Ra)-L3
was used (entry 10 vs entry 9). Both the dr and ee are much lower with (Sphos,Ra)-L3
than with (Rphos,Ra)-L2, indicating that the chiralities in L2 are matched (entry10 vs
entry 9). The use of (Sc,Sphos,Sa)-L4 led to a lower dr and yield compared with
(Sc,Rphos,Ra)-L1, revealing that the chiralities in ligand L4 are mismatched (entry11 vs
entry 5). It is interesting that L4 still gave product 2a with excellent enantioselectivity
but the opposite configuration; this also supported the suggestion that the product’s
configuration was determined by that of the phosphorus atom of the ligand.6b
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Figure 1. P,N-Ferrocene-based SIOCPhox ligands.
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Table 1. Impact of Reaction Parameters on Pd-Catalyzed Reactions of Cinnamyl
Methyl Carbonate (1a) with Nitroethanea
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entry ligand
T
rt
rt
base
solvent
DCM
THF
2a/3ac
drc yield (%)d ee (%)e
1
2
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
DABCO
DABCO
95/5 75/25
91/9 81/19
80
68
51
<10
94
91
89
84
78
71
54
98
98
98
-
3
0 °C DABCO
-20 °C DABCO
THF
93/7
-
91/9
-
4
THF
5
0 °C DABCO THF/DMSOb 93/7
94/6
98
98
-
6
0 °C
0 °C
0 °C
DIPEA THF/DMSOb 86/14 90/10
TEA
THF/DMSOb 90/10 86/14
DMAP THF/DMSOb 91/9 88/12
7
8
96
98
–58f
–98f
9
0 °C DABCO THF/DMSOb 95/5 78/22
0 °C DABCO THF/DMSOb 93/7 49/51
0 °C DABCO THF/DMSOb 91/9 80/20
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aConditions: molar ratio 1a/DABCO/Pd2(dba)3·CHCl3/L = 100/100/2.5/5.0, 0.4 mL
b
c
of CH3CH2NO2, 2.0 mL of solvent. THF/DMSO = 20/1. Determined by GC.
dIsolated yield of products 2a and 3a. eDetermined by chiral GC. fA minus sign means
g
that the product has the opposite configuration. DCM: dichloromethane; THF:
tetrahydrofuran; DMSO: dimethylsulfoxide; DABCO: 1,4-diazabicyclo[2.2.2]octane;
DMAP: N,N-4-dimethylaminopyridine.
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The substrate scope of the Pd-catalyzed AAA reaction of nitroalkanes was
investigated under the optimized reaction conditions (Table 2). The reaction
proceeded smoothly in all cases, affording alkylation products in high yields and with
excellent regio-, diastereo-, and enantio-selectivities; the 2/3 ratio was 80–97/20–3, dr
was 83–97/17–3 for 2, and the ee value was 96–99% for 2 (except for one example,
see below). The nitroalkane structure exerted little influence on the regio-, diastereo-,
and enantio-selectivities of the reaction (entries 1–4). Nitromethylbenzene with an
acidic proton at the α-position of the NO2 group, which is prone to epimerization
under basic conditions, was a suitable nucleophile for affording products with good
diastereoselectivity (entry 5). The reaction is tolerant of various substituents at the
para, meta, or ortho positions of the phenyl group of allyl 1 (entries 6–17). The
reaction also worked well for allylic substrates with two substituents on the phenyl
ring, providing the corresponding products in excellent yields and with excellent
regio-, diastereo- and enantio-selectivities (entries 15 and 16). Allyl 1 with a furanyl
substituent was suitable for the reaction, affording the allyl product in high yield and
with excellent selectivity (entry 17). The diastereoselectivity decreased slightly when
allyl 1 with an electron-donating group was used. A chlorine atom as a substituent at
the para and meta positions and a fluorine atom at the ortho position of the phenyl
ring have negative effects on the regioselectivity (entries 9, 12, and 14). The absolute
configuration of the product 2j was assigned as (R,R) by X-ray diffraction analysis of
its derivative 4j (see Supporting Information).
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Table 2. Substrate Scope for Pd-Catalyzed Reactions of Allyl Methyl Carbonates 1
6
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8
with Nitroalkanesa
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entry 1, Ar
R
yield (%)b
95
2/3c
93/7
91/9
96/4
96/4
93/7
96/4
95/5
93/7
88/12
91/9
92/8
87/13
92/8
80/20
96/4
97/3
2, drc
2a, 94/6
2b, 96/4
2c, 97/3
2d, 95/5
2e, 83/17
2f, 97/3
2g, 96/4
2h, 96/4
2i, 93/7
ee (%)d
98
1
2
Ph
Me
Et
Ph
91
99
3
Ph
n-Pr
n-Bu
Ph
Et
93
99
4
Ph
86
99
5
Ph
69
99
6
p-CH3OC6H4
p-CH3C6H4
p-FC6H4
p-ClC6H4
p-BrC6H4
m-CH3OC6H4
m-ClC6H4
o-CH3OC6H4
o-FC6H4
94
96
7
Et
95
97
8
Et
89
98
9
Et
88
99
10
11
12
13
14
15
16
Et
92
2j, 94/6
2k, 90/10
2l, 92/8
92
Et
91
98
Et
94
98
Et
90
2m, 88/12
2n, 85/15
2o, 95/5
2p, 96/4
97
Et
89
97
m-OCH2O-pC6H4 Et
p-OCH3-m- Et
95
99
91
99
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cC5H9OC6H3
2-furanyl
17
Et
82
95/5
2q, 94/6
99
9
aConditions: molar ratio 1a/DABCO/Pd2(dba)3·CHCl3/L1 = 100/100/3/6, 0.6 mL of
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b
RCH2NO2, THF (2 mL)/DMSO (0.1mL), 0 °C, overnight. Isolated yield of products
2 and 3. cDetermined by GC. dDetermined by chiral HPLC or GC.
The α-H of nitroalkanes is acidic (the pKa values for nitroalkanes are 16–17) and
epimerization occurs easily, which may lead to the poor diastereoselectivity in
transition-metal catalyzed AAA reactions with nitroalkanes.4g,5b We observed that
epimerization was suppressed when the reaction was performed at a lower
temperature; however, the dr declined significantly if the reaction mixture was stirred
at room temperature for a long time. It was also found that the dr of the branched
product 2 could be maintained if the mixture was concentrated in vacuo below 10 °C
during work-up of the reaction product.
To demonstrate the utility of our methodology, the syntheses of optically active
homoallylamine 4b, 2,3-disubstituted tetrahydropyridine 6, and α,β-disubstituted
amino acid derivative 8 were undertaken from the common scaffold 2b (Schemes 1
and 2). The allylic alkylation product 2b was treated with activated zinc powder
followed by protection of the resulting free amine with a Boc group to afford the
protected homoallylamine 4b. Allylation of amine 4b and subsequent ring-closing
metathesis, catalyzed by a second-generation Grubbs’ catalyst, efficiently constructed
tetrahydropyridine 6 in 46% overall yield in four steps (Scheme 1).
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Scheme 1. Synthesis of 2,3-Disubstituted Tetrahydropyridine 6 using 2b
Ozonolysis of allylated 2b followed by a one-pot Pinnick oxidation and
esterification furnished ester 7 in 61% overall yield. Ester 7 was subjected to
reduction with activated zinc powder, and subsequent reductive amination gave the
α,β-disubstituted amino acid derivative 8 in 44% overall yield in five steps (Scheme
2)
Scheme 2. Synthesis of α,β-Disubstituted Amino acid Derivative 8 from 2b
CONCLUSION
We achieved Pd-catalyzed AAA of nitroalkanes and monosubstituted allylic
substrates, providing products with two chiral centers in high yields and with
excellent regio-, diastereo-, and enantio-selectivities. Epimerization of the products
with two chiral centers was suppressed by running the reaction at a lower temperature,
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with DABCO as the base. The resulting products contain two adjacent stereogenic
centers and two functional groups that can be easily elaborated to more complex
products. Further studies of extension of the protocol to other nucleophiles and
applications in organic synthesis are in progress.
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EXPERIMENTAL SECTION
General Methods. The reactions were carried out in flame-dried glassware under a
dry argon atmosphere. All solvents were purified and dried by using standard methods
prior to use. Commercially available reagents were used without further purification.
1H NMR spectra were recorded on a NMR instrument operated at 400 MHz.
Chemical shifts are reported in ppm with the solvent resonance as the internal
standard (CDCl3: δ 7.26 ppm). 13C NMR spectra were recorded on a NMR instrument
operated at 100 MHz with complete proton decoupling. Chemical shifts are reported
in ppm with the solvent resonance as the internal standard (CDCl3: δ 77.1 ppm).
Infrared spectra were recorded from thin films of pure samples. MS and HRMS were
measured in EI or ESI mode and the mass analyzer of the HRMS was TOF. Thin
layer chromatography was performed on pre-coated glassback plates and visualized
with UV light at 254 nm. Flash column chromatography was performed on silica gel.
Enantiomer ratios were determined by chiral GC or HPLC analysis in comparison
with authentic racemic materials.
General Experimental Procedure for Table 2.To a flame dried Schlenk tube were
added Pd2(dba)3·CHCl3 (5.2 mg, 0.005 mmol), ligand (S,Rphos,R)-SIOCPhox L1 (6.8
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mg, 0.010 mmol), freshly distilled anhydrous THF (1.0 mL) and DMSO (0.1 mL).
The resulting mixture was allowed to stir for 30 min. The methyl carbonate 1 (0.15
mmol) and DABCO (0.15 mmol) were added subsequently, then distilled anhydrous
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THF
(1.0
mL)
and
nitroalkane
(0.6
mL)
was
added.
The resulting reaction mixture was stirred at 0 ºC overnight (TLC control). After the
ratio of compound 2 and 3 and diastereoselectivity of compound 2 were determined
by GC, the volatiles were removed in vacuo. The resulting residue was purified by
flash chromatography on silica gel with petroleum ether and EtOAc as eluent to give
mixed products 2 and 3. Pure product 2 was obtained by preparative TLC and
enantioselectivity was determined by HPLC.
(3R,4R)-4-Nitropent-1-en-3-yl benzene (2a): colorless oil; 95% yield (27.2 mg),
20
1
2a/3a: 93/7, dr: 94/6, 98% ee; [α]D = -93° (c = 1.3, CHCl3); H NMR (400 MHz,
CDCl3) δ 1.35 (d, J = 6.8 Hz, 3H), 3.71 (t, J = 9.2 Hz, 1H), 4.85 (dq, J = 10.4, 6.8
Hz, 1H), 5.13 (d, J = 10.4 Hz, 1H), 5.15 (d, J = 17.2 Hz, 1H), 6.01 (ddd, J = 8.8,
10.4, 18.8 Hz, 1H), 7.18-7.20 (m, 2H), 7.25-7.38 (m, 3H); 13C NMR (75 MHz,
CDCl3) δ 17.8, 55.1, 87.5, 118.1, 127.7, 128.0, 129.2, 136.1, 138.1; MS (EI) 65(11),
77 (12), 91 (53), 105 (13), 117 (100), 129 (67), 144 (82), 165 (1), 191 (M+, 1.32);
HRMS Calcd. for C11H13NO2: 191.0946, Found: 191.0941; IR (film) 793, 866, 1018,
1089, 1260, 1452, 1549, 2917, 2962 cm-1; Chiral GC (CHIRALDEX G-BP column,
25 m × 0.25 mm × 0.12 µm, carrier gas: nitrogen ) (Injector temperature: 250 ºC,
split ratio: 60, constant column flow: 12 psi, column temperature: 60 ºC (2 min),
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60-80 ºC (1.0 ºC/min), 80-160 ºC (3 ºC/min) FID detector temperature: 250 ºC): tR =
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38.4 min (major), 38.8 min (minor).
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(3R,4R)-4-Nitrohex-1-en-3-yl benzene (2b): colorless oil; 91% yield (27.9 mg),
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2b/3b: 91/9, dr: 96/4, 99% ee; [α]D = -81° (c = 1.3, CHCl3); H NMR (300 MHz,
CDCl3) δ 0.86 (t, J = 7.2 Hz, 3H), 1.41-1.55 (m, 1H), 1.75-1.89 (m, 1H), 3.71 (t, J =
9.6 Hz, 1H), 4.67 (td, J = 10.8, 3.0 Hz, 1H), 5.13 (d, J = 10.2 Hz, 1H), 5.15 (d, J =
17.1 Hz, 1H), 6.01 (ddd, J = 9.0, 9.9, 16.8 Hz, 1H), 7.18-7.20 (m, 2H), 7.25-7.38 (m,
3H); 13C NMR (75 MHz, CDCl3) δ 10.3, 25.3, 54.4, 94.5, 118.1, 127.6, 127.9, 129.2,
136.0, 138.3; MS (EI) 77 (7), 91 (47), 105 (8), 117 (100), 129 (23), 143 (24), 158
(43), 205 (M+, 0.44); HRMS Calcd. for C12H15NO2: 205.1103, Found: 205.1104; IR
(film) 801, 1016, 1082, 1259, 1368, 1547, 2963 cm-1; Chiral GC (CHIRALDEX
G-BP column, 25 m × 0.25 mm × 0.12 µm, carrier gas: nitrogen ) (Injector
o
temperature: 250 C, split ratio: 60, constant column flow: 10 psi, column
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temperature: 50 C (2 min), 50-80 C (2.0 C /min, 40 min), FID detector
temperature: 250 oC): tR = 91.6 min (major), 92.1 min (minor).
(3R,4R)-4-Nitrohept-1-en-3-yl benzene (2c): colorless oil; 93% yield (30.5 mg),
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2c/3c: 96/4, dr: 97/3, 99% ee; [α]D = -50° (c = 0.45, CHCl3); H NMR (400 MHz,
CDCl3) δ 0.81 (t, J = 7.2 Hz, 3H), 1.19-1.37 (m, 3H), 1.83-1.86 (m, 1H), 3.70 (t, J =
10 Hz, 1H), 4.67 (td, J = 10.8, 2.4 Hz, 1H), 5.13 (d, J = 9.2 Hz, 1H), 5.15 (d, J = 16.8
Hz, 1H), 6.01 (ddd, J = 8.8, 10, 16.8 Hz, 1H), 7.18-7.19 (m, 2H), 7.25-7.31 (m, 1H),
7.34-7.38 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 13.2, 19.1, 33.8, 54.6, 92.8, 118.1,
127.6, 127.9, 129.2, 136.1, 138.4; MS (EI) 51 (5), 65 (7), 77 (7), 91 (54), 117 (100),
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129 (15), 143 (22), 172 (23), 219 (M+, 0.44); HRMS Calcd. for C13H17NO2:
219.1259, Found: 219.1253; IR(film) 700, 796, 1082, 1361, 1493, 1549, 2924, 2962
cm-1; Chiral HPLC (Chiralcel PC-2, 0.46 cm × 250 mm, n-hexane/2-propanol
100/0.5, flow rate 0.5 mL/min, UV 214 nm): tR = 15.8 min (major), 17.2 min
(minor).
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(3R,4R)-4-Nitrooct-1-en-3-yl benzene (2d): colorless oil; 86% yield (30.1 mg),
2d/3d: 96/4, dr: 95/5, 99% ee; [α]D20 = -51° (c = 0.65, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 0.78 (t, J = 7.2 Hz, 3H), 1.15-1.26 (m, 4H), 1.37-1.58 (m, 1H), 1.82-1.86
(m, 1H), 3.69 (t, J = 9.6 Hz, 1H), 4.67 (td, J = 10.8, 2.4 Hz, 1H), 5.13 (d, J = 9.6 Hz,
1H), 5.15 (d, J = 16.4 Hz, 1H), 6.01 (ddd, J = 8.8, 10, 16.8 Hz, 1H), 7.17-7.19 (m,
2H), 7.25-7.30 (m, 1H), 7.34-7.38 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 13.6, 21.8,
27.9, 31.5, 54.6, 93.0, 118.1, 127.6, 127.9, 129.2, 136.1, 138.4; MS (EI) 55 (7), 65
(5), 77 (5), 91 (50), 117 (100), 129 (14), 143 (20), 186 (18), 233 (M+, 0.01); HRMS
Calcd. for C14H19NO2: 233.1416, Found: 233.1413; IR(film) 794, 1014, 1085, 1258,
1462, 1555, 2850, 2920, 2960 cm-1; Chiral HPLC (Chiralcel PC-2, 0.46 cm × 250
mm, n-hexane/2-propanol 98/2, flow rate 0.3 mL/min, UV 230 nm): tR= 15.5 min
(major), 17.5 min (minor).
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(1S,2R)-1-Nitrobut-3-ene-1,2-diyl dibenzene (2e): white solid, mp 108-109 C,
69% yield (21.3 mg), 2e/3e: 93/7, dr: 83/17, 99% ee, [α]D20 = -32° (c = 1.26, CHCl3);
1H NMR (400 MHz, CDCl3) δ 4.40 (dd, J = 11.2, 11.6 Hz, 1H), 5.22 (d, J = 10.8 Hz,
1H), 5.26 (d, J = 17.2 Hz, 1H), 5.76 (d, J = 11.6 Hz, 1H), 6.07-6.16 (m, 1H),
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7.03-7.43 (m, 10H); C NMR (75 MHz, CDCl3) δ 54.0, 95.2, 118.4, 127.2, 128.2,
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128.4, 128.6, 128.7, 129.6, 132.4, 136.2, 137.3; MS (EI) 51 (11), 65 (8), 91 (87), 117
(100), 129 (67), 178 (9), 206 ([M-HNO2]+, 4); HRMS Calcd. for C16H14: 206.1096,
Found: 206.1098; IR(film) 697, 725, 789, 1360, 1547; Chiral HPLC (Chiralcel
AD-H, 0.46 cm × 250 mm, n-hexane/2-propanol 98/2, flow rate 0.5 mL/min, UV 214
nm): tR= 15.4 min (minor),16.2 min (major).
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1-Methoxy-4-[(3’R,4’R)-4’-nitrohex-1’-en-3’-yl]benzene (2f): colorless oil; 94%
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yield (33.1 mg), 2f/3f: 96/4, dr: 97/3, 96% ee; [α]D = -69° (c = 0.65, CHCl3); H
NMR (400 MHz, CDCl3) δ 0.86 (t, J = 7.6 Hz, 3H), 1.47-1.53 (m, 1H), 1.78-1.86 (m,
1H), 3.66 (t, J = 9.6 Hz, 1H), 3.80 (s, 3H), 4.62 (td, J = 10.8, 3.2 Hz), 5.13 (d, J =
10.4 Hz, 1H), 5.15 (d, J = 16.8 Hz, 1H), 6.01 (ddd, J = 8.8, 10.4, 16.8 Hz, 1H), 6.88
13
(d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H); C NMR (75 MHz, CDCl3) δ 10.3,
25.3, 53.4, 55.2, 94.6, 114.5, 117.7, 128.9, 130.3, 136.3, 159.0; MS (EI) 55 (5), 65
(6), 77 (12), 91 (40), 147 (100), 159 (8), 188 (27), 235 (M+, 1.4); HRMS Calcd. for
C13H17NO3: 235.1208, Found: 235.1213; IR (film) 805, 829, 1245, 1511, 1546, 1610,
2973 cm-1; Chiral HPLC (Chiralcel OJ-H, 0.46 cm × 250 mm, n-hexane/2-propanol
90/10, flow rate 0.3 mL/min, UV 230 nm): tR = 32.8 min (major), 35.3 min (minor).
1-Methyl-4-[(3’R,4’R)-4’-nitrohex-1’-en-3’-yl]benzene (2g): colorless oil; 95%
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yield (31.2 mg), 2g/3g: 95/5, dr: 96/4, 97% ee; [α]D = -77° (c = 0.76, CHCl3); H
NMR (400 MHz, CDCl3) δ 0.85 (t, J = 7.2 Hz, 3H), 1.46-1.52 (m, 1H), 1.81-1.86 (m,
1H), 2.33 (s, 3H), 3.67 (t, J = 9.6 Hz, 1H), 4.64 (td, J = 10.8, 3.2 Hz, 1H), 5.08 (d, J
= 10.4 Hz, 1H), 5.12 (d, J = 18.4 Hz, 1H), 5.98 (ddd, J = 8.4, 10, 18.8 Hz, 1H), 7.06
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(d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H); C NMR (100 MHz, CDCl3) δ 10.3,
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21.0, 25.3, 54.0, 94.6, 117.8, 127.8, 129.8, 135.3, 136.2, 137.4; MS (EI) 41 (4), 53
(4), 65 (5), 77 (9), 91 (26), 115 (23), 131 (100), 143 (12), 157 (19), 172 (33), 219
(M+, 0.99); HRMS Calcd. for C13H17NO2: 219.1259, Found: 219.1258; IR (film)
804, 815, 966, 1080, 1548, 2925, 2965 cm-1; Chiral HPLC (Chiralcel IC, 0.46 cm×
250 mm, n-hexane/2-propanol 95/5, flow rate 0.5 mL/min, UV 230 nm): tR = 12.0
min (minor), 12.9 min (major).
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1-Fluoro-4-[(3’R,4’R)-4’-nitrohex-1’-en-3’-yl]benzene (2h): colorless oil; 89%
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yield (29.8 mg), 2h/3h: 93/7, dr: 96/4, 98% ee; [α]D = -42° (c = 0.5, CHCl3); H
NMR (400 MHz, CDCl3) δ 0.87 (t, J = 7.6 Hz, 3H), 1.46-1.51 (m, 1H), 1.79-1.87 (m,
1H), 3.72 (t, J = 9.2 Hz, 1H), 4.63 (td, J = 10.8, 3.2 Hz, 1H), 5.13 (d, J = 10.8 Hz,
1H), 5.14 (d, J = 18.4 Hz, 1H), 5.97 (ddd, J = 9.2, 10, 18.8 Hz, 1H), 7.03-7.08 (m,
2H), 7.15-7.18 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 10.3, 25.4, 53.4, 94.3, 116.1
(d, J = 21 Hz), 118.3, 129.4 (d, J = 8.1 Hz), 134.1 (d, J = 3.1 Hz), 135.8, 162.1 (d, J
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= 245.4 Hz); F NMR (376 MHz) δ -114.5 (m); MS (EI) 55 (6), 65 (2), 77 (3), 83
(8), 109 (58), 115 (26), 135 (100), 147 (13), 161 (20), 176 (35), 223 (M+, 0.24);
HRMS Calcd. for C12H14NO2F: 223.1009, Found: 223.1006; IR (film) 810, 833, 862,
1015, 1223, 1259, 1509, 1548, 2927, 2963 cm-1; Chiral GC (CHIRALDEX G-BP
column, 25 m × 0.25 mm × 0.12 µm, carrier gas: nitrogen ) (Injector temperature:
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250 C, split ratio: 60, constant column flow: 12 psi, column temperature: 60 C (2
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min), 60-80 C (1.0 C/min), 80-160 C (3 C /min, 30 min) FID detector
temperature: 250 oC): tR = 42.8 min (major), 43.1 min (minor).
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1-Chloro-4-[(3’R,4’R)-4’-nitrohex-1’-en-3’-yl]benzene (2i): colorless oil, 88%
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yield (31.6 mg), 2i/3i: 88/12, dr: 93/7, 99% ee; [α]D = -78° (c = 1.42, CHCl3); H
NMR (400 MHz, CDCl3) δ 0.87 (t, J = 7.6 Hz, 3H), 1.46-1.51 (m, 1H), 1.79-1.85 (m,
1H), 3.71 (t, J = 9.6 Hz, 1H), 4.63 (td, J = 10.8, 3.2 Hz, 1H), 5.13 (d, J = 10.8 Hz,
1H), 5.14 (d, J = 17.6 Hz, 1H), 5.95 (ddd, J = 8.4, 9.6, 17.2 Hz, 1H), 7.13 (d, J = 8.4
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Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H); C NMR (100 MHz, CDCl3) δ 10.3, 25.3, 53.5,
94.1, 118.5, 129.3, 129.4, 133.5, 135.5, 136.8; MS (EI) 41 (11), 55 (12), 63 (10), 77
(13), 89 (16), 115 (100), 125 (57), 151 (91), 192 (40), 239 (M+, 0.37); HRMS Calcd.
for C12H14NO2Cl: 239.0713, Found: 239.0710; IR (film) 802, 824, 1091, 1371, 1491,
1547, 2935, 2974 cm-1; Chiral GC (CHIRALDEX G-BP column, 25 m × 0.25 mm ×
0.12 µm, carrier gas: nitrogen ) (Injector temperature: 250 oC, split ratio: 60, constant
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column flow: 10 psi, column temperature: 60 C (2 min), 60-150 C (1.0 C/min, 30
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min), 150-180 C (1 C/min) FID detector temperature: 250 C): tR = 88.4 min
(major), 89.8 min (minor).
1-Bromo-4-[(3’R,4’R)-4’-nitrohex-1’-en-3’-yl]benzene (2j): colorless oil; 92%
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yield (39.1 mg), 2j/3j: 91/9, dr: 94/6, 92% ee; [α]D = -83° (c = 1.46, CHCl3); H
NMR (400 MHz, CDCl3) δ 0.87 (t, J = 7.6 Hz, 3H), 1.44-1.51 (m, 1H), 1.78-1.87 (m,
1H), 3.69 (t, J = 10 Hz, 1H), 4.63 (td, J = 10.8, 2.8 Hz, 1H), 5.13 (d, J = 10.4 Hz,
1H), 5.14 (d, J = 16.8 Hz, 1H), 5.95 (m, 1H), 7.06 (d, J = 8.4 Hz, 2H), 7.48 (d, J =
8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 10.3, 25.3, 53.5, 94.1, 118.5, 129.3,
129.4, 133.5, 135.5, 136.8; MS (EI) 55 (9), 77 (7), 89 (9), 116 (100), 129 (35), 157
(44), 195 (17), 283 (M+, 0.97); HRMS Calcd. for C12H14NO2Br: 283.0208, Found:
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283.0209; IR (film) 801, 819, 1010, 1074, 1260, 1370, 1483, 1548, 2925 cm-1; Chiral
HPLC (Chiralcel PC-2, 0.46 cm× 250 mm, n-hexane/2-propanol 200/1, flow rate 0.3
mL/min, UV 230 nm): tR= 19.5 min (major), 21.3 min (minor).
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1-Methoxy-3-[(3’R,4’R)-4’-nitrohex-1’-en-3’-yl]benzene (2k): colorless oil; 91%
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yield (32.1 mg), 2k/3k: 92/8, dr: 90/10, 98% ee; [α]D = -93° (c = 1.35, CHCl3); H
NMR (400 MHz, CDCl3) δ 0.86 (t, J = 7.2 Hz, 3H), 1.47-1.58 (m, 1H), 1.79-1.87 (m,
1H), 3.67 (t, J = 10 Hz, 1H), 3.81 (s, 3H), 4.65 (td, J = 10.8, 3.2 Hz, 1H), 5.09-5.16
(m, 2H), 5.96 (ddd, J = 8.8, 10.4, 17.2 Hz, 1H), 6.73 (s, 1H), 6.77-6.83 (m, 2H),
7.26-7.30 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 10.3, 25.5, 54.4, 55.2, 94.4, 112.5,
114.0, 118.1, 120.1, 130.2, 135.9, 139.9, 160.1; MS (EI) 55 (14), 65 (16), 81 (30), 91
(80), 121 (62), 147 (100), 188 (21), 235 (M+, 31); HRMS Calcd. for C13H17NO3:
235.1208, Found: 235.1204; IR (film) 704, 810, 1042, 1261, 1547, 2969 cm-1; Chiral
HPLC (Chiralcel OJ-H, 0.46 cm × 250 mm, n-hexane/2-propanol 95/5, flow rate 0.5
mL/min, UV 230 nm): tR= 31.1 min (major), 35.9 min (minor).
1-Chloro-3-[(3’R,4’R)-4’-nitrohex-1’-en-3’-yl]benzene (2l): colorless oil, 94% yield
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(33.7 mg), 2l/3l: 87/13, dr: 92/8, 98% ee; [α]D = -56° (c = 0.81, CHCl3); H NMR
(400 MHz, CDCl3) δ 0.88 (t, J = 7.6 Hz, 3H), 1.45-1.52 (m, 1H), 1.80-1.88 (m, 1H),
3.70 (t, J = 9.6 Hz, 1H), 4.64 (td, J = 10.8, 3.2 Hz, 1H), 5.14 (d, J = 9.6 Hz, 1H), 5.15
(d, J = 18 Hz, 1H), 5.95 (ddd, J = 8.8, 10, 18.8 Hz, 1H), 7.07-7.09 (m, 1H), 7.19 (s,
1H), 7.29-7.32 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 10.3, 25.4, 53.9, 94.0, 118.8,
126.1, 127.9, 128.1, 130.5, 135.0, 135.3, 140.4; MS (EI) 41 (13), 55 (18), 63 (10), 77
(14), 89 (17), 115 (100), 129 (34), 151 (78), 177 (9), 192 (32), 239 (M+, 0.41); HRMS
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Calcd. for C12H14NO2Cl: 239.0713, Found: 239.0718; IR (film) 700, 806, 928, 1081,
1370, 1548, 2974 cm-1; Chiral HPLC (Chiralcel PC-2, 0.46 cm × 250 mm,
n-hexane/2-propanol 100/1, flow rate 0.3 mL/min, UV 230 nm): tR = 21.3 min (major),
24.7 min (minor).
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1-Methoxy-2-[(3’R,4’R)-4’-nitrohex-1’-en-3’-yl]benzene (2m): colorless oil; 90%
yield (31.7 mg), 2m/3m: 92/8, dr: 88/12, 97% ee; [α]D20 = -69° (c = 1.46, CHCl3); 1H
NMR (300 MHz, CDCl3) δ 0.87 (t, J = 7.5 Hz, 3H), 1.41-1.49 (m, 1H), 1.78-1.89 (m,
1H), 3.85 (s, 3H), 4.05 (t, J = 9.6 Hz, 1H), 4.94 (td, J = 10.8, 2.7 Hz, 1H), 5.09 (d, J =
10.5 Hz, 1H), 5.13 (d, J = 17.1 Hz, 1H), 6.07-6.19 (m, 1H), 6.85-6.96 (m, 2H), 7.12
13
(d, J = 7.2 Hz, 1H), 7.26 (t, J = 7.2 Hz, 1H); C NMR (100 MHz, CDCl3) δ 10.3,
25.3, 49.9, 55.3, 93.4, 111.1, 117.9, 121.1, 126.6, 128.7, 129.4, 135.4, 156.8; MS (EI)
51 (27), 65 (31), 77 (56), 91 (100), 115 (89), 147 (100), 173 (33), 188 (83), 235 (M+,
36); HRMS Calcd. for C13H17NO3: 235.1208, Found: 235.1211; IR (film) 798, 1022,
1090, 1258, 1547, 2963 cm-1; Chiral HPLC (Chiralcel PC-2, 0.46 cm × 250 mm,
n-hexane/2-propanol 100/1, flow rate 0.5 mL/min, UV 230 nm): tR = 12.1 min (major),
13.1 min (minor).
1-Fluoro-2-[(3’R,4’R)-4’-nitrohex-1’-en-3’-yl]benzene (2n): colorless oil, 89%
yield (29.8 mg), 2n/3n: 80/20, dr: 85/15, 97% ee; [α]D20 = -44° (c = 0.68, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 0.89 (t, J = 7.6 Hz, 3H), 1.46-1.53 (m, 1H), 1.83-1.92 (m,
1H), 4.02 (t, J = 9.6 Hz, 1H), 4.82 (td, J = 10.8, 3.2 Hz, 1H), 5.13 (d, J = 10.4 Hz, 1H),
5.19 (d, J = 16.8 Hz, 1H), 6.00-6.09 (m, 1H), 7.06-7.22 (m, 3H), 7.28-7.31 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 10.2, 25.4, 48.8, 93.2 (d, J = 3Hz), 116.2 (d, J = 22.3
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Hz), 119.0, 124.8 (d, J = 3.3 Hz), 125.3 (d, J = 14.5 Hz), 129.3 (d, J = 8.1 Hz), 129.6
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(d, J = 4.5 Hz), 134.4, 160.3 (d, J = 244.7 Hz); F NMR (376 MHz) δ -116.3 (m);
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MS (EI) 55 (14), 83 (10), 109 (75), 135 (100), 147 (10), 176 (25), 223 (M+, 0.41);
HRMS Calcd. for C12H14NO2F: 223.1009, Found: 223.1008; IR (film) 756, 798, 1013,
1089, 1259, 1550, 2962 cm-1; Chiral HPLC (Chiralcel OJ-H, 0.46 cm × 250 mm,
n-hexane/2-propanol 80/20, flow rate 0.5 mL/min, UV 230 nm): tR= 14.7 min (major),
16.9 min (minor).
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5-[(3’R,4’R)-4’-nitrohex-1’-en-3’-yl]benzo[d][1,3]dioxole (2o): white solid, mp
58-59 °C, 95% yield (35.5 mg), 2o/3o: 96/4, dr: 95/5, 99% ee; [α]D20 = -68° (c = 1.76,
1
CHCl3); H NMR (300 MHz, CDCl3) δ 0.85 (t, J = 7.2 Hz, 3H), 1.51-1.54 (m, 1H),
1.79-1.83 (m, 1H), 3.63 (t, J = 9.6 Hz, 1H), 4.58 (td, J = 10.8, 3.0 Hz, 1H), 5.08 (d, J
= 9.9 Hz, 1H), 5.13 (d, J = 17.1 Hz, 1H), 5.88-6.00 (m, 3H), 6.64-6,67 (m, 2H), 6.79
(d, J = 7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 10.3, 25.3, 53.9, 94.5, 101.2,
107.9, 108.8, 117.9, 121.3, 131.9, 136.0, 146.9, 148.2; MS (EI) 51 (8), 63 (7), 77 (29),
103 (56), 115 (18), 131 (100), 161 (35), 202 (24), 249 (M+, 23); HRMS Calcd. for
C13H15NO4: 249.1001, Found: 249.1005; IR (film) 796, 928, 1240, 1365, 1488, 1547,
2973 cm-1; Chiral HPLC (Chiralcel AD-H, 0.46 cm × 250 mm, n-hexane/2-propanol
98/2, flow rate 0.5 mL/min, UV 214 nm): tR = 17.1 min (minor), 18.4 min (major).
2-(Cyclopentyloxy)-1-methoxy-4-[(3’R,4’R)-4’-nitrohex-1’-en-3’-yl]benzene (2p):
20
colorless oil, 91% yield (43.6 mg), 2p/3p: 97/3, dr: 96/4, 99% ee; [α]D = -53° (c =
1
2.33, CHCl3); H NMR (400 MHz, CDCl3) δ 0.86 (t, J = 7.2 Hz, 3H), 1.49-1.55 (m,
1H), 1.62-1.65 (m, 2H), 1.79-1.95 (m, 7H), 3.62 (t, J = 10 Hz, 1H), 3.83 (s, 3H), 4.61
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(td, J = 10.4, 2.8 Hz, 1H), 4.75-4.79 (m, 1H), 5.08-5.15 (m, 2H), 5.97 (ddd, J = 8.8,
10.4, 16.8 Hz, 1H), 6.68-6.85 (m, 2H), 6.83 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 10.4, 23.9, 25.3, 32.6, 32.7, 53.7, 56.0, 80.5, 94.6, 112.3, 114.6, 117.7,
120.0, 130.5, 136.2, 147.9, 149.5; MS (EI) 55 (10), 69 (13), 91 (20), 103 (48), 131
(100), 163 (92), 204 (62), 319 (M+, 26); HRMS Calcd. for C18H25NO4: 319.1784,
Found: 319.1787; IR (film) 745, 853, 994, 1136, 1511, 1547, 2873, 2961 cm-1; Chiral
HPLC (Chiralcel IC, 0.46 cm × 250 mm, n-hexane/2-propanol 98/2, flow rate 0.5
mL/min, UV 230 nm): tR = 18.6 min (major), 19.7 min(minor).
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2-[(3’S,4’R)-4’-Nitrohex-1’-en-3’-yl]furan (2q): yellow oil, 82% yield (23.9 mg),
20
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2q/3q: 95/5, dr: 94/6, 99% ee; [α]D = -85° (c = 0.45, CHCl3); H NMR (400 MHz,
CDCl3) δ 0.91 (t, J = 7.6 Hz, 3H), 1.55-1.62 (m, 1H), 1.85-1.92 (m, 1H), 3.89 (t, J =
9.2 Hz, 1H), 4.70 (td, J = 10.4, 3.2 Hz, 1H), 5.16 (d, J = 16.8 Hz, 1H), 5.17 (d, J =
11.2 Hz, 1H), 5.95 (ddd, J = 8.8, 10.0, 17.2 Hz, 1H), 6.17 (d, J = 3.2 Hz, 1H), 6.33 (q,
J = 1.6 Hz, 1H), 7.38 (d, J = 1.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 10.2, 25.3,
47.4, 92.5, 107.8, 110.5, 119.2, 132.9, 142.4, 151.0; MS (EI) 55 (32), 65 (17), 79
(100), 91 (40), 119 (14), 148 (50), 195 (M+, 0.55); HRMS Calcd. for C10H13NO3:
195.0895, Found: 195.0896; IR (film) 736, 796, 930, 1371, 1549, 2930 cm-1; Chiral
GC (CHIRALDEX G-BP column, 25 m × 0.25 mm × 0.12 µm, carrier gas: nitrogen )
o
(Injector temperature: 250 C, split ratio: 60, constant column flow: 10 psi, column
temperature: 60 oC (2 min), 60-150 oC (2 oC/min, 2 min), 150-180 oC (3 oC /min) FID
detector temperature: 250 oC): tR = 26.5 min (major), 27.6 min (minor).
tert-Butyl [(3R,4R)-4-phenylhex-5-en-3-yl]carbamate (4b): To a EtOH (1 mL)
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solution of the compound 2b (31.5 mg, 0.15 mmol) was added an aqueous solution of
HCl (1.5 mL, 1.0 N) and activated Zinc powder (278 mg, 4.4 mmol). The resulting
solution was allowed to stir overnight at room temperature. The reaction mixture was
neutralized with saturated aqueous NaHCO3 (pH = 9) before the aqueous phase was
extracted with EtOAc (10 mL x 3). The combined organic phase was dried with
anhydrous MgSO4. After concentration under reduced pressure, the residue was
dissolved in MeOH (2.0 mL). NEt3 (64 µL, 0.45 mmol) and (Boc)2O (98 mg, 0.45
mmol) were added to the solution, and the resulting mixtures were stirred for 1 h at
room temperature. After concentration in vacuo, the residue was purified by flash
column chromatography to give product 4b as a white solid in 81% yield (33.4 mg).
mp: 78-79 oC; [α]D20 = -44° (c = 3.33, CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.86 (t,
J = 7.2 Hz, 3H), 1.07-1.15 (m, 1H), 1.47-1.52 (m, 10H), 3.25 (t, J = 8.4 Hz, 1H),
3.84-3.86 (m, 1H), 4.34 (d, J = 8.8 Hz, 1H), 5.05 (d, J = 16.4 Hz, 1H), 5.07 (d, J =
10.8 Hz, 1H), 6.02-6.11 (m, 1H), 7.19-7.22 (m, 3H), 7.28-7.33 (m, 2H); 13C NMR
(100 M Hz, CDCl3) δ 10.2, 25.6, 28.3, 55.7, 55.8, 78.9, 116.2, 126.5, 128.1, 128.5,
139.1, 141.7, 155.9; MS (ESI) 298 (M + Na)+; HRMS (ESI) Calcd for C17H25NO2:
275.1885, Found: 275.1873; IR (film) 700, 1173, 1537, 1698, 2976, 3315 cm-1.
tert-Butyl (3R,4R)-4-(4-bromophenyl)hex-5-en-3-ylcarbamate (4j): Compound 4j
was prepared with same procedure for compopund 4b. white solid, 73% yield (38.6
mg); mp: 81-82 oC; 1H NMR (400 MHz, CDCl3) δ 0.87 (t, J = 7.6 Hz, 3H), 1.12-1.13
(m, 1H), 1.43-1.51 (m, 10H), 3.25 (t, J = 8.0 Hz, 1H), 3.74-3,85 (m, 1H), 4.27-4.30
(m, 1H), 5.06 (d, J = 17.6 Hz, 1H), 5.09 (d, J = 10.8 Hz, 1H), 6.01 (ddd, J = 8.8, 10.4,
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17.2 Hz, 1H), 7.08 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 10.2, 25.6, 28.4, 55.1, 55.6, 79.1, 116.9, 120.4, 129.8, 131.6, 138.3, 140.7,
155.8; MS (ESI) 376.0886 (M + Na)+; HRMS (ESI) Calcd. for C17H24BrNNaO2:
376.0883, Found: 376.0886.
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tert-Butyl N-allyl [(3R,4R)-4-phenylhex-5-en-3-yl]carbamate (5): To a stirred
solution of 4b (66.6 mg, 0.24 mmol) in DMF (2.0 mL) was added NaH (60% in
mineral oil, 57.6 mg, 1.44 mmol) at 0 °C. After the mixture was stirred for 30 min at 0
°C, allyl bromide (62 µL, 0.72 mmol) was added. The resulting mixture was stirred
for 1 h at room temperature before quenched with water. After the aqueous layer was
extracted with ether (5 mL x 2), the combined organic layers were washed with water
(1 mL x 2) and brine, and then dried over Na2SO4. After concentration in vacuo, the
residue was purified by flash column chromatography to afford product 5 as a
colorless oil in 76% yield (57.5 mg). The 13C NMR spectrum of compound 5 was
unavailable due to conformational isomers. [α]D20 = -55° (c = 0.75, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 0.74 (t, J = 7.2 Hz, 3H), 1.22-1.28 (m, 2H), 1.47-1.53 (m, 9H),
3.26-3.89 (m, 3H), 4.24-4.54 (m, 1H), 4.94-5.22 (m, 4H), 5.86-6.06 (m, 2H),
7.15-7.38 (m, 5H); MS (EI) 57 (100), 98 (94), 117 (24), 129 (11), 142 (95), 198 (25),
315 (M+, 0.03); HRMS Calcd. for C20H29NO2: 315.2198, Found: 315.2196; IR (film)
796, 1015, 1091, 1259, 1690, 2964 cm-1.
(5R,6R)-tert-Butyl 6-ethyl-5-phenyl-5,6-dihydropyridine-1(2H)-carboxylate (6): A
solution of CH2Cl2 (1 mL) of the compound 5 (24 mg, 0.076 mmol) and the
second-generation Grubbs catalyst (4.36 mg, 0.005 mmol, 6 mol %) was degassed
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using the freeze-pump-thaw cycle. The mixture was refluxed for 2 h under Ar
atmosphere before concentrated under reduced pressure. The reside was purified by
flash column chromatography to provide product 6 as a colorless oil in 75% yield
(16.6 mg). [α]D20 = 202° (c = 0.83, CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.93 (t, J =
7.2 Hz, 3H), 1.16 (s, 9H), 1.57-1.60 (m, 1H), 1.69-1.78 (m, 1H), 3.30 (m, 1H),
3.45-3.49 (m, 1H), 4.06-4.09 (m, 1H), 4.50-4.54 (m, 1H), 5.78-5.93 (m, 2H),
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7.17-7.29 (m, 5H); C NMR (100 MHz, CDCl3) δ 10.9, 25.4, 27.9, 38.9, 45.6, 58.3,
78.9, 124.9, 125.0, 126.3, 127.8, 128.2, 143.1, 155.2; MS (EI) 57 (58), 91 (15), 130
(100), 158 (5), 231 (6), 287 (M+, 2); HRMS Calcd. for C18H25NO2: 287.1885, Found:
287.1883; IR (film) 698, 1117, 1362, 1411, 1688, 2930 cm-1;
(2R,3R)-Methyl 3-nitro-2-phenylpentanoate (7): Dry ozone was bubbled through a
solution of compound 2b (61.5 mg, 0.3 mmol) in CH2Cl2 (3.0 mL) at -78 °C until
complete comsumption of 2b (TLC control). A precooled (-78 °C) solution of
dimethylsulfide (0.3 mL) in CH2Cl2 was then added. The solution was warmed to rt
and removal of the volatiles under reduced pressure gave corresponding aldehyde. To
this crude product was added successively NaH2PO4·2H2O (102 mg, 0.65 mmol),
t
2-methyl-2-butene (0.73 mL), BuOH (2.4 mL), and H2O (0.75 mL). To the resulting
mixture was added NaClO2 (81 mg, 0.9 mmol) at 0 °C. After the reaction mixture was
stirred for 2 h, the reaction was quenched by the addition of saturated aqueous NH4Cl
(0.5 mL) and the resulting mixture was stirred for another 10 min. After the solution
was diluted with EtOAc (2 mL), the aqueous phase was extracted with EtOAc (2 mL) .
The combined organic phase was dried with anhydrous magnesium sulfate. The
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organic layer was filtered through Celite and concentrated in vacuo. The residue was
dissolved in MeOH (2 mL), to which was added 4-dimethylaminopyridine (cat.) and
dicyclohexylcarbodiimide (74.1 mg, 0.36 mmol) at 0 °C. The resulting reaction
mixture was stirred at room temperature until the disappearance of acid (TLC control).
The reaction mixture was concentrated in vacuo. The residue was purified by silica
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gel to afford 7 as a colorless oil in 61% yield (43.1 mg). [α]D = 135.7° (c = 1.75,
1
CHCl3); H NMR (400 MHz, CDCl3) δ 0.87 (t, J = 7.2 Hz, 3H), 1.57-1.68 (m, 1H),
1.70-1.76 (m, 1H), 3.65 (s, 3H), 4.27 (d, J = 11.2 Hz, 1H), 5.05-5.12 (m, 1H),
13
7.27-7.41 (m, 5H); C NMR (100 MHz, CDCl3) δ 9.1, 24.5, 52.6, 53.3, 89.2, 128.3,
128.7, 129.4, 133.2, 171.3; MS (ESI) 255.1342 (M + NH4)+; HRMS (ESI) Calcd for
C12H15NO4: 237.1001, Found: 237.1004; IR (film) 700, 806, 1258, 1548, 1733, 2960
cm-1.
(2R,3R)-Methyl 3-(benzylamino)-2-phenylpentanoate (8): To a EtOH (1 mL)
solution of the compound 7 (34 mg, 0.11 mmol) was added an aqueous solution of
HCl (1.5 mL, 1.0 N) and activated Zinc powder (278 mg, 4.4 mmol). The resulting
solution was allowed to stir overnight at room temperature. The reaction mixture was
neutralized with saturated aqueous NaHCO3 (pH = 9). The aqueous phase was
extracted with EtOAc (10 mL x 3). The combined organic phase was dried with
anhydrous MgSO4. After concentration under reduced pressure, the residue was
dissolved in MeOH (2.0 mL), to which was added benzylaldehyde (13 µL, 0.14
mmol). After the resulting mixture was stirred for 0.5 h, NaBH3CN (29 mg, 0.48
mmol) was added at 0 °C and the resulting mixture was stirred for 0.5 h. After the
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reaction was quenched by HCl (1.0 N), the mixture was extracted with CH2Cl2 (2 mL
x 2). The combined organic layers were washed with NaHCO3 (1 mL x 2) and brine,
and then dried over Na2SO4. After concentration in vacuo, the residue was purified by
flash column chromatography to afford 8 as a white solid in 73% yield (23.8 mg). mp
41-42 oC, [α]D20 = 1.8° (c = 0.57, CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.82 (t, J =
7.2 Hz, 3H), 1.10-1.21 (m, 1H), 1.43-1.48 (m, 1H), 3.29-3.34 (m, 1H), 3.63 (d, J =
10.4 Hz, 1H), 3.67 (s, 3H), 3.76 (d, J = 12.8 Hz, 1H), 3.86 (d, J = 12.8 Hz, 1H),
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7.24-7.37 (m, 10H); C NMR (100 MHz, CDCl3) δ 8.6, 22.6, 50.8, 51.8, 56.8, 60.6,
126.8, 127.4, 128.1, 128.3, 128.5, 128.7, 136.9, 140.7, 174.0; MS (ESI) 298.1801 (M
+ H)+; HRMS (ESI) Calcd for C19H24NO2: 297.1729, Found: 297.1729; IR (film) 679,
793, 1025, 1732, 2959 cm-1; Chiral HPLC (Chiralcel PA-2, 0.46 cm × 250 mm,
n-hexane/2-propanol 98/2, flow rate 0.5 mL/min, UV 230 nm): tR = 21.0 min (major),
19.1 min (minor).
ACKNOWLEDGMENTS
Financial supported by the Major Basic Research Development Program
(2011CB833300), National Natural Science Foundation of China (21272251,
21121062, 21032007), the External Cooperation Program of Chinese Academy of
Sciences, the Technology Commission of Shanghai Municipality and the Croucher
Foundation of Hong Kong.
Supporting Information
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Spectra of compounds 2a-2q, 4-8, and X-ray analysis data of 4j in cif format. This
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material is available free of charge via the Internet at http://pubs.acs.org.
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