Development of a catalytic enantioselective conjugate addition of 1,3-dicarbonyl compounds to nitroalkenes for the synthesis of endothelin-A antagonist ABT-546. Scope, mechanism, and further application to the synthesis of the antidepressant rolipram

Article abstract of DOI:10.1021/ja026788y

The enantioselective synthesis of endothelin-A antagonist ABT-546 has been accomplished via the discovery and development of a highly selective catalytic asymmetric conjugate addition of ketoesters to nitroolefins. Employing just 4 mol % bis(oxazoline)-Mg

Full text of DOI:10.1021/ja026788y

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SUPPORTING INFORMATION
Experimental.
1
Experimental Procedures, Analytical Instrumentation and Data. H NMR spectra
were recorded on GE QE-300 (300 MHz) and Bruker AMX-400 (400 MHz)
spectrometers. Chemical shifts are reported in parts per million (ppm) down field from
TMS as an internal standard. Data are reported as follows: chemical shift, multiplicity
(s=singlet, d=doublet, t=triplet, q=quartet, dd=doublets of doublets, m=multiplet,
br=broad), coupling constant(s), integration and peak assignment. 13C NMR spectra were
recorded on a GE QE-300 (75 MHz) and Bruker AMX-400 (100 MHz) spectrometers
using broad band proton decoupling. Chemical shifts are reported in parts per million
(ppm) down field from TMS, using the middle resonance of CDCl3 (77.0 ppm) as an
internal standard. Mass spectra were acquired on a Joel JMS-SX-102 spectrometer.
HPLC analyses were carried out on Hewlett-Packard system model 1100. Rotations and
elemental analysis were performed by Robertson Microlit Laboratories, Inc., Madison,
New Jersey.
Typical Procedure for Enantioselective Michael Addition of 1 to 2: Mg(OTf)2*4H2O
(19.6 mg, 0.05 mMol, 0.05 equiv.) and ligand 6 (20.1 mg, 0.055 mMol, 0.055 equiv.) are
combined in the reaction flask. 1 mL of CHCl3 (hydrocarbon stabilized) is added and the
mixture is stirred for 0.5-1h. 4 mL of CHCl3 is added, followed by 200 mg of 4A
molecular sieves, and the resulting mixture is stirred for an additional 90 min. Following
this, nitrostyrene 2 (1 mMol, 1 equiv.) is added, followed by ketoester 1 (1.2 mMol, 1.2

S2
equiv.) and N-methylmorpholine (6.6 µL, 0.06 mMol, 0.06 equiv.). Conversion and
selectivity are determined by HPLC analysis. After the reaction is complete, 15 mL of
hexane is added and stirred for 20 min. The solid is filtered off and the wet cake is
washed with MTBE (5 mL). The combined filtrate is washed with 5 mL of aqueous
H3PO4 (5%) and 5mL of brine, then dried over MgSO4. The drying reagent is filtered and
the solution is concentrated under reduced pressure. The product is purified by
chromatography on silica gel using hexane/EtOAc (v. 80/20).
Ligands screened in the asymmetric conjugate addition reaction.
Me Me
O
O
O
O
O
O
O
O
O
O
O
O
N
N
N
N
N
N
N
N
N
N
6
80% ee
40% ee
Me Me
28% ee
43% ee
Me Me
45% ee
Me Me
Me Me
O
O
O
O
O
O
O
O
Ph
Ph Ph
Ph
N
N
N
N
N
N
N
N
N
N
N
N
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph Me3C
CMe3 Me2HC
CHMe2
77% ee
44% ee
36% ee
< 5% ee
32% ee
35% ee
Ligand Preparation
Parent Ligand 9:21a A reaction vessel equipped with overhead stirrer, thermometer,
and condenser, and N2 inlet is charged with diethyl malonimidate dihydrochloride (1.527
kg, 6.61 mol). 14.5 L of dry THF is added, and once stirring is commenced,
aminoindanol (1.793 kg, 12.02 mol) is added and washed in with 0.5 L of THF. The
o
reaction is heated to 45–55 C, until remaining aminoindanol is less than 10% by area
(HPLC), and subsequent readings 30 min apart indicate a drop of less than 0.5 area%.

S3
o
When the reaction is complete (4 h), the temperature is adjusted to < 5 C. 0.5 N
aqueous sodium bicarbonate [48 kg, 24 mol, prepared by dissolving 2.52 kg of NaHCO3
(30 mol) in 61.5 kg of water] is added at such a rate that the internal temperature remains
below 15 oC. The temperature is again brought to < 5 oC. By HPLC, <0.1 mg/mL of the
product remains in the liquors. The product is filtered, and thoroughly washed twice with
water (9 kg then 7.5 kg). The filter cake is dried in vacuo to yield 1.639 kg of parent
ligand 9 (98 wt%, 1.606 kg assay, 81% yield) as a white crystalline solid.
o
o
Parent ligand 9: mp > 200 C (lit.1 207-209 C); 1H (CDCl3) δ 7.40-7.36 (m,
2H), 7.22-7.14 (m, 6H), 5.50 (d, J = 7.7 Hz, 2H), 5.27 (m, 2H), 3.32 (dd, J = 7.0, 18.0
Hz), 3.20 (m, 2H), 3.10 (dd, J = 1.5, 18.0 Hz). 13C (CDCl3) δ 161.4, 141.2, 139.2, 128.2,
25
127.1, 125.1, 124.9, 83.5, 76.6, 39.8, 28.9. [α]D25 = -271.9o (c 3.11, CHCl3) (lit.1 [α]D
=
-352.7o (c 3.0, CHCl3)).
Anal. Cacld for C21H18N2O2: C, 76.34; H, 5.49; N, 8.48. Found: C, 76.12; H,
5.60; N, 8.54.
Ligand 6:21a A round bottom flask is charged with parent ligand 9 (1.491 kg, 98 wt%,
4.422 mol) followed by 11.3 L of THF, and stirring is commenced. Dibromoethane
(0.780 L, 1.700 kg, 9.05 mol) is added. LiHMDS solution (1M in THF, 4.5 L, 4.5 mol) is
then added over 30 min. The addition is mildly exothermic, and the internal temperature
is maintained below 25 oC. Following the initial addition, the remainder of the LiHMDS
solution (7.4 L) is added over 4 h.
The following morning, HPLC analysis shows little remaining starting material (<5%).
26.2 kg of a 20% aqueous ammonium chloride solution is added: the addition is mildly

S4
exothermic, and the temperature increases slightly (23 oC). The mixture is transferred to
a 100-L cylindrical flask, and washed in with 0.5 L of THF. The aqueous layer is drawn
off, and the THF layer is washed with 29.1 kg of a 25% aqueous sodium chloride
solution. The THF layer is then dried over 3 kg of magnesium sulfate. After 2.5 h, the
mixture is filtered, and concentrated to a thick slurry. Ethanol (5 L) is added and the
reaction reconcentrated.
The ethanol content of the reaction is adjusted to 6.5 L. The slurry is heated to 55–60
oC for 25 min. The heat is turned off, and the reaction cooled to ambient, then an
ice/water bath is employed to lower the temperature to < 5 oC. The solid is collected by
filtration and dried in vacuo at 32 oC to yield 1.342 kg (1.339 kg assay, 85% yield) of the
product as a light green solid.
Ligand 6: mp = 165-166 oC; 1H (CDCl3) δ 7.47-7.44 (m, 2H), 7.28-7.22 (m, 4H),
5.53 (d, J = 8.0 Hz, 2H), 5.33 (m, 2H), 3.39 (dd, J = 6.6, 17.7 Hz, 2H), 3.20 (dd, J = 1.8,
17.8 Hz, 2H), 1.34 (m, 2H), 1.29 (m, 2H). 13C (CDCl3) δ 165.2, 141.3, 139.3, 128.0,
126.9, 125.2, 124.8, 83.2, 76.3, 39.8, 18.5, 16.0. [α]D25 = -308.8o (c 3.04, CHCl3).
Anal. Cacld for C23H20N2O2: C, 77.51; H, 5.66; N, 7.86. Found: C, 77.51; H,
5.66; N, 7.86.
Nitrostyrene 2: A vessel is charged with 5-methoxypiperonal (4.208 kg, 18.0 mol).
Acetic acid (24.0 kg) is added, followed by nitromethane (7.94 kg, 124 mol). Finally,
o
ammonium acetate (3.37 kg, 43.7 mol) is added. Heating is commenced to 90–100 C,
during the course of which, the aldehyde is observed to go into solution then the
nitrostyrene precipitates as a yellow solid.

S5
After 4.5 h, heating is stopped and the reaction stirred overnight while cooling to
ambient at which point the yellow solid is filtered. The wetcake is reslurried in 40.8 kg
of water. After stirring overnight, the product is filtered and dried in vacuo at 50 oC with
a N2 bleed.
In order to remove residual acetic acid, the following wash was employed. A round
bottom flask is charged with nitrostyrene (5.165 kg). 16.5 kg of ethyl acetate is added and
stirring is commenced. 14.5 kg of methanol is then added, and the mixture is heated to
o
45–55 C for 7 h. After cooling overnight, the solid is filtered and dried in vacuo at 57
1
oC until H NMR indicates that <0.5 mol% HOAc remains. This procedure provides
4.616 kg of nitrostyrene 2 (88% assay, 4.061 kg assay, 89% recovery). This wash was
performed in two batches. The combined yield of the two runs (corrected for purity) was
7.65 kg, which represents an 87% overall yield from 5-methoxypiperonal.
o
1
A sample was chromatographed. Nitrostyrene 2: mp > 200 C. H (DMSO-d6, 300
MHz) δ 8.11 (d, J = 13.6 Hz, 1H), 7.96 (d, J = 13.6 Hz, 1H), 7.20 (d, J = 1.5 Hz, 1H),
7.15 (d, J = 1.5 Hz, 1H), 6.02 (s, 2H), 3.78 (s, 3H). 13C (DMSO-d6, 300 MHz) δ 148.4,
142.8, 139.1, 138.0, 136.0, 124.2, 111.3, 102.5, 101.9, 56.4. Anal. Cacld for C10H9NO5:
C, 53.82; H, 4.06; N, 6.28. Found: C, 54.34; H, 3.90; N, 5.77.
Ethyl 3,3-dimethylhexanoate (11): A reaction vessel is charged with THF (25.6 L),
chlorotrimethylsilane (3.40 L, 26.5 mol), copper(I) iodide (429 g, 2.21 mol) and ethyl
3,3-dimethylacrylate (2.89 kg, 22.1 mol). The reaction mixture is stirred at room
o
temperature for 15 min, then cooled to –15 C with an ice/methanol bath. n-
Propylmagnesium chloride (2M in diethyl ether, 13.3 L, 26.6 mol) is added over about 2

S6
h with vigorous stirring such that the reaction temperature is maintained between –15 oC
and –10 oC. During the addition, the reaction mixture becomes gray, then green, blue and
o
finally black. The reaction temperature is kept below –10 C. After the addition is
finished, the reaction mixture is stirred at –15 oC to –10 oC.
When <3 area% (GC) of ethyl 3,3-dimethylacrylate remains, the reaction is slowly
quenched with 8.2 kg of 20% aqueous ammonium chloride solution while maintaining
o
o
the temperature between –15 C and 0 C. The mixture is then transferred to a vessel
equipped with a mechanical stirrer and a nitrogen inlet. The reaction mixture is stirred
under nitrogen and aqueous hydrochloric acid (1.28 L of concentrated hydrochloric acid
in 11.5 L of water) is added and stirred for 0.5 h. Separation of layers affords 32.0 kg of
a solution of 11 (11.3 wt% by GC, 3.62 kg assay, 95%) in THF which is stored at 0–10
1
oC. Ethyl 3,3-dimethylhexanoate (11): H NMR (CDCl3, 300MHz) δ 4.12 (q, J=7.0
Hz, 2H), 2.18 (s, 2H), 1.32-1.25 (m, 7H), 0.98 (s, 6H), 0.90 (m, 3H).
3,3-Dimethylhexanoic acid (12): A THF solution of ethyl 3,3-dimethylhexanoate
(11.24 kg by assay) is concentrated to a 45 weight% (11.09 kg by assay) solution then
charged to a vessel followed by ethanol (17.1 L), and a solution of 5.23 kg of sodium
hydroxide in 17.1 L of water. The resulting mixture is stirred and heated to 72oC.
After GC shows that <2 area% of ester 11 remains, the reaction mixture is cooled to
room temperature. Most of the organic solvents are removed under reduced pressure, and
the residue is slowly acidified with a solution of 22.0 L of 1:1 conc. HCl/water until the
pH of the aqueous layer = 2–3. Ethyl acetate (23.5 L) is added and the mixture is stirred
for 20 min. Following separation of layers, the aqueous layer is extracted twice with 14.7

S7
L of ethyl acetate. The EtOAc layers are combined and concentrated under reduced
pressure, then chased with dry THF (24 L) until no ethyl acetate or ethanol peaks are
observed by 1H NMR, to yield 15.4 kg of a solution of 3,3-dimethylhexanoic acid (12) in
1
THF (58.7 wt%, 9.04 kg assay, 97%). 3,3-Dimethylhexanoic acid (12): H NMR
(CDCl3, 300MHz) δ 2.08 (s, 2H), 1.32–1.25 (m, 4H), 0.98 (s, 6H), 0.90(t, J = 7.0Hz,
3H).
Ethyl 5,5-dimethyl-3-oxo-octanoate (1): A vessel is charged with ethyl malonate,
potassium salt (6.55 kg, 38.5 mol), and 22.0 L of THF. Magnesium chloride (3.66 kg,
o
38.5 mol) is added with cooling. The reaction mixture is stirred at 50 C for 5 h under
nitrogen, then allowed to cool to room temperature overnight.
A second reaction vessel is charged with 1,1’-carbonyldiimidazole (CDI, 4.87 kg, 30.0
mol) and 11 L of THF. A solution of 3,3-dimethylhexanoic acid (12) in THF (6.30 kg
solution, 3.70 kg assay, 25.7 mol) is added to the stirred reaction mixture over 30 min at
ambient temperature. After 15 additional min no starting material is observed by GC,
and the solution is transferred to the malonate salt suspension over 10 min. After the
o
addition is complete, the mixture is heated to 50 C. The reaction is monitored by GC;
after 2.5 h, < 0.5 area% of acyl imidazolide intermediate is observed. The reaction
mixture is transferred over 20 min to a vessel containing a 33% aqueous phosphoric acid
solution [10.9 kg of 85% phosphoric acid in 22 L of distilled water]. The mixture is
stirred until all of the solid dissolves then the aqueous layer is separated.
A 20% aqueous NaHSO4 solution (6.88 kg) is added to the organic solution. The
mixture is vigorously stirred until <0.5 area% of acyl imidazolide is observed by GC in

S8
the organic layer. Following separation, the organic layer is washed first with 17.3 kg of
a 20% aqueous sodium carbonate solution then with 13.75 kg of a 20% aqueous sodium
chloride solution to yield 32.43 kg of a solution of ethyl 5,5-dimethyl-3-oxo-octanoate
(1) in THF (15.91 wt%, 5.16 kg assay, 93%). Ethyl 5,5-dimethyl-3-oxo-octanoate (1):
1H NMR (CDCl3, 300 MHz) ketoester/ enolester = 4/1 δ 12.1 (br s, 0.2H enolester), 4.92
(s, 0.2H, enolester), 4.19 (q, J = 7.0 Hz, 1.6H, ketoester), 4.18(q, J = 7.0 Hz, 0.4H,
enolester), 3.40 (s, 1.6H, ketoester), 2.49 (s, 1.6H, ketoester), 2.06 (br s, 0.4H, enolester),
1.35–1.20 (m, 7H), 0.96 (s, 4.8H, ketoester), 0.95 (s, 1.2H, enolester), 0.87 (m, 3H); MS
+
(DCI/NH3) m/z 232 (M + NH4 ).
O
O
O
O
MeO
O
MeO
O
NO2
NO2
CO2Et
CO2Et
Ethyl 5,5-dimethyl-2-[2-nitro-1-(4,5-methylenedioxy-3-methoxy-phenyl)ethyl]-3-
oxooctanoate, 2: The solution of ketoester 1 in THF is turned over to CHCl3 by first
concentrating, then coevaporating with 58 L of CHCl3.
A round bottom flask is charged with Mg(OTf)2 (0.173 kg, 0.536 mol). Water (38 mL,
2.11 mol) is added over 30 min with vigorous stirring. Mixing is continued for 1 h, until
homogenization is indicated by a sample KF of 15–25 wt% water. The gray powder
Mg(OTf)2 *4 H2O is transferred to a round bottom flask. Ligand 6 (0.211 kg, 0.592 mol)
is added, followed by 13 L of chloroform. The mixture is stirred for 2 h, then diluted

S9
with 52 L of chloroform. 4A molecular sieves (2.60 kg) are added, and the reaction
stirred for a further 20 min.
Nitrostyrene 2 (2.88 kg assay, 12.85 mol) is added, followed by ketoester 1 (5.5 L, 3.33
kg assay, 15.54 mol) and N-methylmorpholine (0.080 L, 0.73 mol). The reaction is then
heated to 34–38 oC. After 19 h, chloroform is removed in vacuo to ⅓ to ½ volume. 50 L
of hexane is added, followed after 10 min by 3.03 kg of activated charcoal. After stirring
an additional 40 min the mixture is filtered and the cake washed with 15 L of 2:1
hexanes/chloroform. The resulting solution is washed with 3 kg of 5% aqueous H3PO4
then with 3 kg of water. The organic solution is concentrated under reduced pressure and
chased with 30 L of THF to remove CHCl3. The process provided 14.37 kg of a THF
solution of nitroketone 3 (32.2 wt%, 4.63 kg assay, 82%, 88% ee).
A sample was chromatographed. Nitroketone 3: mixture of diastereomers.
1
Rf=0.50(EtOAc/hexane =20:80); H (CDCl3, 300 MHz) δ 6.31 (m, 1H), 6.28 (m, 1H),
5.87 (m, 2H), 4.77–4.62 (m, 2H), 4.21–3.89 (m, 4H), 3.80 (s, 3H), 2.46 (d, J = 17.3 Hz,
0.5 H), 2.35 (d, J = 17.6 Hz, 0.5 H), 2.32 (d, J = 16.9 Hz, 0.5 H), 2.03 (d, J = 17.6 Hz, 0.5
H), 1.26–1.14 (m, 4H), 1.13–0.98 (m, 4H), 0.90 (s, 3H), 0.85–0.71 (m, 5H). MS
+
(DCI/NH3) m/z 455 (M + NH4 ); Anal. Calcd for C22H31NO8: C, 60.40; H, 7.14; N, 3.20.
Found: C, 60.07; H, 7.03; N, 2.98. HPLC conditions: Zorbax RX-C8 column 4.6 x 250
mm with solvents H2O (0.1v.% H3PO4)/MeCN (from v. 90:10 to 10:90 within 15 min.) at
o
1.5 mL/min., UV detection @210 nm, 35 C. 3: tR: 15.0, 15.2 min.; Chiral HPLC
conditions: Chiralcel AD column with hexane/i-PrOH (v. 90:10) at 1.0 mL/min., UV
detection @ 210 nm. tR: [(2S, 1’R) and (2R, 1’R)] = 6.5, 7.2 min.; [(2S, 1’S) and (2R,
1’S)] = 7.8, 8.9 min.

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Cyclic imine 13: A reactor equipped with a mechanical stirrer, a thermocouple, and
nitrogen and hydrogen inlets is purged three times with nitrogen. Raney-nickel (6.6 kg) is
washed four times with 7.5 L of water and charged to the reactor. After purging the
reactor three times with nitrogen, a solution of nitroketone 3 in THF (15.35 kg, 27.5 wt%,
4.22 kg, 9.65 mol) is charged to the reactor, followed by H3PO4 in THF (100g, 0.87 mol,
of 85 wt% H3PO4 in 4 kg of THF), and 25 kg of THF.
The reaction is stirred while the reactor is purged three times with hydrogen. The
reaction pressure is kept between 40–50 psi. During the hydrogen purge, the reaction
o
temperature increases to 30–35 C. When the temperature holds steady for 5 min, the
reaction is slowly heated to 50 oC. When HPLC indicates that <0.5 area% of nitroketone
3 remains in the reaction mixture, the reaction is cooled to room temperature. Raney-
nickel is filtered off and the catalyst is washed with 30 kg of THF under nitrogen. The
resulting THF solution of imine 13 is very air-sensitive and is carefully maintained under
a nitrogen atmosphere in preparation for the next step.
Pyrrolidine 4: The solution of imine 13 in THF is concentrated under reduced
pressure and chased with MeCN. When <0.5 area% of THF peak on GC is observed, the
solution of imine 13 in MeCN is transferred under nitrogen to a reaction vessel equipped
with mechanical stirrer, thermocouple and nitrogen inlet. 34 L of MeCN is added.
NaBH(OAc)3 (4.42 kg, 19.8 mol) is added slowly with stirring; the reaction temperature
is maintained at 10–30 oC. After the addition is complete, the suspension is cooled to 5–
o
10 C. Hydrochloric acid (2.11 L) is slowly added at a rate such that gas evolution is

S11
o
kept under control and the reaction temperature at 10–20 C. At the end of the
hydrochloric acid addition, the pH is 3–4. If the pH is above 4, extra hydrochloric acid
can added until 2<pH<4. After the addition is complete, the reaction mixture is stirred at
o
20±5 C. When the reaction is complete, potassium carbonate solution (6.33 kg of
K2CO3 in 15.0 kg of water) is added to the reaction mixture over 20 min. The rate is
adjusted to maintain the reaction temperature under 30 oC. At the end of the addition, the
pH should be >8. After the addition is complete, the reaction mixture is stirred under
nitrogen overnight. The layers are separated, yielding 42.6 kg of an MeCN solution of
pyrrolidine 4 (7.24 wt%, 3.08 kg assay, 82%, 88–90% ee). The solution is stored at 0–10
oC.
The enantiomeric excess of the free base is assayed by forming the Cbz derivative,
which is assayed by HPLC. Chiral HPLC sample preparation: 10 uL of amine solution is
diluted with 990 ul of MTBE. CbzCl (100 uL) and 10% aqueous K2CO3 are added and
shaken. 200 uL of the organic layer is diluted with 800 uL of hexane. Chiral HPLC
conditions: Chiralpak® AD column; 90/10 hexane / EtOH; flow rate 1.0 mL/min.;
210nm; retention times: Cbz-4, 8.8 min, ent-Cbz-4, 11.1 min.
Pyrrolidine 4: 1H NMR (CD3OD/300 MHz) δ 6.50 (d, J = 1.8 Hz, 1H), 6.41 (d, J = 1.5
Hz, 1H), 5.93 (s, 2H), 4.21–4.17 (m, 2H), 3.88 (s, 3H), 3.53–3.36 (m, 3H), 3.03 (dd, J =
10.3, 6.6 Hz, 1H), 2.55 (t, J = 8.8 Hz, 1H), 1.69 (dd, J = 14.3, 1.8 Hz, 1H), 1.45 (dd, J =
14.4, 9.2 Hz, 1H), 1.30–1.18 (m, 4H), 1.22 (t, J = 7.0 Hz, 3H), 0.92 (s, 6H), 0.89 (t, J =
6.6 Hz, 3H); 13C NMR (CDCl3, 300 MHz) δ 173.8, 148.9, 143.2, 137.2, 133.6, 106.7,
101.2, 100.8, 61.2, 60.8, 60.4, 56.4, 54.7, 49.9, 47.8, 45.0, 32.9, 27.5, 27.4, 17.0, 14.8,

S12
14.2; [α]D25=67.65o (c 1.00, CHCl3); MS (DCI/NH3) m/z 392 (amine+H); Anal. Cacld
for C22H33NO5: C, 67.49; H, 8.50; N, 3.58. Found: C, 67.20; H, 8.57; N, 3.54.
Pyrrolidine-tartrate salt 5: The solution of pyrrolidine 4 in MeCN (8.0 wt%, 81.1 kg,
6.50 kg assay) is concentrated to 15±2 L under reduced pressure. The residue is diluted
with 71 L of tert-butyl methyl ether and transferred to a vessel equipped with a
mechanical stirrer and a nitrogen inlet. K2CO3 solution (1.2 kg of K2CO3 in 10.8 kg of
water) is added to remove residual HOAc. The mixture is stirred vigorously until no
solids remain (about 1–2 hours). The organic layers are collected and washed twice with
water (6 L then 3 L). The MTBE solution (63.75 kg) is collected (10.22 wt %, 6.5 kg
assay).
The pyrrolidine solution is then concentrated to 15±2 L under reduced pressure. MTBE
1
is chased with MeCN until no MTBE peaks are observed by GC or H NMR (DMSO-
D6). To the resulting MeCN solution (10±1 L) is added 48.5 L of MeCN, and the
mixture is stirred for 10 min. A MeOH solution of D-tartaric acid (1.24 kg of D-tartaric
acid in 19.5 L of MeOH) is added over 10 min. The mixture is then heated to 65 oC and
o
stirred until no solid is observed. The brown solution is allowed cool to 55 C and
seeded. When precipitation has begun, the reaction is allowed to cool to room
temperature. The mixture is stirred at room temperature until <20 mg/mL product
remains in the supernatant. The white solid is collected by filtration and washed
o
sequentially with MeCN (12 L) and MTBE (12 L). The solid is dried in vacuo at 50 C
with a N2 bleed for 2 days to yield 6.4 kg of salt 5 (assay 78.5 wt% pyrrolidine, 5.02 kg
1
assay, 93.6 wt% salt, 77% yield, 96–97 % ee). Pyrrolidine-tartrate salt 5: H NMR

S13
(CD3OD, 500 MHz) δ 6.55 (s, 4H), 5.91 (s, 4H), 4.37 (s, 2H), 4.15–4.07 (m, 4H), 3.87 (s,
6H), 3.85 (m, 2H), 3.67 (dd, J = 11.1, 8.4 Hz, 2H), 3.58 (td, J = 11.0, 8.4 Hz, 2H), 3.34 (t,
J = 11.0 Hz, 2H), 2.99 (t, J = 11.0 Hz, 2H), 1.86 (dd, J = 15.2, 8.7 Hz, 2H), 1.73 (dd, J =
15.2, 2.3 Hz, 2H), 1.33–1.22 (m, 4H), 1.14 (t, J = 7.0 Hz, 6H), 0.95 (s, 6H), 0.94 (s, 6H),
13
0.91 (t, J = 6.5 Hz, 6H); C NMR (DMSO-D6, 300 MHz) δ 175.9, 171.0, 148.5, 143.1,
133.8, 133.4, 107.4, 101.4, 101.1, 90.0, 72.8, 60.5, 59.2, 58.1, 56.3, 51.4, 47.8, 44.2, 43.2,
32.4, 26.9, 26.8, 16.6, 14.8, 14.0; [α]D25 = 47.15o (c 1.00, DMSO); MS (DCI/NH3) m/z
392 (6+H); Anal. Cacld for C44H72N2O16: C, 61.79; H, 7.78; N, 3.00. Found: C, 61.72; H,
7.69; N, 2.87.
ABT-546: A flask is charged with 10L of THF and 20% aqueous K2CO3 (0.993 kg,
7.18 mol, dissolved in 4 L of water). Tartrate salt 5 (2.0 kg, 1.87 kg assay, 4.00 mol) is
added and the mixture is stirred vigorously for 1.5 h, after which all of the solid has
typically dissolved. The layers are separated, and the organic layer is assayed to contain
1.54 kg (98%) of the free base.
The THF layer is charged into a vessel and N,N-dibutylbromoacetamide (15, 1.053 kg,
3.93 mol) is added, followed by a 5% aqueous NaHCO3 solution (0.528 kg dissolved in
10 L of water). The resulting mixture is heated to reflux for 2 h, after which another
0.105 kg of acetamide 15 is added. After another 1 h, another 0.105 kg of acetamide 15
is added. Reflux is continued until HPLC analysis indicates that less than 0.5 area% of
the unalkylated pyrrolidine 4 remains (typically 5 h). The reaction is allowed to cool to
ambient overnight at which point the level of the starting material is typically less than
0.15%. The layers are separated, and the organic layer is assayed to contain 2.19 kg

S14
1
(99.4%) of the desired ester. Ester: H NMR (CDCl3, 300MHz) δ 6.60 (d, J = 1.5 Hz,
1H), 6.55 (d, J = 1.5 Hz, 1H), 5.92 (m, 2H), 4.16 (m, 2H), 3.89 (s, 3H), 3.73 (d, J = 13.7
Hz, 1H), 3.67 (m, 1H), 3.51 (dt, J = 7.7, 13.3 Hz), 3.34 (m, 1H), 3.19 (m, 1H), 3.11 (m,
1H), 2.98–2.85 (m, 2 H), 2.69 (dd, J = 5.5, 6.6 Hz), 1.68–1.43 (m, 4 H), 1.34 (m, 1H),
1.30–1.18 (m, includes t, J = 7.0 Hz, 5H), 1.15–1.09 (m, 1H), 0.97 (t, J = 7.0 Hz, 2H),
0.90–0.80 (m, 8H).
The THF solution of the ester is transferred into a reaction vessel. A 15% aqueous
NaOH solution (0.312 kg, 7.8 mol in 1.768 L of water) is added, followed by 9.27 L of
95% EtOH. The reaction is heated to reflux for 2 h, at which point HPLC analysis
o
indicates complete reaction. The reaction is cooled to 35–40 C and treated with a
solution of TsOH*H2O (1.558 kg, 8.19 mol) in 2.73 L of water. The addition is mildly
o
exothermic, and controlled so that the reaction temperature does not exceed 45 C. The
organic solvents are removed under reduced pressure, and the remaining mixture is
diluted with 9.27 L of water and extracted twice with 9.27 L of i-PrOAc. The resulting
organic layer is assayed to contain 2.06 kg (99.3%) of ABT-546.
ABT-546 tosylate salt: A solution of ABT-546 in i-PrOAc (19.555 kg, 2.018 kg
assay, assayed to contain 0.33 equiv TsOH) is concentrated under reduced pressure to 1/3
to 1/4 volume, and 6.3 L of i-PrOAc is added, followed by TsOH*H2O (0.524 kg, 0.73
equiv). Stirring is continued until the acid has dissolved. HPLC assay indicates 1.05
equiv of TsOH. The resulting solution is azeotropically dried with i-PrOAc until < 6
mol% water remains. i-PrOAc is added to achieve the target i-PrOAc content (10.1 L)
and the mixture is heated to 80 oC. 10.1 L of heptane is added over 35 min, maintaining

S15
o
the temperature at 75–85 C. Following the addition, the temperature is maintained for
50 min and the reaction is allowed to cool to ambient temperature overnight, at which
point the liquor concentration is 6.1 mg/mL. The product is isolated by filtration and
washed with 5.3 L of 3:1 heptane/ i-PrOAc. The salt is dried in vacuo at 50 oC overnight
to yield 2.458 kg of an off-white solid. HPLC analysis typically indicates 1.02–1.04
equiv TsOH. The solid is loaded into a vessel and 12.3 L of water is added. The slurry is
stirred for 3 h then filtered and washed with 4.15 L of water, and dried in vacuo at 50 oC
with a N2 bleed for two days. The process yields 2.328 kg of ABT-546 tosylate salt
o
1
(99.2 wt%, 1.00 equiv TsOH, 89% yield). ABT-546 tosylate salt: mp 185–186 C; H
NMR (CDCl3, 300MHz) δ 7.71 (d, J = 8.5 Hz, 2H), 7.10 (d, J = 8.1 Hz, 2H), 6.55 (br s,
1H), 6.39, (d, J = 1.1 Hz, 1H), 5.93 (s, 2H), 4.5–4.25 (m, 2H), 4.13 (br s, 1H), 3.96 (m,
2H), 3.70 (s, 3H), 3.60 (br s, 1H), 3.34–2.99 (m, 5H), 2.32 (s, 3H), 2.00 (m, 1H), 1.75 (m,
1H), 1.48–1.33 (m, 4H), 1.32–1.0 (m, 10 H), 0.89 (t, J = 7.0 Hz, 3H), 0.83–0.76 (m,
11H); 13C NMR (CDCl3, 300MHz) δ 173.5, 163.4, 148.9, 143.8, 142.0, 139.9, 134.6,
128.6, 126.0, 107.3, 101.5, 100.8, 90.4, 57.0, 56.4, 46.9, 45.9, 44.9, 32.7, 30.5, 29.4, 26.6,
26.4, 21.3, 20.1, 19.8, 17.0, 14.7, 13.8, 13.7. [α]D25 = 21.7o (c 3.02, CHCl3). Anal. Cacld
for C37H56N2O9S: C, 63.04; H, 8.01; N, 3.97. Found: C, 62.90; H, 8.00; N, 3.96.
Typical Procedure for Enantioselective Michael Addition of 1,3-Diacrbonyl
Compounds to Niroalkenes. Preparation of 18a: Mg(OTf)2.4H2O (19.6 mg, 0.05
mmol, 0.05 equiv) and ligand 6 (20.1 mg, 0.055 mmol, 0.055 equiv) were combined in
the reaction flask. 1 mL of CHCl3 (hydrocarbon stablized) was added and the mixture
was stirred for 0.5–1h. 4 mL of CHCl3 was added, followed by 200 mg of 4A molecular

S16
sieves, and the resulting mixture was stirred for an additional 90 min. Following this,
nitrostyrene (149 mg, 1 mmol, 1 equiv) was added, followed by ethyl acetoacetate (17,
144 mg, 1.2 mmol, 1.2 equiv) and N-methylmorpholine (6.6 µL, 0.06 mmol, 0.06 equiv).
Conversion and selectivity were determined by HPLC analysis. After the reaction was
complete, 15 mL of hexane was added and stirred for 20 min. The solid was filtered off
and the wet cake was washed with MTBE (5 mL). The combined filtrate was washed
with 5 mL of aqueous H3PO4 (5% v/v) and 5mL of brine, then dried over MgSO4. The
drying reagent was removed by filtration and the solution was concentrated under
reduced pressure. The product was purified by chromatography on silica gel using
hexane/EtOAc (v. 80/20).
By 1H NMR, Michael adducts 18a-18f of ketoesters with nitrostyrenes appear as a 1:1
mixture of two compounds with are diastereomeric at the ester-bearing stereocenter, in
addition to a varying amount of the enol tautomer. For the purposes of determining
selectivity, chiral HPLC conditions were developed which separated the four
diastereomers. In the case of 18e, the two diastereomeric compounds were separable by
reverse phase HPLC.
The absolute stereochemistry of adducts 18b and 18k was established by conversion to
known compounds (vide infra). The sense of induction of the other adducts was assigned
by analogy.
O
OH
O
NO2
NO2
NO2
CO2Et
CO2Et
CO2Et

S17
Ethyl 2-acetyl-4-nitro-3-phenylbutyrate, 18a: mixture of diastereomers and
1
enol tautomer. Rf=0.4 (EtOAc/hexane=20:80); mp. 74-76oC;. H NMR (CDCl3/300
MHz) δ 7.32-7.19(m, 5H, C6H5-), 4.85-4.74(m, 2H, -CH2NO2), 4.28-3.92(m, 4H),
{[2.32(s, 1.3H), 2.28(s, 0.4H), 2.06(s, 1.3H)], CH3CO-} {[1.29(t, J=7.0Hz, 0.4H), 1.28(t,
J=7.0Hz, 1.3H), 1.02(t, J=7.1Hz, 1.3H)], OCH2CH3}; MS (DCI/NH3) m/z 279 (M +
+
NH4 ); Anal. Calcd for C14H17NO5: C, 60.21; H, 6.13; N, 5.01. Found: C, 60.00; H, 6.10;
N, 4.78. HPLC conditions: Zorbax-XDB-C8 RX column 4.6x250mm with solvents H2O
(0.1v.% H3PO4)/MeCN (from v. 95:5 to 10:90 within 15 min.) at 1.0 mL/min., UV
detection @210 nm. 18a: tR: 12.7 min.; Chiral HPLC conditions: Chiralcel AD column
with hexane/ethanol (v. 90:10) at 0.8 mL/min., UV detection @ 210 nm. tR: [(2S, 3R)
and (2R, 3R)] = 8.4, 11.4 min.; [(2S, 3S) and (2R, 3S)]= 10.4, 13.2 min.
O
OH
CO2Bui
O
NO2
NO2
NO2
CO2Bui
CO2Bui
2’-Methylpropyl 2-acetyl-4-nitro-3-phenylbutyrate, 18b: mixture of
diastereomers and enol tautomer. Rf=0.5 (EtOAc/hexane=20:80); oil; 1H NMR
(CDCl3/300 MHz) δ 7.32-7.18(m, 5H, C6H5-), 4.90-4.74(m, 2H, -CH2NO2), 4.28-
3.90(m, 3H), 3.76-3.63(m, 1H), {[2.32(s, 1.2H), 2.28(s, 0.6H), 2.07(s, 1.2H)], CH3CO}
2.00-1.90(m, 0.5H), 1.80-1.66(m, 0.5H), {[0.96 -0.91(m, 4.5H), 0.78(d, J=6.6Hz, 1.5H)],
+
CH(CH3)2}; MS (DCI/NH3) m/z 325 (M + NH4 ) Anal. Calcd for C16H21NO5: C, 62.53;
H, 6.89; N, 4.56. Found: C, 62.25; H, 6.79 ; N, 4.35. HPLC conditions: Zorbax-XDB-
C8 RX column 4.6x250mm with solvents H2O (0.1v.% H3PO4)/MeCN (from v. 95:5 to
10:90 within 15 min.) at 1.0 mL/min., UV detection @210 nm. 18b: tR: 14.1 min.; Chiral

S18
HPLC conditions: Chiralcel AD column with hexane/ethanol (v. 90:10) at 0.8 mL/min.,
UV detection @ 210 nm. tR: [(2S, 3R) and (2R, 3R)] = 7.8, 10.3 min.; [(2S, 3S) and (2R,
3S)] = 9.2, 14.4 min.
O
O
NO2
NO2
CO2But
CO2But
1’,1’-Dimethylethyl 2-acetyl-4-nitro-3-phenylbutyrate, 18c: mixture of
1
diastereomers. Rf=0.45 (EtOAc/hexane=20:80); mp. 123-126oC;. H NMR (CDCl3/300
MHz) δ 7.35-7.16(m, 5H, Ph-), 4.90-4.64(m, 2H), 4.23-4.10(m, 1H), 4.02(d, J=9.7Hz,
0.7H), 3.93(d, J=9.5Hz, 0.3H), 2.31(s, 2.1H), 2.06(s, 0.9H), 1.48(s, 2.7H), 1.17(s, 6.3H);
+
MS (DCI/NH3) m/z 325 (M + NH4 ); Anal. Calcd for C16H21NO5: C, 62.53; H, 6.84; N,
4.51. Found: C, 62.07; H, 6.84; N, 4.51. HPLC conditions: Zorbax-XDB-C8 RX column
4.6x250mm with solvents H2O (0.1v.% H3PO4)/MeCN (from v. 95:5 to 10:90 within 15
min.) at 1.0 mL/min., UV detection @210 nm. 18c: tR: 14.1 min.; Chiral HPLC
conditions: Chiralcel AD column with hexane/ethanol (v. 90:10) at 0.8 mL/min., UV
detection @ 210 nm. tR: [(2S, 3R) and (2R, 3R)] = 8.0, 9.7 min.; [(2S, 3S) and (2R, 3S)]
= 8.9, 11.1 min.
O
O
NO2
NO2
CO2Et
CO2Et
Ethyl 4-methyl-2-(2-nitro-1-phenylethyl)-3-oxopentanoate, 18d: mixture of
diastereomers. Rf=0.5 (EtOAc/hexane=20:80); mp. 65-68oC;. 1H NMR (CDCl3/300 MHz)

S19
δ 7.31-7.19(m, 5H), 4.90-4.73(m, 2H), 4.29-4.10(m, 3H), 3.98(q, J=7.0Hz, 1H), 2.74(m,
0.5H), 2.45(m, 0.5H), 1.27(t, J=6.9Hz, 1.5H), 1.10-0.7(m, 6.0H), 0.69(d, J=6.9Hz,
+
1.5H); MS (DCI/NH3) m/z 325 (M + NH4 ); Anal. Calcd for C16H21NO5: C, 62.53; H,
6.89; N, 4.56. Found: C, 62.34 ; H, 6.93; N, 4.48. HPLC conditions: Zorbax-XDB-C8
RX column 4.6x250mm with solvents H2O (0.1v.% H3PO4)/MeCN (from v. 95:5 to
10:90 within 15 min.) at 1.0 mL/min., UV detection @210 nm. 18d: tR: 14.0 min.; Chiral
HPLC conditions: Chiralcel AD column with hexane/i-PrOH (v. 95:5) at 1.0 mL/min.,
UV detection @ 210 nm. tR: [(2S, 1’R) and (2R, 1’R)] = 7.0, 8.2 min.; [(2S, 1’S) and
(2R, 1’S)] = 9.7, 10.1 min.
O
OH
O
NO2
NO2
NO2
CO2Et
CO2Et
CO2Et
Ethyl 5,5-dimethyl-2-(2-nitro-1-phenylethyl)-3-oxooctanoate, 18e: mixture of
diastereomers and enol tautomer. Rf=0.65 (EtOAc/hexane=20:80); oil; 1H NMR
(CDCl3/300 MHz) δ 7.33-7.18(m, 5H), 4.92-4.75(m, 2H), 4.30-3.92(m, 4H), 2.56-
+
2.34(m, 2H), 1.34-0.76(m, 16H); MS (DCI/NH3) m/z 381 (M + NH4 ); Anal. Calcd for
C20H29NO5: C, 66.09; H, 8.04; N, 3.85. Found: C, 66.36; H, 8.56 ; N, 3.22. HPLC
conditions: Zorbax-XDB-C8 RX column 4.6x250mm with solvents H2O (0.1v.%
H3PO4)/MeCN (from v. 95:5 to 10:90 within 15 min.) at 1.0 mL/min., UV detection
@210 nm. 18e: tR: 16.4, 16.5 min.; Chiral HPLC conditions: Chiralcel AD column with

S20
hexane/i-PrOH (v. 95:5) at 1.0 mL/min., UV detection @ 210 nm. tR: [(2S, 1’R) and (2R,
1’R)] = 7.8, 10.4 min.; [(2S, 1’S) and (2R, 1’S)] = 9.2, 14.4 min.
O
O
OH
NO2
NO2
NO2
Ph
Ph
Ph
CO2Et
CO2Et
CO2Et
Ethyl 2-phenylcarbonyl-4-nitro-3-phenylbutyrate, 18f: The product was
purified by flash column chromatography (25% EtOAc/hexanes, Rf = 0.08), and was
obtained as a white solid (1.91 g, 83% yield). Enantiomeric excesses (ee’s) was
measured by chiral HPLC (Chiralpack AD column, 95:5 hexane/EtOH mobile phase, 1
mL/min flow rate, 210 nm). The ee was determined to be 87% for both pairs of
1
enantiomers, [α]D 25 –2.31 (c = 1.03, CHCl3). Mp 95.6 oC. H NMR (CDCl3, 400 MHz):
δ 8.04-8.02 (m, 1.4 H), 7.85-7.82 (m, 0.6 H), 7.61-7.58 (m, 0.7 H), 7.55-7.51 (m, 0.3 H),
7.49-7.45 (m, 1.4 H), 7.42-7.38 (m, 0.6 H), (7.33-7.15 (m, 5 H), 4.94-4.89 (m, 1.5 H),
4.82-4.73 (m, 1.5 H), 4.51-4.40 (m, 1 H), 4.17 (q, J = 7.2 Hz, 0.6 H), 3.90-3.82 (m, 1.4
13
H), 1.17 (t, J = 7.2 Hz, 0.9 H), 0.89 (t, J = 7.2 Hz, 2.1 H). C {1H} NMR (CDCl3, 100
MHz): δ 192.1, 167.2, 166.4, 152.0, 136.4, 135.9, 135.7, 135.5, 133.9, 133.5, 128.6(3),
128.5(9), 128.5(8), 128.4, 128.2, 128.0, 127.9(7), 127.8, 127.6, 77.9, 62.3, 62.0, 57.1,
56.5, 43.3, 43.3, 14.2, 13.9. Elemental Analysis, Calc’d: C, 66.85; H, 5.61; N, 4.10.
Found: C, 66.60; H, 5.61; N, 4.10.

S21
O
O
O
O
O
O
O
OH
O
NO2
NO2
NO2
CO2Et
CO2Et
CO2Et
MeO
MeO
MeO
Ethyl 3-Benzo[1,3]dioxol-5-yl-2-(-4-methoxy-benzoyl)-4-nitro-butyrate, 18g:
The product was purified by flash column chromatography (10% EtOAc/hexanes, Rf =
0.14), and obtained as a viscous yellow oil (2.04 g, 94% yield). Ee’s were measured by
chiral HPLC (80:20 EtOH/hexanes mobile phase, 1 mL/min flow rate, 210 nm, major
enantiomer: 14.2, 26.2 min; minor enantiomer: 16.4, 20.1 min). The ee was determined
1
to be 70% for both sets of diastereomers, [α]D 25 –19.20 (c = 1.05, CHCl3). H NMR
(CDCl3, 400 MHz): δ 8.04-8.02 (m, 1.2 H), 7.88-7.86 (m, 0.8 H), 6.95-6.92 (m, 1.2 H),
6.90-6.88 (m, 0.8 H), 6.77-6.61 (m, 3 H), 5.92 (s, 1.2 H), 5.85 (dd, J = 1.2, 4.0 Hz, 0.8
H), 4.92-4.63 (m, 3 H), 4.42-4.31 (m, 1 H), 4.21-4.14 (m, 1 H), 3.95-3.85 (m, 4 H), 1.18
(t, J = 7.0 Hz, 1.2 H), 0.97 (t, J = 7.0 Hz, 1.8 H). 13C {1H} NMR (CDCl3, 100 MHz): δ
190.2, 190.0, 167.3, 166.6, 163.9, 163.6, 147.5, 147.0, 146.8, 131.1, 130.8, 130.2, 129.6,
128.5, 128.4(7), 121.5, 121.1, 113.8, 113.7, 108.3(4), 108.3(1), 108.1, 101.1, 101.0, 78.2,
62.2, 61.9, 56.9, 56.1, 55.7, 55.6, 43.1, 14.2, 14.0. FAB HRMS: Calcd. For C21H22NO8
(M + H): 416.1345. Observed: 416.1337.
1H NMR of Ethyl 3-Benzo[1,3]dioxol-5-yl-2-(-4-methoxy-benzoyl)-4-nitro-butyrate,
18g (400 MHz, CDCl3):

S22
0.60
0.55
0.50
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
1.20
8
0.07 2.95
7
2.00
6
3.03 1.00 4.45
4
1.75
1
9
5
3
2
0
13C NMR of Ethyl 3-Benzo[1,3]dioxol-5-yl-2-(-4-methoxy-benzoyl)-4-nitro-
butyrate, 18g (400 MHz, CDCl3):

S23
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
200
150
100
50
0
EtO2C
NO2
CO2Et
Ethyl 2-carboethoxy-4-nitro-3-phenylbutyrate, 21a: Rf=0.4 (EtOAc/hexane =
20:80); mp. 55-57oC;. 1H NMR (CDCl3/300 MHz) δ 7.34-7.20(m, 5H), 4.93(dd, J=13.3,
5.1Hz, 1H), 4.85(dd, J=13.3, 9.2Hz, 1H), 4.30-4.16(m, 3H), 4.0(q, J=7.3Hz, 2H), 3.82(d,
J=9.2Hz), 1.27(t, J=7.0Hz, 3H), 1.04(t, J=7.0Hz, 3H); 13C NMR (CDCl3/75 MHz) δ
167.4, 166.8, 136.2, 128.9, 128.3, 128.0, 77.6, 62.1, 61.9, 55.0, 43.0, 14.0, 13.7; MS
(DCI/NH3) m/z 325 (M+NH3); [α]D25=7.09o (c 1.00, CHCl3); Anal. Calcd for C15H19NO6:
C, 58.24; H, 6.19; N, 4.53. Found: C, 58.18; H, 5.89; N, 4.29. HPLC conditions: Zorbax-
XDB-C8 RX column 4.6x250mm with solvents H2O (0.1v.% H3PO4)/MeCN (from v.

S24
95:5 to 10:90 within 15 min.) at 1.0 mL/min., UV detection @210 nm. 21a: tR: 13.6 min.;
Chiral HPLC conditions: Chiralcel AD column with hexane/EtOH (v. 95:5) at 1.0
mL/min., UV detection @ 210 nm. tR: (R) = 10.1 min.; (S)= 8.5 min.
Ph
EtO2C
O
Ph
O
Ph
1) NaOH, EtOH
Ra-Ni, H2
90%
NO2
EtO
O
2) TsOH, IPAC
94%
N
H
N
H
CO2Et
21a (99% ee after recrystallization)
22
23
Absolute stereochemistry of adduct 21a: The absolute stereochemistry of
adduct 21a was determined by conversion to 4-phenyl-2-pyrrolidone. The nitroester was
hydrogenated to form the lactam which was decarboxylated (1. NaOH; 2. TsOH). (R)-4-
Phenylpyrrolidinone (23) thus obtained had a rotation of [α]D25 = +35.2 (c 1.02 MeOH)
25
(lit. [α]D = -33.8 (c 0.89 MeOH) for the (S)-isomer. Meyers, A. I.; Snyder, L. J. Org.
Chem. 1993, 58, 36-42).
MeO2C
NO2
CO2Me
Methyl 2-carbomethoxy-4-nitro-3-phenylbutyrate, 21b: Rf=0.3 (EtOAc/
1
hexane = 20:80); mp. 63-65oC;. H NMR (CDCl3/300 MHz) δ 7.36-7.21(m, 5H),
4.93(dd, J=13.2, 5.5Hz, 1H), 4.85(dd, J=13.2, 8.5Hz, 1H), 4.25(td, J=8.8, 5.5Hz, 1H),
3.87(d, J=8.8Hz, 1H), 3.76(s, 3H), 3.56(s, 3H); 13C NMR (CDCl3/75 MHz) δ 167.8,
167.2, 136.1, 129.0, 128.4, 127.8, 77.4, 54.7, 53.0, 52.8, 42.9; ; [α]D25=4.40o (c 1.02,
CHCl3); Anal. Calcd for C13H15NO6: C, 55.51; H, 5.38; N, 4.98. Found: C, 55.50; H,
5.38; N, 4.89. HPLC conditions: Zorbax-XDB-C8 RX column 4.6x250mm with solvents

S25
H2O (0.1v.% H3PO4)/MeCN (from v. 95:5 to 10:90 within 15 min.) at 1.0 mL/min., UV
detection @210 nm. 21b: tR: 12.3 min.; Chiral HPLC conditions: Chiralcel AD column
with hexane/i-PrOH (v. 90:10) at 1.0 mL/min., UV detection @ 210 nm. tR: (R) = 15.3
min.; (S)= 11.8 min.
PriO2C
NO2
CO2Pri
1-Methylethyl
2-(1-methylethoxycarbo)-4-nitro-3-phenylbutyrate,
21c:
1
Rf=0.5 (EtOAc/hexane=20:80); mp. 53-55oC;. H NMR (CDCl3/300 MHz) δ 7.34-
7.22(m, 5H), 5.09(m, 1H), 4.93(dd, J=12.9, 4.8Hz, 1H), 4.87-4.79(m, 2H), 4.20(td, J=8.8,
4.8Hz, 1H), 3.78(d, J=9.6Hz), 1.24(d, J=6.2Hz, 6H), 1.07(d, J=6.2Hz, 3H), 1.01(d,
13
J=6.6Hz, 3H); C NMR (CDCl3/75 MHz) δ 167.0, 166.3, 136.3, 128.8, 128.2, 128.1,
+
77.9, 69.9, 69.5, 55.1, 42.9, 21.6, 21.4, 21.2; MS (DCI/NH3) m/z 267 (M + NH4 );
[α]D25=8.17o (c 1.01, CHCl3); Anal. Calcd for C17H23NO6: C, 60.52; H, 6.87; N, 4.15.
Found: C, 60.45; H, 6.74; N, 4.05. HPLC conditions: Zorbax-XDB-C8 RX column
4.6x250mm with solvents H2O (0.1v.% H3PO4)/MeCN (from v. 95:5 to 10:90 within 15
min.) at 1.0 mL/min., UV detection @210 nm. 21c: tR: 14.7 min.; Chiral HPLC
conditions: Chiralcel AD column with hexane/i-PrOH (v. 90:10) at 1.0 mL/min., UV
detection @ 210 nm. tR: (R) = 15.2 min.; (S)= 8.1 min.

S26
BnO2C
NO2
CO2Bn
Phenylmethyl 2-(1-carbophenylmethoxy)-4-nitro-3-phenylbutyrate, 21d: Rf
1
= 0.6 (20% EtOAc/hexanes); H NMR (CDCl3/300 MHz) δ 7.35-7.23 (m, 11H), 7.18-
7.15 (m, 2H), 7.10-7.06 (m, 2H), 5.18 (d, J = 12.1 Hz, 1H), 5.14 (d, J = 12.1 Hz, 1H),
4.94 (s, 2H), 4.85-4.83 (m, 2H), 4.25 (ddd, J = 6.2, 7.7, 8.8 Hz, 1H), 3.94, (d, J = 9.2 Hz);
13C NMR (CDCl3/75 MHz) δ 167.1, 166.5, 136.0, 134.7, 134.6, 129.0, 128.6, 128.5,
128.5, 128.4, 128.3, 128.3, 127.9, 77.4, 67.8, 67.6, 55.0, 42.9; [α]D25 = -4.82o (c 1.03,
CHCl3); Anal. Calcd for C25H23NO6: C, 69.27; H, 5.35; N, 3.23. Found: C, 68.65; H,
5.25; N, 3.24; Chiral HPLC conditions: Chiralcel AD column with hexane/i-PrOH (v.
90:10) at 1.0 mL/min., UV detection @ 210 nm. tR: (R) = 19.8 min.; (S) = 21.2 min.
ButO2C
NO2
CO2But
1,1-Dimethylethyl
2-(1,1-dimethylethoxycarbo)-4-nitro-3-phenylbutyrate,
1
21e: Rf = 0.5 (EtOAc/hexane = 20:80); mp. 115-117oC;. H NMR (CDCl3/300 MHz) δ
7.31-7.22(m, 5H), 4.94(dd, J=12.9, 4.4Hz, 1H), 4.79(dd, J=12.9, 9.6Hz, 1H), 4.12(td,
13
J=9.7, 4.4Hz, 1H), 3.62(d, J=9.9Hz, 1H), 1.49(s, 9H), 1.25(s, 9H); C NMR (CDCl3/75
MHz) δ 166.9, 165.0, 136.5, 128.7, 128.3, 128.1, 82.8, 82.3, 78.2 , 56.4, 43.0, 27.8, 27.4;
[α]D25=3.86o (c 1.03, CHCl3); Anal. Calcd for C19H27NO6: C, 62.45; H, 7.45; N, 3.83.

S27
Found: C, 62.17; H, 7.27; N, 3.52. HPLC conditions: Zorbax-XDB-C8 RX column
4.6x250mm with solvents H2O (0.1v.% H3PO4)/MeCN (from v. 95:5 to 10:90 within 15
min.) at 1.0 mL/min., UV detection @210 nm. 21e: tR: 15.8 min.; Chiral HPLC
conditions: Chiralcel AD column with hexane/i-PrOH (v. 90:10) at 1.0 mL/min., UV
detection @ 210 nm. tR: (R) = 14.4 min.; (S) = 7.0 min.
O
O
MeO
EtO2C
NO2
CO2Et
Ethyl
2-carboethoxy-4-nitro-3-(3-methoxy-4,5-
methtylenedioxyphenyl)butyrate, 21j: Rf = 0.2 (30% EtOAc/hexanes), mp = 95-97
oC; 1H NMR (CDCl3/300 MHz) δ 6.41 (d, J = 1.8 Hz, 1H), 6.40 (d, J = 1.6 Hz, 1H), 5.95
(s, 2H), 4.88 (dd, J = 5.2, 12.9 Hz, 1H), 4.82 (dd, J = 9.0, 13.0 Hz, 1H), 4.28-4.18 (m,
2H), 4.16-4.04 (m, 3H), 3.87 (s, 3H), 3.77 (d, J = 9.2 Hz, 1H), 1.28 (t, J = 7.2 Hz), 1.13
13
(t, J = 7.2 Hz); C NMR (CDCl3/75 MHz) δ 167.3, 166.6, 149.1, 143.5, 135.0, 130.4,
108.0, 101.7, 101.6, 77.7, 62.1, 61.8, 56.5, 54.9, 42.9, 13.9, 13.8; MS (DCI/NH3) m/z 401
(M + NH4 ); [α]D25=3.63o (c 1.02, CHCl3); Anal. Calcd for C17H21NO9: C, 53.26; H,
+
5.52; N, 3.65. Found: C, 52.99; H, 5.41; N, 3.47.

S28
O
O
EtO2C
NO2
CO2Et
Ethyl 2-carboethoxy-4-nitro-3-(4,5-methtylenedioxyphenyl)butyrate, 21k: Rf
o
= 0.3 (30% EtOAc/hexanes), mp = 82-84 C; 1H NMR (CDCl3/300 MHz) δ 6.75-6.67
(m, 3H), 5.95 (s, 2H), 4.88 (dd, J = 4.8, 12.9 Hz, 1H), 4.79 (dd, J = 9.2, 12.9 Hz, 1H),
4.26-4.18 (m, 2H), 4.17-4.11 (m, 1H), 4.06 (q, J = 7.0 Hz, 2H), 3.75 (d, J = 9.2 Hz, 1H),
13
1.27 (t, J = 7.4 Hz, 3H), 1.12 (t, J = 7.0 Hz, 3H); C NMR (CDCl3/75 MHz) δ 167.4,
166.7, 148.0, 147.5, 129.7, 121.5, 108.5, 108.3, 101.2, 77.8, 62.1, 61.9, 55.0, 42.7, 14.0,
+
13.8 ppm; MS (DCI/NH3) m/z 371 (M + NH4 ); [α]D25=4.85o (c 1.01, CHCl3); Anal.
Calcd for C16H19NO8: C, 54.39; H, 5.42; N, 3.96. Found: C, 54.37; H, 5.33; N, 3.69.
MeO
EtO2C
OMe
NO2
CO2Et
Ethyl 2-carboethoxy-4-nitro-3-(2,6-dimethoxyphenyl)butyrate, 21l: Rf=0.4
1
(EtOAc/hexane=20:80); oil;. H NMR (CDCl3/300 MHz) δ 7.21(t, J=8.3Hz, 1H), 6.51(d,
J=8.4Hz, 2H), 5.08-4.96(m, 1H), 4.93(d, J=8.4Hz, 1H), 4.84(dd, J=11.8, 4.8Hz, 1H),
4.30-4.16(m, 3H), 3.92-3.81(m, 3H), 3.83(s, 6H), 1.29(t, J=7.0Hz, 3H), 0.94(t, J=7.2Hz,
13
3H); C NMR (CDCl3/75 MHz) δ 168.3, 167.2, 158.8, 129.6, 112.4, 104.2, 76.6, 61.8,
+
61.2, 55.8, 52.5, 33.2, 14.0, 13.6; MS (DCI/NH3) m/z 387 (M + NH4 ); [α]D25=14.10o (c
1.00, CHCl3); HPLC conditions: Zorbax-XDB-C8 RX column 4.6x250mm with solvents

S29
H2O (0.1wt% H3PO4)/MeCN (from v. 95:5 to 10:90 within 15 min.) at 1.0 mL/min., UV
detection @210 nm. 21l: tR: 13.6 min.; Chiral HPLC conditions: Chiralcel AD column
with hexane/i-PrOH (v. 95:5) at 1.0 mL/min., UV detection @ 210 nm. tR: (R) = 6.6
min.; (S)= 5.9 min. Anal. Calcd for C17H23NO8: C, 55.28; H, 6.28; N, 3.79. Found: C,
55.15; H, 6.18; N, 3.60.
F
EtO2C
NO2
CO2Et
Ethyl 2-carboethoxy-4-nitro-3-(4-fluorophenyl)butyrate, 21m: Rf=0.6
1
(EtOAc/hexane=20:80); oil;. H NMR (CDCl3/300 MHz) δ 7.31-7.22(m, 2H), 7.04-
6.98(m, 2H), 4.93(dd, J=13.2, 4.87Hz, 1H), 4.82(dd, J=12.9, 9.6Hz, 1H), 4.29-4.16(m,
3H), 4.06(q, J=7.4Hz, 2H), 3.82(d, J=9.5Hz, 1H), 1.25(t, J=7.0Hz, 3H), 1.06(t, J=7.0hz,
3H); 13C NMR (CDCl3/300 MHz) δ 167.1, 166.5, 163.9, 160.6, 132.0, 131.9, 129.8,
129.7, 115.8, 115.5, 77.5, 62.0, 61.7, 54.7, 42.1, 13.7, 13.5; MS (DCI/NH3) m/z 345 (M +
+
NH4 ); [α]D25=6.60o (c 1.03, CHCl3); Anal. Calcd for C15H18FNO6: C, 55.04; H, 5.54; N,
4.28; F, 5.80. Found: C, 55.12; H, 5.61; N, 4.17; F, 6.05. HPLC conditions: Zorbax-
XDB-C8 RX column 4.6x250mm with solvents H2O (0.1v.% H3PO4)/MeCN (from v.
95:5 to 10:90 within 15 min.) at 1.0 mL/min., UV detection @210 nm. 21m: tR: 13.6
min.; Chiral HPLC conditions: Chiralcel AD column with hexane/EtOH (v. 90:10) at 1.0
mL/min., UV detection @ 210 nm. tR: (R) = 16.8 min.; (S)= 12.2 min.

S30
O
EtO2C
NO2
CO2Et
Ethyl 2-carboethoxy-3-(2-furyl)-4-nitro-butyrate, 21n: 1H NMR (CDCl3/300
MHz) δ 7.35 (dd, J=1.8, 0.7Hz, 1H), 6.29 (dd, J=3.3, 1.8Hz, 1H), 6.22 (dt, J=3.3, 0.8 Hz,
1H), 4.39 (td, J=7.8, 5.2Hz, 1H), 4.22 (q, J=6.9Hz, 2H), 4.15 (q, J=7.3Hz, 2H), 3.90 (d,
13
J=8.0Hz, 1H), 1.27 (t, J=7.0Hz, 3H), 1.20 (t, J=7.3Hz, 3H) ppm; C NMR (CDCl3/300
MHz) δ 167.1, 166.5, 163.9, 160.6, 132.0, 131.9, 129.8, 129.7, 115.8, 115.5, 77.5, 62.0,
61.7, 54.7, 42.1, 13.7, 13.5 ppm; [α]D25= -4.04o (c 1.03, CHCl3); Anal. Cacld for
C13H17NO7: C, 52.17; H, 5.73; N, 4.68. Found: C, 52.23; H, 5.79; N, 4.60. Chiral HPLC
conditions: Chiralcel AD column with hexane/EtOH (v. 90:10) at 1.0 mL/min., UV
detection @ 210 nm. tR: (R) = 7.6 min.; (S)= 8.1 min.
EtO2C
NO2
CO2Et
Ethyl 2-carboethoxy-3-(nitromethyloctanoate, 21o: Rf=0.5 (EtOAc/hexane =
1
20:80); oil; H NMR (CDCl3/300 MHz) δ 4.71(dd, J=13.3, 4.8Hz, 1H), 4.54(dd, J=13.3,
7.0Hz, 1H), 4.23(q, J=7.0Hz, 2H), 4.22(q, J=7.0Hz, 2H), 3.63(d, J=5.9Hz, 1H), 3.02-
2.91(m, 1H), 1.50-1.30(m, 8H), 1.28(t, J=7.0Hz, 6H), 0.88(t, J=6.6Hz, 3H); 13C NMR
(CDCl3/300 MHz) δ 170.0, 167.8, 77.00, 61.9, 61.7, 52.6, 36.9, 31.4, 30.0, 26.2, 22.3,
+
14.0, 13.9; MS (DCI/NH3) m/z 321 (M + NH4 ); [α]D25=4.82 (c 1.00, CHCl3); Anal.
Calcd for C14H25NO6: C, 55.53; H, 8.31; N, 4.62;. Found: C, 55.65; H, 8.16; N, 4.64.