Stereoselective catalytic hydrogenation and conjugate reduction of 4-methyl itaconate derivatives bearing a chiral auxiliary

Article abstract of DOI:10.1016/j.tet.2013.02.045

The catalytic hydrogenation of 4-methyl itaconate derivatives bearing a chiral auxiliary and their conjugate reduction with n-Bu₃SnH in the presence of Lewis acid were examined to reveal their diastereoselectivity. The homogeneous catalytic hydrogenation of 4-methyl itaconyl (1S)-(-)-2,10- camphorsultam with the Crabtree's catalyst [Ir(COD)(PCy₃)(py)]PF ₆ in CH₂Cl₂-MeOH (2:1 v/v) gave less polar (1S,2′S)-diastereomer in 84% yield, while the conjugate reduction of the α-methylene amide with n-Bu₃SnH (2 equiv) using MgI₂ (7 equiv) as an additive in CH₂Cl₂ gave more polar (1S,2′R)-diastereomer in 70% yield.

Full text of DOI:10.1016/j.tet.2013.02.045

Accepted Manuscript
Stereoselective catalytic hydrogenation and conjugate reduction of 4-methyl itaconate
derivatives bearing chiral auxiliary
Eri Kumazaki, Hajime Nagano
PII:
S0040-4020(13)00256-1
10.1016/j.tet.2013.02.045
TET 24040
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 18 December 2012
Revised Date: 12 February 2013
Accepted Date: 16 February 2013
Please cite this article as: Kumazaki E, Nagano H, Stereoselective catalytic hydrogenation and
conjugate reduction of 4-methyl itaconate derivatives bearing chiral auxiliary, Tetrahedron (2013), doi:
10.1016/j.tet.2013.02.045.
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ACCEPTED MANUSCRIPT
Stereoselective catalytic hydrogenation and conjugate reduction of 4-methyl
itaconate derivatives bearing chiral auxiliary
Eri Kumazaki and Hajime Nagano*
Department of Chemistry, Ochanomizu University,
Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan
Abstract—The catalytic hydrogenation of 4-methyl itaconate derivatives bearing chiral
auxiliary and their conjugate reduction with n-Bu3SnH in the presence of Lewis acid
were examined to reveal their diastereoselectivity. The homogeneous catalytic
hydrogenation of 4-methyl itaconyl (1S)-(-)-2,10-camphorsultam with the Crabtree’s
catalyst [Ir(COD)(PCy3)(py)]PF6 in CH2Cl2-MeOH (2:1 v/v) gave less polar
(1S,2’S)-diastereomer in 84% yield, while the conjugate reduction of the α-methylene
amide with n-Bu3SnH (2 equiv) using MgI2 (7 equiv) as an additive in CH2Cl2 gave
more
polar
(1S,2’R)-diastereomer
in
70%
yield.
Keywords: Itaconyl camphorsultam, Crabtree’s catalyst, Conjugate reduction,
Tributyltin hydride, Lewis acid, Solvent effect
1. Introduction
The 1,5-dimethylalkyl motif is ubiquitous in many natural products such as several
insect pheromones, vitamins E and K1, and membrane lipids of archaebacteria.1 C5
Chiral unit A bearing two different functional groups, such as X=CH2OH,2 CO2H,3 or
CONRR’,4-6 Y=CO2Me (Fig.1) is a versatile intermediate for the synthesis of these
natural products. Enantio- and diastereoselective syntheses of C5 chiral unit A have
been investigated extensively. Asymmetric hydrogenation of 4-methyl itaconate (1)
using chiral rhodium catalyst is an efficient and direct method to obtain C5 chiral unit
A.3 Base-mediated alkylations of N-propanoyl oxazolidinones derived from L-valinol or
(1S,2R)-(+) norephedrine,4 and N-propanoyl camphorsultam5 using alkyl bromoacetate
1

ACCEPTED MANUSCRIPT
as electrophile is highly diastetreoselective. Regio- and stereocontrolled conjugate
radical addition to fumarate bearing chiral auxiliary is also an efficient method
providing chiral C5 unit A.6
* Corresponding author. e-mail: nagano.hajime@ocha.ac.jp
Fig.1.
In our previous work we reported the diastereoselective heterogeneous catalytic
7
hydrogenation of α,β-unsaturated esters in the presence of MgBr2 and the
diastereoselective conjugate reduction of α,β-unsaturated esters and amides using
n-Bu3SnH and Lewis acid MgBr2ꢀOEt2,8 both with high diastereoselectivity, i.e.,
1,3-stereoinduction controlled by the seven-membered chelate formation.
We now report the catalytic hydrogenation of 4-methyl itaconate derivatives bearing
chiral auxiliary 2-7 by the use of Pd/C or the Crabtree’s catalyst,
(1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)iridium(I) hexafluorophosphate,
and the conjugate reduction of 2, 3, 5 and 6 with n-Bu3SnH in the presence of Lewis
acid (Scheme 1). The products 8-14 of these diastereoselective reactions will be
versatile intermediate A (X = CONRR’, CO2R, Y = CO2Me) for the synthesis of the
natural products bearing 1,5-dimethylalkyl motif.
2

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Scheme 1. (i) Catalytic hydrogenation. (ii) Conjugate reduction with n-Bu3SnH in the
presence of Lewis acid.
2. Results and discussion
2.1 Catalytic hydrogenation of compounds 2-7
Compounds 2-7 were prepared from 4-methyl itaconate (1) using chiral auxiliaries,
(S)-(-)-2,10-camphorsultam
(15),
(R)-4-benzyl-2-oxazolidinone
(16),
(S)-4-isopropyl-2-oxazolidinone (17), L-proline methyl ester hydrochloride (18),
L-phenylalanine ethyl ester (19) and pantolactone (racemic) (20), respectively (Scheme
2).9
3

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Scheme 2. Preparation of substrates 2-7 and their yields.
We first performed the catalytic hydrogenation of camphorsultam derivative 2 (Table
1).7,10 The catalytic hydrogenation of 2 on Pd/C (10%) in THF at room temperature
gave a mixture of diastereomers 8 and 9 in a ratio of 2.7:1 in high yield (entry 1). The
o
diastereomer ratio was ameliorated by lowering the reaction temperature to -20 C
(entry 2), but the reaction did not proceed in the presence of MgBr2ꢀOEt2 as an
additive.7 The hydrogenation using the Crabtree’s catalyst, [Ir(COD)(PCy3)(py)]PF6, in
CH2Cl2 at room temperature showed a similar diastereoselectivity (entry 3) and at -20
oC increased the selectivity (entry 4). The diastereomer ratio depended significantly on
solvent. The hydrogenation with the homogeneous catalyst in THF gave 8 and 9 in a
ratio of 8.7:1, but in poor yield (entry 5). Activation of the reaction of 2 in THF by
adding I2 (2 equiv) or KI (2equiv) was attempted, 11 but the reaction did not proceed at
all. In a mixed-solvent of CH2Cl2-THF (2:1 v/v) the homogeneous hydrogenation
proceeded in high yield and with good diastereoselectivity (entry 6). A higher
4

ACCEPTED MANUSCRIPT
diastereoselectivity (8/9 = 6.4:1) was achieved by using CH2Cl2-MeOH (2:1 v/v) as
solvent (entry 7). The reaction using [Ir(1,5-cyclooctadiene)(PMePh2)2]PF6 was
attempted, but did not proceed.
Table 1
Diastereoselective catalytic hydrogenation of sulfonamide 2
Entry Catalyst (mol%)
Solvent
Temp (oC) Yield (%) Diastereomer ratioa
8 : 9
1
2
3
4
5
6
7
Pd/C (30)
THF
THF
rt
-20
rt
96
97
2.7 : 1
3.6 : 1
3.5 : 1
5.6 : 1
8.7 : 1
5.2 : 1
6.4 : 1
Crabree’s (10)b
CH2Cl2
80
(20)
(10)
(5)
CH2Cl2
-20
rt
quant
36
THF
CH2Cl2-THF (2:1)
rt
99
(5.8)
CH2Cl2-MeOH (2:1) rt
97
a Diastereomer ratio was determined by 1H NMR integration of CHMe.
b [Ir(COD)(PCy3)(py)]PF6.
The stereochemistry of 8 and 9 was determined as follows. The diastereomers were
separated using silica gel column chromatography and their respective hydrolysis with
lithium hydroxide, followed by acidification, afforded (S)-methylsuccnic acid (S)-21
23
D
25
D
{[
α
]
-15 (c 0.50, EtOH); lit.12
[
α
]
-15.55 (c 2.16, EtOH)} and (R)-methylsuccnic
acid (R)-21 {[
α
]
25 +17 (c 0.47, EtOH); lit.13 [ 20 +16.88 (c 2.16, EtOH)} (Scheme 3).
α]
D
D
5

ACCEPTED MANUSCRIPT
Scheme 3. Determination of the absolute configuration of 8 and 9.
Subsequently, we examined the diastereoselective hydrogenation of 3-7 (Table 2). The
catalytic hydrogenation of
3
and
5
using the Crabtree’s catalyst
[Ir(COD)(PCy3)(py)]PF6 in CH2Cl2 gave 10 and 12, respectively, but in poor yields and
with low diastereoselectivities. The hydrogenation of 3-7 on Pd/C without Lewis acid
showed poor diastereoselectivities. We therefore examined the reaction using various
catalysts (Pd/C, Pt/C, PtO2), Lewis acids (MgBr2, MgBr2 OEt2, Yb(OTf)3), solvents, and
ꢀ
temperatures.7 The catalytic hydrogenation of oxazolidinones 3 and 4 on Pd/C in the
presence of MgBr2 (3 equiv) gave diastereomeric mixtures 10 (88% yield; dr 3.8:1) and
11 (96% yield; dr 4.0:1), respectively (entries 1 and 2). The reaction of amides 5 and 6
on Pd/C in the presence of MgBr2 (1.5 equiv) gave diastereomeric mixtures 12 (97%
yield; dr 3.8:1) and 13 (quantitative yield; dr 2.8:1), respectively (entries 3 and 4). The
hydrogenation of ester 7 on Pd/C in the presence of MgBr2 OEt2 (1.5 equiv) gave 14
ꢀ
(81% yield) (entry 5) with a lower diastereoselectivity (dr 1.8:1) compared to those of
10-13. Thus the addition of MgBr2 increased the diastereoselectivity in the
hydrogenation of 3-6 on Pd/C, although the diastereoselectivity in the hydrogenation of
ester 7 was not affected. However, the reactions of 3-6 were inferior in
diastereoselectivity compared to that of 2 using the Crabtree’s catalyst (Table 1, entry 7),
and furthermore, it was difficult to separate the diastereomers 10, 12, 13 and 14 using
silica gel column chromatography except for oxazolidinone 11. The stereochemistry of
the hydrogenation products 10-14 was not assigned. Thus the combination of
appropriate chiral auxiliary, camphorsultam, and the Crabtree’s catalyst realized the
preparation of a C5 chiral unit 8 with high diastereoselectivity and high yield.
6

ACCEPTED MANUSCRIPT
Table 2
Diastereoselective catalytic hydrogenation of 3-7 on 10% Pd/C at room temperaturea
Entry Substrate
Additive (equiv)
Solvent Yield (%) Diastereomer ratio
1
2
3
4
5
3
4
5
6
7
MgBr2 (3)
MgBr2 (3)
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
88
96
3.8 : 1
4.0 : 1
3.8 : 1
2.8 : 1
1.8 : 1
MgBr2 (1.5)
MgBr2 (1.5)
97
quant
81
MgBr2ꢀOEt2 (1.5) THF
a
25 mol% Pd/C was used.
2.2 Conjugate reduction of compounds 2, 3, 5 and 6
We next carried out the conjugate reduction of 2, 3, 5 and 6 using
or (
n
-Bu3SnH (2 equiv)
n
-C8H17)3SnH (2 equiv) in the presence of Lewis acid to reveal their
diastereoselectivity. First, the conjugate reduction of sulfonamide 2 was performed
(Table 3). As reported before,8 the reduction did not achieve without Lewis acid (entry
1). When the reduction was performed in the presence of MgBr2 (3 equiv) and LiI (0.1
equiv) at 0 oC in CH2Cl2 under N2 atmosphere, diastereomer 9 was yielded
predominantly (entry 2). Entry 3 shows that the reduction using MgI2 (3 equiv) as an
additive gave a mixture of 8 and 9 quantitatively, but the diastereoselectivity was lower.
The use of 7 equiv of MgI2 as an additive gave 9 with higher diastereoselectivity and in
o
high yield (entry 4).14 When the reduction performed at -78 C, both the yield and
diastereoselectivity were lowered (entry 5). The conjugate reduction of 2 using
o
(
n
-C8H17)3SnH (2 equiv) and MgI2 (7 equiv) at 0 C showed lower selectivity (8/9 =
1:2.4) (entry 6). Thus, as shown in entry 4, the reduction of 2 with n-Bu3SnH in the
presence of MgI2 (7 equiv) gave compound 9 predominantly in contrast to the catalytic
hydrogenation of 2 yielding compound 8 predominantly (Table 1, entry 7).
7

ACCEPTED MANUSCRIPT
Table 3
Diastereoselective conjugate reduction of sulfonamide 2 with Bu3SnH or (n-C8H17)3SnH
in CH2Cl2
Entrya
Lewis acid (equiv)
Temp (oC) Yield (%)
Diastereomer ratiob
8
:
9
1
2
3
4
5
6
−
0
0
nr
76
−
MgBr2 (3)c
MgI2 (3)
MgI2 (7)
MgI2 (7)
MgI2 (7)
1
1
1
1
1
: 3.1
: 2.5
: 4.4
: 3.2
: 2.4
0
quant
86
0
-78
0
43
62
a n-Bu3SnH (2 equiv) was used for entries 1-5 and (n-C8H17)3SnH (2 equiv) was used
for entry 6. b Diastereomer ratio was determined by 1H NMR integration of CHMe. c LiI
(0.1 equiv) was added.
The conjugate reduction of 3 and 6 with n-Bu3SnH in the presence of MgI2 proceeded in
high yield, but with poor diastereoselectivity (dr 1.6:1 for 10 and dr 1:1.6 for 13). The
conjugate reduction of amide 5 did not proceed even in the presence of Lewis acid.
We confirmed subsequently the chelate ring formation of 2 by the complexation
experiment with MgI2 in CDCl3.1a,8b,15 The large difference of chemical shift increments
∆δ values [δH (substrate 2 + MgI2) - δH (substrate 2)] suggests the chelate ring formation,
which lowered the LUMO energy of 2 and consequently accelerated the conjugate
reduction (Fig. 2). The reactivity and the diastereoselectivity may be enhanced by the
seven membered chelate ring formation through the coordination of Mg2+ to the amide
carbonyl oxygen and ester carbonyl oxygen atoms as well as by the six membered
chelate ring formation through the coordination of Mg2+ to the amide carbonyl oxygen
and sulfone oxygen atoms.15
8

ACCEPTED MANUSCRIPT
Fig. 2. ∆δ values: ∆δ (ppm) = [
The H (substrate 2 + 3 equiv of MgI2) values were obtained after sonication of 2 with
MgI2 (7 equiv) in CDCl3.
δH (substrate 2 + 3 equiv of MgI2) - δH (substrate 2)].
δ
The origin of diastereoselectivity in the catalytic hydrogenation and the conjugate
reduction of 2 can be rationalized as below (Fig.3).
(1) The catalytic hydrogenation of 2 proceeds probably through the conformation which
minimizes the unfavorable dipole-dipole interaction by adopting anti (S-N-C=O)
conformation and the steric repulsion by adopting twisted conformation close to s-cis
(CH2-C-C=O).16 The attack of hydrogen atom to the prochiral
α-carbon preferentially
from the less hindered Re-face (opposite the sulfonamide oxygen) gives diastereomer 8.
(2) In the conjugate reduction of 2 with n-Bu3SnH in the presence of MgI2, the
formation of six and seven membered chelate rings was suggested by the complexation
experiment mentioned above. The
intermediate.8b Subsequently, the protonation to the prochiral
β
-attack of hydride ion gives the (Z)-enolate
-carbon occurs
α
preferentially from the less hindered Si-face to give diastereomer 9. In the catalytic
hydrogenation of 3-5 (Table 2, entries 1-3) chelate ring formation plays an important
role as well,7 because of the poor diastereoselectivity in the hydrogenation without
Lewis acid. The catalytic hydrogenation of oxazolidinone 22 on Pd/C in the presence of
MgBr2 gave 23 (73% yield, dr = 1:2.3) together with isomerized product 24 (7% yield)
(Scheme 4). The lower diastereoselective hydrogenation of 23 lacking methoxycarbonyl
group suggests the contribution of seven membered chelate ring to enhance the
diastereoselectivity in the reaction of 3.
9

ACCEPTED MANUSCRIPT
Fig. 3 Diastereoselective reaction pathways of 2.
Scheme 4. Catalytic hydrogenation of 22.
3. Conclusion
hydrogenation
The
homogeneous
catalytic
of
4-methyl
itaconyl
(1S)-(-)-2,10-camphorsultam (2) with the Crabtree’s catalyst [Ir(COD)(PCy3)(py)]PF6 in
CH2Cl2-MeOH (2:1 v/v) gave less polar (1S,2’S)-diastereomer 8 in 84% yield, while the
conjugate reduction of the α-methylene amide 2 with n-Bu3SnH (2 equiv) using MgI2 (7
equiv) as an additive in CH2Cl2 gave more polar (1S,2’R)-diastereomer 9 in 70% yield.
These complementary reactions will be efficient and direct methods to obtain C5 chiral
units useful for the synthesis of natural products possessing 1,5-dimethylalkyl motif.
10

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4. Experimental
4.1 General
Melting points were determined with Yanaco micro melting point apparatus. Optical
1
rotations were measured on a JASCO P-2200 polarimeter. H NMR spectra were
recorded on a JEOL JNM-AL 400 (400 MHz) spectrometer or Bruker DRX600 (600
MHz) with CDCl3 as a solvent and tetramethylsilane as an internal standard. 13C NMR
spectra were recorded on the instruments operating at 100 MHz or 150 MHz with
CDCl3 as a solvent and an internal standard (δ
77.0). Mass spectra (EI+) were obtained
on a JEOL JMS-700 mass spectrometer. Mass spectra (ESI) and high resolution mass
spectra (ESI) were obtained on a JMS-T100TD (AccuTOF TLC) mass spectrometer. IR
spectra were taken on a Perkin-Elmer 2000 spectrometer. For thin layer chromatography
(TLC) analysis, Merck precoated plates (silica gel 60 F254) were used. Visualization was
accomplished by UV light and potassium permanganate or phosphomolybdic acid.
Products were purified by column chromatography using Kanto silica gel 60 (spherical
neutral).
4.2 Preparation of substrates 2-7 and 22.
4.2.1
Methyl
3-{(1S,5R,7R
)-10,10-dimethyl-3,3-dioxo-3λ6-thia-4-azatricyclo
[5.2.1.01,5]decane-4-carbonyl)}but-3-enate (2)
To a stirred solution of 4-methyl itaconate (1) (864 mg, 6.0 mmol) in dry CH2Cl2 (23
ml) were added 4-(dimethylamino)pyridine (161 mg, 1.3 mmol) and
o
(S)-(-)-2,10-camphorsultam (15) (431 mg, 2.0 mmol). The mixture was cooled to 0 C
and N,N’-dicyclohexylcarbodiimide (1.36 g, 6.6 mmol) was added. The mixture was
o
stirred at 0 C for 1 h under N2 atmosphere. The solution was warmed to room
temperature and further stirred overnight. The resulting precipitates of
N,N’-dicyclohexylurea were filtered off and the filtrate was washed successively with
5% aqueous NaHCO3, water, 1 N HCl, water and brine. The organic layer was dried
over anhydrous Na2SO4 and evaporated in vacuo. The residue was purified by column
chromatography on silica gel [SiO2 51 g; hexane-EtOAc (5:1 then 3:1 v/v)] to afford
22
D
amide 2 (612 mg, 90%) as a colorless solid. Mp 86.2 oC (from diethyl ether); [
α]
-82.9 (c 1.95, CHCl3); IR (KBr) 3119, 1738, 1674, 1633, 1436, 1328, 1175, 1132, 1114,
1063, 979, 764 cm-1; 1H-NMR (600 MHz)
6.05 (1H, d, J = 1.0 Hz, =CHH), 5.88 (1H,
δ
d, J = 1.0 Hz, =CHH), 4.06 (1H, dd, J = 7.5, 4.9 Hz, NCH), 3.69 (3H, s, OMe), 3.52
(1H, d, J = 13.7 Hz, CHHSO2), 3.47 (1H, d, J = 16.1 Hz, CHHCO2Me), 3.45(1H, d, J =
11

ACCEPTED MANUSCRIPT
13.7 Hz, CHHSO2), 3.25 (1H, d, J = 16.1 Hz, CHHCO2Me), 2.05-2.00 (2H, m, CH2),
2.00-1.85 (3H, m, CH, CH2), 1.49-1.29 (2H, m, CH2), 1.22 (3H, s, Me), 1.00 (3H, s,
Me); 13C-NMR (100 MHz)
δ 169.9, 169.0, 135.6, 127.7, 65.4, 53.2, 51.8, 47.8, 47.5,
44.9, 38.0, 32.9, 26.2, 20.9, 19.7; MS (EI+) (m/z) 341 (M+, 1%), 310 (15), 277 (16), 218
(19), 127 (100), 99 (72), 69 (32), 59 (25); HRMS calcd for C16H24NO5S (MH+)
342.1375, found 342.1396.
4.2.2 Methyl 3-[(4
To a solution of 4-methyl itaconate (1) (432 mg, 3.00 mmol) in dry THF (8 ml) at -25
oC under N2 atmosphere was added triethylamine (800
l, 5.78 mmol). Pivaloyl chloride
(720 l, 5.94 mmol) was added and the mixture was stirred for 2 h. The solution was
R)-4-benzyl-2-oxooxazolidine-3-carbonyl]but-3-enoate (3)
µ
µ
warmed to -20 oC. Lithium chloride (218 mg, 5.18 mmol) and
(R)-4-benzyl-2-oxazolidinone (16) (356 mg, 2.01 mmol) were added and the mixture
was stirred for 1.5 h. 0.2 N HCl and water were added and the product was extracted
with EtOAc. The organic layer was washed with saturated aqueous NaHCO3 and brine
(twice). The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo.
The residue was purified by silica gel column chromatography [SiO2 30 g;
26
hexane-EtOAc (3:1 v/v)] to afford 3 (594 mg, 97%) as an oil. [
α
]
-46.9 (c 2.83,
D
CHCl3); IR (neat) 3063, 3029, 3003, 2954, 1784, 1733, 1682, 1640, 1584, 1495, 1354,
1
1331, 1210, 1109, 921, 796, 760, 705 cm-1; H-NMR (400 MHz)
δ 7.36-7.22 (5H, m,
Ph), 5.69 (1H, s, =CHH), 5.65 (1H, s, =CHH), 4.75 (1H, m, NCH), 4.26 (1H, t, J = 8.8
Hz, OCHH), 4.18 (1H, dd, J = 8.8, 4.8 Hz, OCHH), 3.70 (3H, s, OMe), 3.62 (1H, d, J =
16.8 Hz, CHHCO2Me), 3.48 (1H, d, J = 16.8 Hz, CHHCO2Me), 3.44 (1H, dd, J = 13.2,
3.2 Hz, CHHPh), 2.80 (1H, dd, J = 13.2, 9.8 Hz, CHHPh); 13C-NMR (100 MHz)
δ
170.3, 168.9, 152.6, 136.0, 135.0, 129.1, 128.5, 126.9, 124.2, 66.2, 55.1, 51.7, 38.5,
37.1; MS (ESI+) (m/z) 304 (MH+); HRMS calcd for C16H18NO5 (MH+) 304.1185, found
304.1178.
4.2.3 Methyl 3-[(4S)-4-isopropyl-2-oxooxazolidine-3-carbonyl]but-3-enoate (4)
To a solution of 4-methyl itaconate (1) (432 mg, 3.0 mmol) in dry THF (8 ml) was
o
added triethylamine (800
chloride (720
µ
l, 5.8 mmol) at -25 C under N2 atmosphere. Pivaloyl
µ
l, 5.9 mmol) was added and the mixture was stirred for 2 h. The solution
was warmed to -20 oC. Lithium chloride (219 mg, 5.2 mmol) and
(S)-4-isopropyl-2-oxazolidinone (17) (260 mg, 2.0 mmol) were added and the mixture
was stirred for 1.5 h. Treatment of the reaction mixture as described for the preparation
of 3 and subsequent silica gel column chromatography [SiO2 30 g; hexane-EtOAc (2:1
12

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26
then 1:1 v/v)] gave 4 (452 mg, 90%) as an oil. [
α
]
+53.5 (c 2.98, CHCl3); IR (neat)
D
2965, 1781, 1735, 1685, 1636, 1330, 1302, 1202, 1016, 927, 796 cm-1; H-NMR (400
1
MHz)
δ 5.67 (1H, s, =CHH), 5.63 (1H, s, =CHH), 4.56 (1H, dt, J = 8.8, 4.4 Hz, NCH),
4.34 (1H, t, J = 8.8 Hz, OCHH), 4.23 (1H, dd, J = 8.8, 4.3 Hz, OCHH), 3.68 (3H, s,
OMe), 3.62 (1H, d, J = 16.8 Hz, CHHCO2Me), 3.42 (1H, d, J = 16.8 Hz, CHHCO2Me),
2.42 (1H, m, CHMe2), 0.93 (6H, t, J = 6.7 Hz, Me×2); 13C-NMR (100 MHz)
δ 170.0,
168.7, 152.9, 136.1, 123.5, 63.1, 57.9, 51.5, 38.3, 27.9, 17.3, 14.3; MS (ESI+) (m/z) 256
(MH+); HRMS calcd for C12H18NO5 (MH+) 256.1185, found 256.1191.
4.2.4
(2 )-1-(2-Methoxycarbonylmethylpropenoyl)pyrrolidine-2-carboxylate (5)
To a stirred solution of L-proline methyl ester hydrochloride (18) (166 mg, 1.00 mmol)
in dry CH2Cl2 (3 ml) at 0 oC were added diisopropylethylamine (180
l),
Methyl
S
µ
1-hydroxybenzotriazole hydrate (34.1 mg, 0.25 mmol) and 4-methyl itaconate (1)
(132 mg, 0.92 mmol). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (192 mg, 1.00
mmol) was added and the mixture was stirred at room temperature under N2 atmosphere
overnight. 3 N HCl was added and the organic layer was washed successively with
saturated aqueous NaHCO3 and brine. The organic layer was dried over anhydrous
Na2SO4 and evaporated in vacuo. The residue was purified by silica gel column
chromatography [SiO2 5 g; hexane-EtOAc (7:1 to 1:1 v/v)] to afford 5 (128 mg, 55%;
rotational isomers ratio 4.2:1) as an oil. [
α
]
23 -37 (c 0.38, CHCl3); IR (neat) 3091, 1741,
D
1653, 1620, 1441, 1199, 1174, 1016, 949, 797 cm-1; H-NMR (600 MHz) major
1
rotational isomer:
δ 5.51 (1H, s, =CHH), 5.49 (1H, s, =CHH), 4.54 (1H, t, J = 7.3 Hz,
NCH), 3.88 (1H, m, NCHH), 3.71 (1H, m, NCHH), 3.73 (3H, s, CO2Me), 3.68 (3H, s,
CO2Me), 3.60 (1H, d, J = 17.1 Hz, CHHCO2Me), 3.27 (1H, d, J = 17.1 Hz,
CHHCO2Me), 2.30 (1H, m, CHH), 2.08-1.89 (3H, m, CHH, CH2); minor rotational
isomer:
δ 5.31 (1H, s, =CHH), 5.23 (1H, s, =CHH), 4.86 (1H, d, J = 8.2 Hz, CH), 3.74
(1H, m, NCHH), 3.68 (1H, m, NCHH), 3.73 (3H, s, CO2Me), 3.68 (3H, s, CO2Me), 3.57
(1H, d, J = 17.1 Hz, CHHCO2Me), 3.14 (1H, d, J = 17.1 Hz, CHHCO2Me), 2.25-2.17
(1H, m, CH), 2.11 (1H, m, CH), 2.08-1.89 (2H, m, CH2); 13C-NMR (100 MHz) major
rotational isomer:
δ
172.3, 171.0, 168.8, 137.5, 120.0, 58.6, 51.9, 51.7, 49.5, 38.8, 29.3,
173.1, 170.7, 169.6, 138.3, 118.6, 61.3, 52.1, 51.7, 45.8,
25.2; minor rotational isomer:
δ
39.0, 30.9, 22.4; MS (EI+) (m/z) 255 (M+, 10%), 224 (16), 196 (49), 127 (100), 99 (29),
70 (65), 69 (21), 59 (14); HRMS calcd for C12H18NO5 (MH+) 256.1185, found
256.1188.
13

ACCEPTED MANUSCRIPT
4.2.5 Methyl
(6)
3-{[(1S)-1-ethoxycarbonyl-2-phenylethyl]carbamoyl}but-3-enoate
To a solution of L-phenylalanine (331 mg, 2.00 mmol) in dry ethanol (6 ml) was added
thionyl chloride (300
l). The reaction mixture was stirred at 100 oC overnight under N2
µ
atmosphere. The solution was evaporated in vacuo. The residue was dissolved in
ethanol and the solution was evaporated in vacuo again. The residue was dissolved in
10% aqueous NaOH. The product was extracted with EtOAc. The organic layer was
dried over anhydrous Na2SO4 and evaporated in vacuo. The residue afforded
1
L-phenylalanine ethyl ester (19) (289 mg, 75%) as an oil. H-NMR (400 MHz)
δ
7.33-7.19 (5H, m, Ph), 4.17 (2H, q, J = 7.2 Hz, CH2Me), 3.71 (1H, dd, J = 7.8, 5.4 Hz,
CH), 3.09 (1H, dd, J = 13.5, 5.4 Hz, CHHPh), 2.87 (1H, dd, J = 13.5, 7.8 Hz, CHHPh),
1.49 (2H, brs, NH2), 1.24 (3H, t, J = 7.2 Hz, Me).
To a stirred solution of 4-methyl itaconate (1) (211 mg, 1.46 mmol) in dry CH2Cl2 (2
ml) were added 4-(dimethylamino)pyridine (16.2 mg, 0.133 mmol) and
o
L-phenylalanine ethyl ester (19) (257 mg, 1.33 mmol). The mixture was cooled to 0 C
and N,N’-dicyclohexylcarbodiimide (301 mg, 1.46 mmol) was added. The mixture was
o
stirred at 0 C for 1 h under N2 atmosphere. The solution was warmed to room
temperature and further stirred overnight. The resulting precipitates of
N,N’-dicyclohexylurea were filtered off and the filtrate was washed successively with
5% aqueous NaHCO3, water, 1 N HCl, water and brine. The organic layer was dried
over anhydrous Na2SO4 and evaporated in vacuo. The residue was purified by silica gel
column chromatography [SiO2 11 g; hexane-EtOAc (5:1 to 3:1 v/v)] to afford
23
D
L-phenylalanine ethyl ester amide (6) (250 mg, 59%) as an oil. [
α
]
+51.5 (c 1.40,
CHCl3); IR (neat) 3393, 1745, 1715, 1669, 1632, 1536, 1447, 1298, 1283, 1229, 1211,
1
1190, 1020, 942, 756, 709 cm-1; H-NMR (400 MHz)
δ 7.32-7.12 (5H, m, Ph), 6.56
(1H, brd, J = 7.3 Hz, NH), 5.72 (1H, s, =CHH), 5.49 (1H, s, =CHH), 4.89 (1H, dt, J =
7.8, 5.9 Hz, OCH), 4.18 (2H, q, J = 7.3 Hz, CH2Me), 3.68 (3H, s, CO2Me), 3.36 (2H, s,
CH2CO2Me), 3.17 (1H, dd, J = 13.6, 5.9 Hz, CHHPh), 3.16 (1H, dd, J = 13.6, 5.4 Hz,
CHHPh), 1.25 (3H, t, J = 7.3 Hz, CH2Me); 13C-NMR (100 MHz)
δ 171.0, 170.8, 166.5,
137.6, 135.7, 129.0, 128.1, 126.7, 121.6, 61.2, 53.2, 51.8, 37.6, 37.5, 13.9; MS (EI+)
(m/z) 319 (M+, 7%), 288 (5), 246 (8), 214 (6), 176 (74), 148 (15), 127 (100), 120 (13),
99 (31), 91 (20), 69 (14), 58 (19); HRMS calcd for C17H22NO5 (MH+) 320.1498, found
320.1507.
4.2.6 4-Methyl 1-(4,4-dimethyl-2-oxotetrahydrofuran-3-yl)-2-methylenesuccinate
(7)
14

ACCEPTED MANUSCRIPT
To a stirred solution of 4-methyl itaconate (1) (476 mg, 3.30 mmol) in dry CH2Cl2 (6
ml) were added 4-(dimethylamino)pyridine (37.0 mg, 0.303 mmol) and pantolactone
(20) (390 mg, 3.00 mmol). The mixture was cooled to
0
oC and
N,N’-dicyclohexylcarbodiimide (742 mg, 3.59 mmol) was added. The mixture was
stirred at room temperature overnight under N2 atmosphere. Ethyl acetate was added
and the solution was stirred for 1 h and the resulting mixture was filtered and the filtrate
was evaporated in vacuo. The residue was purified by silica gel column chromatography
[SiO2 28 g; hexane-EtOAc (10:1 to 3:1 v/v)] to afford pantolactone ester 7 (649 mg,
85%) as an oil. IR (neat) 3113, 1796, 1739, 1643, 1438, 1200, 1145, 1033, 1014, 998,
1
944, 812 cm-1; H-NMR (400 MHz)
δ 6.47 (1H, s, =CHH), 5.84 (1H, s, =CHH), 5.43
(1H, s, OCH), 4.08 (1H, d, J = 8.8 Hz, OCHH), 4.04 (1H, d, J = 8.8 Hz, OCHH), 3.71
(3H, s, OMe), 3.43 (1H, d, J = 17.1 Hz, CHHCO2Me), 3.39 (1H, d, J = 17.1 Hz,
CHHCO2Me), 1.23 (3H, s, Me), 1.13 (3H, s, Me); 13C-NMR (100 MHz)
δ 171.2, 169.8,
164.0, 132.2, 129.4, 75.3, 74.9, 51.1, 39.6, 36.6, 21.8, 19.0; MS (EI+) (m/z) 225 (M+ -
OMe, 6%), 143 (23), 127 (100), 113 (11), 99 (28), 69 (25), 59 (14); HRMS calcd for
C12H17O6 (MH+) 257.1025, found 257.1025.
4.2.7 (4
To a solution of 2-butylpropenoic acid (293 mg, 2.3 mmol)17 in dry THF (10 ml) at -30
oC was added triethylamine (620
l, 4.5 mmol) under N2 atmosphere. Pivaloyl chloride
(540 l, 4.5 mmol) was carefully added and the mixture was stirred for 2 h. The solution
R)-4-Benzyl-3-(2-butylpropenoyl)oxazolidin-2-one (22)
µ
µ
was warmed to -20 oC. Lithium chloride (163 mg, 3.9 mmol) and
(R)-4-benzyl-2-oxazolidinone (266 mg, 1.5 mmol) were added and the mixture was
stirred for 2 h. The product was extracted with ethyl acetate. The organic layer was
washed with saturated aqueous NH4Cl, 1N aqueous NaOH and brine. The organic layer
was dried over anhydrous Na2SO4 and the solution was evaporated in vacuo. The
residue was purified by column chromatography on silica gel [ehexane-EtOAc (7:1)] to
afford 22 (388 mg, 90%) as a colorless solid. Mp 47.6 oC (from diethyl ether); IR (neat)
1
1786, 1682, 1393, 1353, 1312, 1220, 1056, 1043, 1006, 757, 703 cm-1; H-NMR (400
MHz)
δ 7.36-7.19 (5H, m, Ph), 5.41 (1H, s, =CHH), 5.39 (1H, s, =CHH), 4.71 (1H, m,
NCH), 4.24 (1H, t, J = 9.2 Hz, OCHH), 4.16 (1H, dd, J = 9.2, 4.6 Hz, OCHH), 3.35 (1H,
dd, J = 13.5, 3.5, CHHPh), 2.83 (1H, dd, J = 13.5, 9.4, CHHPh), 2.42-2.37 (2H, m,
CH2), 1.53-1.44 (2H, m, CH2), 1.43-1.33 (2H, m, CH2), 0.92 (3H, t, J = 7.3 Hz, CH3);
13C-NMR (100 MHz)
δ 170.4, 152.3, 143.9, 134.8, 129.0, 128.3, 126.8, 118.2, 65.9,
54.6, 37.0, 32.2, 29.4, 21.7, 13.4; MS (ESI+) m/z 288 (MH+); HRMS calcd for
C17H22NO3 (MH+) 288.1600, found 288.1619.
15

ACCEPTED MANUSCRIPT
4.3 Catalytic hydrogenation
4.3.1 Catalytic hydrogenation of 2 using Crabtree’s catalyst.
To a solution of amide 2 (34 mg, 0.10 mmol) in CH2Cl2-MeOH (2:1 v/v) (3 ml) was
added [Ir(1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)]PF6 (4.7 mg, 5.8
mol%) and the mixture was stirred under H2 atmosphere at room temperature for 5 h.
After filtration through a pad of Celite and Florisil, the solvent was evaporated in vacuo.
The residue was purified by silica gel column chromatography [SiO2 3 g;
hexane-EtOAc (9:1 to 5:1 v/v)] to afford a mixture of 8 and 9 (33 mg, 97% yield; dr
6.4:1).
4.3.2 Isolation of compounds 8 and 9
A mixture of the hydrogenated products 8 and 9 (272 mg) was submitted to silica gel
column chromatography [SiO2 8 g; hexane-EtOAc (8:1 then 4:1 v/v)] to give 8 (210
mg) and 9 (53 mg).
Methyl
[5.2.1.01,5]dec-4-yl}-3-methyl-4-oxobutanoate (
(3S)-4-{(1S,5R,7R)-10,10-dimethyl-3,3-dioxo-3λ6-thia-4-azatricyclo
8
)
Less polar diastereomer [Rf 0.57 (hexane-EtOAc 1:1 v/v)]; mp 112.9 oC (from diethyl
25
D
ether); [
α
]
-56.5 (c 1.02, CHCl3); IR (KBr) 1733, 1682, 1333, 1166, 1137 cm-1;
1H-NMR (400 MHz)
δ
3.90 (1H, dd, J = 7.8, 4.8 Hz, NCH), 3.64 (3H, s, OMe),
3.50(1H, d, J = 13.7 Hz, CHHSO2), 3.46 (1H, d, J = 13.7 Hz, CHHSO2), 3.45 (1H, m,
CHMe), 2.84 (1H, dd, J = 16.1, 9.3 Hz, CHHCO2Me), 2.47 (1H, dd, J = 16.1, 9.3 Hz,
CHHCO2Me), 2.16 (1H, m, CH), 2.03 (1H, dd, J = 13.7, 7.6 Hz, CH), 1.95-1.84 (3H, m,
CH2, CH), 1.45-1.32 (2H, m, CH2), 1.24 (3H, s, Me), 1.23 (3H. d, J = 6.8 Hz, CHMe),
0.98 (3H, s, Me); 13C-NMR (100 MHz)
δ 174.4, 171.4, 65.3, 53.0, 51.6, 48.4, 47.7, 44.6,
38.9, 38.1, 36.1, 32.8, 26.5, 20.6, 20.0, 17.0; MS (EI+) (m/z) 343 (M+, 0.5%), 312 (13),
279 (19), 129 (100), 101 (22), 93 (9), 69 (9), 59 (51); HRMS calcd for C16H26NO5S
(MH+) 344.1531, found 344.1573.
(3R)-4-{(1S,5R,7R)-10,10-dimethyl-3,3-dioxo-3λ6-thia-4-azatricyclo[5.2.1.01,5]dec-4-y}
-3-methyl-4-oxobutanoate (9)
o
More polar diastereomer [Rf 0.49 (hexane-EtOAc 1:1 v/v)]; mp 134.8-135.0 C (from
25
diethyl ether); [
α
]
-74.6 (c 0.765, CHCl3); IR (KBr) 1732, 1682, 1339, 1227, 1138
3.92 (1H, t, J = 6.4 Hz, NCH), 3.66 (3H, s, OMe), 3.50(1H,
D
cm-1; 1H-NMR (400 MHz)
δ
d, J = 13.7 Hz, CHHSO2), 3.46(1H, d, J = 13.7 Hz, CHHSO2), 3.51 (1H, m, CHMe),
2.86 (1H, dd, J = 16.6, 8.8 Hz, CHHCO2Me), 2.40 (1H, dd, J = 16.6, 9.3 Hz,
CHHCO2Me), 2.10-2.07 (2H, m, CH2), 1.95-1.83 (3H, m, CH2, CH), 1.45-1.30 (2H, m,
16

ACCEPTED MANUSCRIPT
CH2), 1.26 (3H, d, J = 7.3 Hz, CHMe), 1.16 (3H, s, Me), 0.97 (3H, s, Me); 13C-NMR
(100 MHz)
δ 174.5, 171.7, 65.0, 53.0, 51.7, 48.4, 47.7, 44.6, 38.4, 36.7, 36.6, 32.8, 26.4,
20.8, 19.9, 18.3; MS (EI+) (m/z) 343 (M+, 1%), 312 (16), 279 (14), 129 (100), 101 (34),
93 (11), 69 (11), 59 (61); HRMS calcd for C16H26NO5S (MH+) 344.1531, found
344.1557.
4.3.3 Hydrolysis of 8
To a solution of sulfonamide 8 (30 mg, 0.09 mmol) in THF (1 ml) and water (1 ml) was
added lithium hydroxide monohydrate (11 mg, 0.27 mmol). The mixture was stirred at
room temperature for 5 h and evaporated in vacuo to remove THF. The aqueous layer
was acidified with HCl (pH 1) and then washed with CH2Cl2. To the aqueous layer was
added anhydrous Na2SO4, and the resulting solid was put on a silica gel column and
eluted successively with hexane-EtOAc (4:1 v/v; 100 ml) and EtOAc (20 ml). Ethyl
acetate fraction was evaporated in vacuo to afford (S)-methylsuccinic acid (S)-(21) (5.0
23
D
1
mg, 42% yield) as a colorless solid. [
α
]
-15 (c 0.50, EtOH); H-NMR (400 MHz) δ
2.93 (1H, m, CH), 2.71 (1H, dd, J = 17.2, 8.8 Hz, CHH), 2.59 (1H, dd, J = 17.2, 4.7 Hz,
CHH), 1.29 (3H, d, J = 6.8 Hz, Me).
4.3.4 Hydrolysis of 9
Sulfonamide 9 (31 mg, 0.09 mmol) was hydrolyzed with lithium hydroxide
monohydrate (11 mg, 0.27 mmol) in THF (1 ml)-H2O (1 ml) as described above to give
(R)-methylsuccnic acid (R)-(21) (4.7 mg, 40% yield). [α]
23 +17 (c 0.47, EtOH).
D
4.3.5 Catalytic hydrogenation of 3 on Pd/C in the presence of MgBr2
To a solution of 3 (25 mg, 0.082 mmol) in CH2Cl2 (3 ml) was added MgBr2 (47 mg,
0.25 mmol) and the mixture was stirred at room temperature for 15 min. 10% Pd/C (22
mg, 25 mol%) was added and the mixture was stirred for 20 h under H2 atmosphere.
After filtration through a pad of Celite and Florisil, the solvent was evaporated in vacuo
and the residue was purified by silica gel column chromatography [SiO2 3 g;
hexane-EtOAc (5:1 v/v)] to afford 10 (22 mg, 88% yield; dr 3.8:1).
Methyl (3RS))-4-[(4R)-4-benzyl-2-oxooxazolidin-3-yl]-3-methyl-4- oxobutanoate (10
IR (neat) 1783, 1733, 1700, 1559, 1506, 1353, 1197, 1106 cm-1; H-NMR (400 MHz)
)
1
major diastereomer:
δ 7.36-7.16 (5H, m, Ph), 4.67 (1H, m, NCH), 4.22-4.14 (3H, m,
OCH2, CHMe), 3.67 (3H, s, OMe), 3.33 (1H, dd, J = 13.7, 3.2 Hz, CHHPh), 2.95 (1H,
dd, J = 17.0, 10.0 Hz, CHHCO2Me), 2.76 (1H, dd, J = 13.7, 10.0 Hz, CHHPh), 2.47
(1H, dd, J = 17.0, 4.6 Hz, CHHCO2Me), 1.23 (3H, d, J = 7.3 Hz, CHMe); minor
17

ACCEPTED MANUSCRIPT
diastereomer:
δ
7.30-7.12 (5H, m, Ph), 4.62 (1H, m, NCH), 4.14-4.06 (3H, m, OCH2,
CHMe), 3.59 (3H, s, OMe), 3.24 (1H, dd, J = 13.3, 3.2 Hz, CHHPh), 2.93 1H, dd, J =
17.0, 10.0 Hz, CHHCO2Me), 2.77 (1H, dd, J = 13.7, 10.0 Hz, CHHPh), 2.43 (1H, dd, J
= 17.0, 4.6 Hz, CHHCO2Me), 1.27 (3H, dd, J = 7.3, 1.4 Hz, CHMe); 13C-NMR (100
MHz) major diastereomer:
δ
175.8, 172.06, 152.78, 135.3, 129.28, 128.7, 127.1, 65.8,
172.3, 170.08, 152.80,
55.1, 51.5, 37.30, 37.26, 34.24, 17.0; minor diastereomer:
135.0, 129.25, 128.7, 127.0, 66.0, 54.9, 51.5, 37.7, 36.8, 34.19, 17.2; MS (ESI+) (m/z)
δ
306 (MH+); HRMS calcd for C16H20NO5 (MH+) 306.1341, found 306.1357.
4.3.6 Catalytic hydrogenation of 4 on Pd/C in the presence of MgBr2
To a solution of 4 (46 mg, 0.18 mmol) in CH2Cl2 (4 ml) was added MgBr2 (101 mg,
0.54 mmol) and the mixture was stirred at room temperature for 15 min. 10% Pd/C (53
mg, 27 mol%) was added and the mixture was stirred for 20 h under H2 atmosphere.
After filtration through a pad of Celite and Florisil, the solvent was evaporated in vacuo
and the residue was purified by silica gel column chromatography [SiO2 2 g;
hexane-EtOAc (2:1 v/v)] to afford 11 (45 mg, 96% yield; dr 4.0:1).
Methyl (3RS)-4-[(4S)-4-isopropyl-2-oxooxazolidin-3-y])-3-methyl-4-oxobutanoate (11
IR (neat) 1783, 1733, 1699, 1360, 1301, 1197, 1016 cm-1; H-NMR (400 MHz) less
)
1
polar [Rf 0.60 (hexane-EtOAc (1:1 v/v)], major diastereomer:
δ 4.44 (1H, dt, J = 8.2,
3.5 Hz, NCH), 4.30-4.20 (2H, m, OCH2), 4.15 (1H, m, CHMe), 3.65 (3H, s, OMe), 2.92
(1H, dd, J = 16.9, 10.1 Hz, CHHCO2Me), 2.43 (1H, dd, J = 16.9, 4.6 Hz, CHHCO2Me),
2.38 (1H, m, CHMe2), 1.20 (3H, d, J = 6.9 Hz, CHMe), 0.93 (6H, t, J = 6.9 Hz,
CHMe2); more polar [Rf 0.51 (hexane-EtOAc (1:1 v/v)], minor diastereomer: δ 4.47 (1H,
dd, J = 8.2, 3.7 Hz, NCH), 4.32 (1H, t, J = 8.7 Hz, OCHH), 4.21 (1H, dd, J = 9.2, 2.7
Hz, OCHH), 4.14 (1H, m, CHMe), 3.66 (3H, s, OMe), 2.89 (1H, dd, J = 16.9, 10.5 Hz,
CHHCO2Me), 2.40 (1H, dd, J = 16.9, 4.1 Hz, CHHCO2Me), 2.33 (1H, m, CHMe2),
1.26 (3H, d, J = 7.3 Hz, CHMe), 0.91 (3H, d, J = 7.3 Hz, CHMeMe), 0.88 (3H, d, J =
6.9 Hz, CHMeMe); 13C-NMR (100 MHz) major diastereomer:
δ
175.7, 171.9, 153.42,
175.9,
62.96, 58.4, 51.48, 37.4, 34.2, 28.0, 17.73, 17.0, 14.2; minor diastereomer
172.4, 153.46, 63.37, 58.2, 51.51, 36.7, 34.2, 28.4, 17.67, 17.5, 14.6; MS (ESI+) (m/z)
δ
258 (MH+); HRMS calcd for C12H20NO5 (MH+) 258.1341, found 258.1338.
4.3.7 Catalytic hydrogenation of 5 on Pd/C in the presence of MgBr2
To a solution of 5 (31 mg, 0.12 mmol) in CH2Cl2 (3 ml) was added MgBr2 (34 mg, 0.18
mmol) and the mixture was stirred at room temperature for 15 min. 10% Pd/C (32 mg.
25 mol%) was added and the mixture was stirred under H2 atmosphere for 3.5 h. After
18

ACCEPTED MANUSCRIPT
filtration through a pad of Celite and Florisil, the solvent was evaporated in vacuo to
afford 12 (30 mg, 97% yield; dr 3.8:1).
Methyl (2S)-1-[(2RS)-3-methoxycarbonyl-2-methylpropanoyl]pyrrolidine-2-carbonate
(
12
IR (neat) 1746, 1733, 1652, 1436, 1360, 1197, 1173 cm-1; H-NMR (400 MHz) major
diastereomer: 4.52, (1H, dd, J = 8.3, 4.4 Hz, NCH), 3.78-3.63 (2H, m, NCH2), 3.72
)
1
δ
(3H, s, CO2Me), 3.65 (3H, s, CO2Me), 3.06 (1H, m, CHMe), 2.89 (1H, dd, J = 16.6, 9.6
Hz, CHHCO2Me), 2.38 (1H, m, CHHCO2Me), 2.24 (1H, m, CHHCH), 2.13-1.96 (3H,
m, CHHCH, CH2CH2N), 1.20, (3H, d, J = 6.8 Hz, CHMe); minor diastereomer:
δ 4.47
(1H, dd, J = 8.3, 4.4 Hz, NCH), 3.78-3.63 (2H, m, NCH2), 3.72 (3H, s, CO2Me), 3.65
(3H, s, CO2Me), 3.06 (1H, m, CHMe), 2.81 (1H, dd, J = 16.6, 7.8 Hz, CHHCO2Me),
2.38 (1H, m, CHHCO2Me), 2.24 (1H, m, CHHCH), 2.13-1.96 (3H, m, CHHCH,
CH2CH2N), 1.16 (3H, d, J = 6.8 Hz, CHMe); 13C-NMR (100 MHz) major rotational
isomer of the major diastereomer:
δ 174.2, 173.1, 172.59, 58.6, 52.12, 51.6, 46.85, 37.4,
34.1, 29.10, 24.9, 16.9; minor rotational isomer of the major diastereomer:
δ
175.0, 173.1, 172.56, 59.4, 52.43, 51.6, 46.6, 38.6, 34.2, 31.4, 22.8, 17.7;
rotational isomer of the minor diastereomer:
174.0, 172.9, 172.62, 58.8, 52.1, 51.7, 46.88, 37.8, 34.3, 29.18, 24.8, 17.0;
major
δ
minor
rotational isomer of the minor diastereomer: δ (three carbonyl carbon signals were not
observed or overlapped with those of diastereomers mentioned above),
59.2, 52.64, 51.6, 46.4, 37.6, 34.6, 29.1, 22.5, 17.6; MS (ESI+) (m/z) 258 (MH+);
HRMS calcd for C12H20NO5 (MH+) 258.1341, found 258.1341.
4.3.8 Catalytic hydrogenation of 6 on Pd/C in the presence of MgBr2
To a solution of 6 (25 mg, 0.078 mmol) in dry CH3CN (3 ml) was added MgBr2 (22 mg,
0.12 mmol) and the mixture was stirred at room temperature for 15 min. 10% Pd/C (20
mg, 24 mol%) was added and the mixture was stirred for 2 h under H2 atmosphere.
After filtration through a pad of Celite and Florisil, the solvent was evaporated in vacuo
to afford 13 (25 mg, 100% yield; dr 2.8:1).
Methyl (3RS)-N-[(1S)-1-ethoxycarbonyl-2-phenylethyl]-3-methylsuccinamate (13
IR (KBr) 3329, 1738, 1657, 1535, 1439, 1263, 1200, 1032, 702 cm-1; H-NMR (600
)
1
MHz) major diastereomer:
δ 7.30-7.10 (5H, m, Ph), 6.15 (1H, brd, J = 7.2 Hz, NH),
4.83 (1H, dt, J = 7.6, 6.0 Hz, NCH), 4.18, (2H, q, J = 7.1 Hz, OCH2Me), 3.648, (3H, s,
OMe), 3.14 (1H, dd, J = 13.7, 5.8 Hz, CHHPh), 3.12 (1H, dd, J = 13.7, 8.0 Hz,
CHHPh), 2.78-2.68 (2H, m, CH2CO2Me), 2.34 (1H, m, CHMe), 1.25 (3H, t, J = 7.3 Hz,
CH2Me); minor diastereomer
δ
7.30-7.10 (5H, m, Ph), 6.15 (1H, brd, J = 7.2 Hz, NH),
19

ACCEPTED MANUSCRIPT
4.86 (1H, dt, J = 7.9, 6.0 Hz, NCH), 4.16 (2H, q, J = 7.1 Hz, OCH2Me), 3.653, (3H, s,
OMe), 3.11 (1H, dd, J = 13.7, 8.0 Hz, CHHPh), 3.10 (1H, dd, J = 13.7, 8.0 Hz,
CHHPh), 2.78-2.68 (2H, m, CH2CO2Me), 2.34 (1H, m, CHMe), 1.23 (3H, t, J = 7.1 Hz,
CH2Me), 1.16 (3H, d, J = 6.8 Hz, CHMe); 13C-NMR (100 MHz) major diastereomer:
174.19, 172.44, 171.32, 135.79, 129.22, 128.32, 126.86, 61.36, 53.0, 51.64, 38.0, 37.64,
36.86, 17.7, 14.1; minor diastereomer:
δ
δ 174.21, 173.42, 171.27, 135.82, 129.21, 128.30, 126.88, 60.31, 51.66, 37.85, 37.66,
36.82, 21.0, 14.2; MS (EI+) (m/z) 321 (M+, 6%), 290 (8), 248 (10), 216 (10), 176 (83),
148 (18), 129 (100), 120 (24), 101 (20), 91 (25), 69 (11), 59 (32); HRMS calcd for
C17H24NO5 (MH+) 322.1654, found 322.1688.
4.3.9 Catalytic hydrogenation of 7 on Pd/C in the presence of MgBr
2ꢀOEt2
To a solution of 7 (50 mg, 0.19 mmol) in dry THF (3 ml) was added MgBr2
ꢀ
OEt2 (77
mg, 0.30 mmol) and the mixture was stirred at room temperature for 15 min. 10% Pd/C
(54 mg, 27 mol%) was added and the mixture was stirred for 3.3 h under H2
atmosphere. After filtration through a pad of Celite and Florisil, the solvent was
evaporated in vacuo and the residue was purified by silica gel column chromatography
[SiO2 2 g, hexane-EtOAc (10:1 to 4:1 v/v)] to afford 14 (40 mg, 81% yield; dr 1.8:1).
4-Methyl 1-(4,4-dimethyl-2-oxotetrahydrofuran-3-yl)-2-methylsuccinate (14
IR (neat) 1795, 1743, 1159, 1096, 1071 cm-1; 1H-NMR (400 MHz) major diastereomer:
5.37 (1H, s, OCH), 4.04 (2H, dd, J = 15.6, 9.3 Hz, CH2O), 3.70 (3H, s, OMe), 3.09
)
δ
(1H, m, CHMe), 2.81 (1H, dd, J = 16.6, 7.3 Hz, CHHCO2Me), 2.52 (1H, dd, J = 16.6,
6.3 Hz, CHHCO2Me), 1.32 (3H, d, J = 7.3 Hz, CHMe), 1.21 (3H, s, Me), 1.11 (3H, s,
Me); minor diastereomer
δ 5.38 (1H, s, OCH), 4.04 (2H, dd, J = 15.6, 9.3 Hz, OCH2),
3.69 (3H, s, OMe), 3.04 (1H, m, CHMe), 2.79 (1H, dd, J = 17.0, 8.3 Hz, CHHCO2Me),
2.51 (1H, dd, J = 17.0, 5.4 Hz, CHHCO2Me), 1.31 (3H, d, J = 7.3 Hz, CHMe), 1.22
(3H, s, Me), 1.14 (3H, s, Me); 13C-NMR (100 MHz) major diastereomer:
δ 173.7,
171.9, 171.6, 76.07, 74.99, 51.77, 40.25, 37.23, 35.8, 22.97, 19.8, 16.9; minor
diastereomerδ 174.4, 172.1, 171.8, 76.11, 74.96, 51.73, 40.31, 37.2, 35.6, 22.89, 21.0,
17.0; MS (EI+) (m/z) 227 (M+ - OMe, 16%), 129 (100), 113 (39), 101 (50), 69 (16), 59
(79), 55 (6); HRMS calcd for C12H19O6 (MH+) 259.1181, found 259.1200.
4.3.10 Catalytic hydrogenation of 22 on Pd/C in the presence of MgBr2
To a solution of 22 (49 mg, 0.17 mmol) in dry CH2Cl2 (3 ml) was added MgBr2 (96 mg,
0.51 mmol) and the mixture was stirred at room temperature for 15 min. 10% Pd/C (43
mg, 24 mol%) was added and the mixture was stirred overnight under H2 atmosphere.
20

ACCEPTED MANUSCRIPT
After filtration through a pad of Celite and Florisil, the solvent was evaporated in vacuo
and the residue was purified by silica gel column chromatography [SiO2 2 g,
hexane-EtOAc (10:1 v/v)] to afford a mixture of 23 (less polar diastereomer /more
polar diastereomer =1.9:1) and 24 (42 mg). Separation of the mixture was performed
using silica gel column chromatography [SiO2 10 g, hexane-EtOAc (30:1 to 15:1 v/v)]
to afford less polar diastereomer of 23 (11 mg, 22% yield), more polar diastereomer of
23 (25 mg, 51% yield) and 24 (3.4 mg, 7% yield).
(4R)-4-Benzyl-3-[(2RS)-2-methylhexanoyl]oxazolidin-2-one (23) MS (ESI+) m/z 290
(MH+); HRMS calcd for C17H24NO3 (MH+) 290.1756, found 290.1789.
Less polar minor diastereomer of 23
IR (neat) 1784, 1699, 1386, 1349, 1208, 1099, 762, 703 cm-1; H-NMR (400 MHz)
1
δ
7.35-7.21 (5H, m, Ph), 4.68 (1H, ddt, J = 9.6, 6.4, 3.2 Hz, NCH), 4.23-4.15 (2H, m,
OCH2), 3.71 (1H, sextet, J = 6.9 Hz, COCH), 3.27 (1H, dd, J = 13.5, 3.5, CHHPh),
2.77 (1H, dd, J = 13.5, 9.6, CHHPh), 1.75 (1H, m, COCHCHH), 1.43 (1H, m,
COCHCHH), 1.35-1.28 (4H, m, CH2×2), 1.22 (3H, d, J = 6.9 Hz, CHMe), 0.89 (3H, t,
13
J = 7.1 Hz, CH2Me); C-NMR (100 MHz)
δ 177.4, 153.1, 135.3, 129.4, 128.9, 127.3,
66.0, 55.3, 37.9, 37.7, 33.1, 29.4, 22.7, 17.4, 14.0.
More polar, major diastereomer of 23
IR (neat) 1784, 1699, 1386, 1349, 1208, 1098, 762, 703 cm-1; H-NMR (400 MHz)
1
δ
7.35-7.21 (5H, m, Ph), 4.69 (1H, ddt, J = 11.1, 7.4, 3.7 Hz, NCH), 4.21-4.11 (2H, m,
OCH2), 3.75 (1H, sextet, J = 6.9 Hz, COCH), 3.30 (1H, dd, J = 13.3, 3.7, CHHPh),
2.74 (1H, dd, J = 13.3, 9.6, CHHPh), 1.79 (1H, m, COCHCHH), 1.45 (1H, m,
COCHCHH), 1.35-1.34 (4H, m, CH2×2), 1.18 (3H, d, J = 6.9 Hz, CHMe), 0.91 (3H, t,
J = 6.9 Hz, CH2Me); 13C-NMR (100 MHz)
δ177.4, 153.1, 135.4, 129.4, 128.9, 127.3,
65.9, 55.3, 38.0, 37.4, 33.5, 29.2, 22.7, 16.7, 14.0.
(4R)-4-Benzyl-3-[(Z)-2-methylhex-2-enoyl]oxazolidin-2-one (24
)
1H-NMR (400 MHz)
δ 7.35-7.19 (5H, m, Ph), 6.10 (1H, td, J = 7.3, 1.4 Hz, =CH), 4.72
(1H, m, NCH), 4.25 (1H, t, J = 8.8 Hz, OCHH), 4.15 (1H, dd, J = 8.8, 5.7 Hz, OCHH),
3.36 (1H, dd, J = 13.3, 3.2, CHHPh), 2.83 (1H, dd, J = 13.3, 9.2, CHHPh) , 2.18 (2H, q,
J = 7.3 Hz, =CHCH2), 1.91 (3H, s, =CMe), 1.49 (2H, sextet, J = 7.3 Hz, CH2Me), 0.96
(3H, t, J = 7.3 Hz, CH2Me); 13C-NMR (100 MHz)
δ 172.0, 153.2, 140.1, 135.2, 130.7,
129.5, 128.9, 127.3, 66.3, 55.5, 37.5, 30.4, 21.7, 13.9, 13.5; MS (ESI+) m/z 288 (MH+).
4.4 Conjugate reduction.
Following the procedures described in the literature8, 2, 3, 5 and 6 were reduced using
n-Bu3SnH in the presence of Lewis acid.
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ACCEPTED MANUSCRIPT
4.4.1 Conjugate reduction of 2 with
n-Bu3SnH in the presence of MgI2
To a solution of 2 (30 mg, 0.087 mmol) in CH2Cl2 (3 ml) was added MgI2 (178 mg, 0.64
mmol) and the mixture was stirred at room temperature for 15 min. To the mixture
o
cooled to 0 C was added n-Bu3SnH (50
µl, 0.19 mmol) and the reaction mixture was
stirred at the temperature for 16 h. KF and water were added and the mixture was stirred
at room temperature overnight. After filtration and evaporation, the residue was purified
by silica gel column chromatography [SiO2 3 g; hexane-EtOAc (15:1 v/v) then
hexane-EtOAc (9:1 v/v)] to give a mixture of 8 and 9 (26 mg, 86% yield; 8/9 = 1:4.4).
4.4.2 Conjugate reduction of 3 with n-Bu3SnH in the presence of MgI2
To a solution of 3 (49 mg, 0.16 mmol) in CH2Cl2 (3 ml) was added MgI2 (123 mg, 0.43
mmol) and the mixture was stirred at room temperature for 15 min. To the mixture
o
cooled to 0 C was added n-Bu3SnH (80
µl, 0.30 mmol) and the reaction mixture was
stirred at the temperature for 15 h. KF and water were added and the mixture was stirred
at room temperature overnight. After filtration and evaporation, the residue was purified
by silica gel column chromatography [SiO2 3 g; hexane-EtOAc (20:1 v/v) then
hexane-EtOAc (5:1 v/v)] to give an inseparable mixture of 10 (50mg, 100% yield; dr
1.6:1).
4.4.3 Conjugate reduction of 6 with n-Bu3SnH in the presence of MgI2
To a solution of 6 (26 mg, 0.081 mmol) in CH2Cl2 (3 ml) was added MgI2 (69 mg, 0.25
mmol) and the mixture was stirred at room temperature for 15 min. To the mixture
o
cooled to 0 C was added n-Bu3SnH (30
µl, 0.16 mmol) and the reaction mixture was
stirred at the temperature for 17 h. KF and water were added and the mixture was stirred
at room temperature overnight. After filtration and evaporation, the residue was purified
by silica gel column chromatography [SiO2 3 g; hexane-EtOAc (5:1 v/v) then
hexane-EtOAc (3:1 v/v)] to give an inseparable mixture of 13 and the starting material 6
(23mg, 86% yield; 13/6 = 6.4:1; dr 1:1.6 for 13).
References
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22

ACCEPTED MANUSCRIPT
Helv. Chim. Acta 1990, 73, 1276-1299.
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16. (a) Garner, P.; Dogan, Ö.; Youngs, W. J.; Kennedy, V. O.; Protasiewicz, J.;
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Graphical Abstract
25

ACCEPTED MANUSCRIPT
Fig. 1. C5 Chiral unit A for the synthesis of natural products having 1,5-dimethylalkyl
motif.