A Facile, Six-Step Process for the Synthesis of (3 S,5 S)-3-Isopropyl-5-((2 S,4 S)-4-isopropyl-5-oxo-tetrahydrofuran-2-yl)-2-oxopyrrolidine-1-carboxylic Acid tert -Butyl Ester, the Key Synthetic Intermediate of Aliskiren

Article abstract of DOI:10.1021/acs.oprd.5b00009

A facile, six-step process for the synthesis of (3S,5S)-3-isopropyl-5-((2S,4S)-4-isopropyl-5-oxotetrahydro- furan-2-yl)-2-oxopyrrolidine-1-carboxylic acid tert-butyl ester from (S)-4-benzyloxazolidin-2-one 2 in an overall 50% yield is reported. The key transformations include: a highly efficient diastereoselective epoxidation, Lewis acid-catalyzed ring-opening with bromide, an S_N2 reaction using NaN₃, and a tandem reduction-cyclization reaction.

Full text of DOI:10.1021/acs.oprd.5b00009

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Full Paper
A facile, six-step process for the synthesis of (3S,5S)-3-isopropyl-5-
(2S,4S)-4-isopropyl-5 -oxo-tetrahydrofuran-2-yl)-2-oxopyrrolidine-1-
(
carboxylic acid tert-butyl ester, the key synthetic intermediate of aliskiren
Xianhua Pan, Siyao Xu, Rui Huang, Wansheng Yu, and Feng Liu
Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 21 May 2015
Downloaded from http://pubs.acs.org on May 21, 2015
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A facile, six-step process for the synthesis of
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(
-
3S,5S)-3-isopropyl-5-((2S,4S)-4-isopropyl-5
oxo-tetrahydrofuran-2-yl)-2-oxopyrrolidine-1-car
boxylic acid tert-butyl ester, the key synthetic
intermediate of aliskiren
‡
‡
†
Xianhua Pan, Siyao Xu, Rui Huang, Wansheng Yu and Feng Liu*
School of Perfume and Aroma Technology, Shanghai Institute of Technology, 100
Haiquan Rd, Shanghai, 201418, P.R. China.
*
Eꢀmail: liufeng@sit.edu.cn.
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ABSTRACT:
A facile, sixꢀstep process for the synthesis of (3S,5S)ꢀ3ꢀisopropylꢀ5ꢀ((2S,4S)ꢀ4ꢀisopropylꢀ5ꢀoxotetrahydroꢀ
furanꢀ2ꢀyl)ꢀ2ꢀoxopyrrolidineꢀ1ꢀcarboxylic acid tertꢀbutyl ester from (S)ꢀ4ꢀbenzyloxazolidinꢀ2ꢀone 2 in an
overall 50% yield is reported. The key transformations include: a highly efficient diastereoselective
epoxidation, Lewis acidꢀcatalyzed ringꢀopening with bromide, an S 2 reaction using NaN and a tandem
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N
3
reductionꢀcyclization reaction.
KEYWORDS: aliskiren, diastereoselective, epoxidation, Lewis acid, azidation, tandem
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INTRODUCTION:
Aliskiren (1) is the first of a new class of orally effective direct renin inhibitors, which was approved by
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®
®
the U.S. Food and Drug Administration (FDA) in 2007 and marketed by Novartis AG (Rasilez , Enviage ,
®
® 1ꢀ4
Sprimeo and Tekturna ). Although it has received a warning and contraindication from the U.S. FDA in
2012 because of the potential risk of renal failure and angioedema, its superior blood pressureꢀlowering
efficacy and unique chemical structure still captures the interest of pharmaceutical companies and
synthetic chemists.
The difficulty and challenge of synthesizing aliskiren lies in the construction of its four chiral centers
(
Scheme 1). Lots of effort and several synthetic approaches towards the synthesis of aliskiren have been
5
reported in the recent literature. Göschke etc. provided a protocol that the core 4,5ꢀ(S)ꢀaminoꢀhydroxy
5
a
was introduced by haloꢀlactonization and the following azidation.
Rüeger etc. reported in 2000 a
convergent synthetic route, the key reaction employed the coupling of Grignard reagent with the
5b
5c
diastereomeric pure γꢀlactone and enantioselective reduction. The linchpin of Sandham’s synthesis
routes was the enantioselective Grignard addition to the amide spiroacetal, which was introduced by the
pseudoephedrine chiral auxiliary. Dondoni and colleagues synthesized the core chiral βꢀamino alcohol
5d
segment via the Grignard addition to the pseudoephedrine spiroanellated γꢀbutyolactone derivative.
5e
Göschke etc. reported another convergent synthesis of aliskiren in 2003, in which the key chiral amine
was introduced by the alkylation of the chiral Schöllkopf dihydropyrazine. Ma’s synthetic route was based
5f
on the approach reported by Göschke along with modifications. Hanessian devised a “macrocycle route”
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toward aliskiren, include a chllenging RCM reaction to produce a nineꢀmembered unsaturated lactone, a
highly enantioselective catalytic Du Bois aziridination, and a regioꢀ and diastereoselective aziridine ring
5
g
opening to a vicinal amino alcohol. Prasad etc. described a 12ꢀstep synthesis of aliskiren that features a
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5
h
Curtius rearrangement to transform carboxylic acid to the benzyl carbamate via the isocyanate. Ko
reported a total synthesis of aliskiren, in there route they used the symmetric transꢀcisoidꢀtransꢀbis latone
5i
as a key precursor.
Scheme 1. A convergent synthetic route towards aliskiren.
Among the synthetic approaches reported, the convergent routes that disconnect aliskiren into three
5a, j, m
independent segments are the most effective and convenient (Scheme 1).
As part of our continuing interest in developing efficient and practical processes for the synthesis of active
6
pharmaceutical ingredients (API) and intermediates, we now report a facile and convergent sixꢀstep
approach towards the synthesis of (3S,5S)ꢀ3ꢀisopropylꢀ5ꢀ((2S,4S)ꢀ4ꢀisopropylꢀ5ꢀoxoꢀtetrahydrofuranꢀ
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ꢀyl)ꢀ2ꢀoxopyrrolidineꢀ1ꢀcarboxylic acid tertꢀbutyl ester (Segment B), the key synthetic intermediate of
aliskiren (Scheme 2).
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Scheme 2. Original retrosynthetic analysis of Segment B.
RESULTS AND DISCUSSION:
Choice of Synthetic Strategy
Our original synthetic strategy was based on the approaches reported by Göschke, Mickel and Kidemet
5a, j, m
respectively.
In order to simplify the reaction steps and optimize the workꢀup procedures, we have
suggested an alternative synthetic route (Scheme 2). We found that 2,7ꢀ(S)ꢀisopropyl and 1,8ꢀdicarbonyl
groups of Segment
B could be easily prepared using the Evans chiral auxillary 4 and
(
Z)ꢀ1,4ꢀdibromoꢀbutꢀ2ꢀene 5a. The adjacent 4ꢀ(S)ꢀamino and 5ꢀ(S)ꢀhydroxyl groups could be introduced in
one step by the nucleophilic NaN ringꢀopening at the C4ꢀposition of (4R,5S)ꢀepoxide 7a. As 6a is a C2
3
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symmetrical chiral compound, epoxidation on either face of the alkene will produce the same enantiomer,,
(4R,5S)ꢀepoxide 7a. However, there is not much regioꢀselectivity of C4ꢀ and C5ꢀ position of 7a in the
epoxide opening reaction we did not expect high diastereoelectivity for this direct azidation (Scheme 3).
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Epoxidation on either face of the
alkene produces same enantiomer
C2 axis in the plane of the paper
O
O
5
5
7
(S)
7
(S)
5
4
2
(S)
4
2
(S)
4
O
2
7
O
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O
O
O
(
S)
(S)
(R) (S)
+
(S) (R)
epoxidation
N
N
(S) N
N
(S)
Bn
Bn
(
S) N
N
(S)
Bn (S)
O
O
(S) Bn
Bn
O
O
O
O
Bn
NaN3
NaN3
O
O
O
O
O
O
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a
7
a
6a
O
O
O
(
S)
Bn
O
Bn
O
(
S)
N
O
O
N
O
2
(S)
4
(R)
(R)
(S)
5
(S)
(S)
(S)
(S)
7
O
O
5
N3
7
2
4
N3
9
'
9
Scheme 3. The nucleophilic ringꢀopening reaction of (4R,5S)ꢀepoxide 7a with NaN3.
Since the direct azidation of 7a was not feasible, we have designed a double inversion strategy (Scheme
4). We envisaged that azide 9 could be prepared via a ringꢀopening reaction of 7 with bromide and the
following nucleophilic azidation. The absolute configuration of the chiral center would undergo a double
inversion to form the (4S)ꢀamino and (5S)ꢀhydroxy functionality in compound 9. Therefore, epoxide 7a was
replaced by (4S,5S)ꢀepoxide 7. No matter which position (C4ꢀ or C5ꢀ) of 7 was attacked, the axis
symmetry of 7 could guarantee the formation of a same enantiomer 8 bearing the required (4S)ꢀamino and
(5R)ꢀbromide. Compound 9 with the anticipated (4S)ꢀamino and (5S)ꢀhydroxy functionality would be easily
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formed after the SNꢀ2 azidation.. And the desired (4S, 5S)ꢀepoxide 7 could be constructed by the
7
epoxidation of the related unsaturated dicarbonyl compound 6, which could be prepared from the Evans
chiral auxillary 4 and (E)ꢀ1,4ꢀdibromobutꢀ2ꢀene 5.
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(S)
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O 8
(S)
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(
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N
O
(S)
5
7 (S)
(S)
(R)
2
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(S)
(
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5
NBoc
(S)
(S)
7
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6
O
(S)
Br
O
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4
N3
8
Segment B
9
5
3
(E)
Br
6
O
O
(
S)
(S)
Br
4
5
Bn
(S)
Bn
O
O
O
N
N
+
7
(S)
5
O
O
4
(S)
6
(S)
(
S)
(S)
O
O
4
O
2
N (S)
N (S) Bn
O
2,7
Bn
O
O
Br
N 1,8
(S)
O
O
O
6
7
Bn
C2 axis preserved perpendicular to
the plane of paper. Epoxide
opening at either position produce
same result.
4
C2 axis perpendicular to
the plane of paper.
Scheme 4. Modified retrosynthetic analysis of Segment B.
Synthesis of (4S,5S)-epoxide 7.
Our synthesis begins from (S)ꢀ4ꢀbenzyloxazolidinꢀ2ꢀone 2 (Scheme 5). Upon treatment with nꢀBuLi and
isoamyl chloride 3, the Evans chiral auxillary 4 was formed in 94% yield. Then, an alkylation reaction using
2
eq. of oxazolidinone 4 and 1 eq. of 1,4ꢀdibromoꢀbutꢀ2ꢀene 5 in the presence of lithium
hexamethyldisilazide (LiHMDS) and 1,3ꢀdimethylꢀ3,4,5,6ꢀtetrahydroꢀ2(1H)ꢀpyrimidinone
(DMPU) at ꢀ40 °C
gave alkene 6 in 88% yield with the expected (2S,7S)ꢀdiisopropyl configuration.
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Scheme 5. Synthesis of 7
We were pleased to find out that the following epoxidation reaction of 6 could be carried out smoothly
1
and gave 7 in 91% yield with excellent diastereoselectivity (d.e. >99%, as ascertained by H NMR
7
spectroscopy). We envisioned that the high steric hindrance of 6 should facilitate the diastereospecific
8
epoxidation at the topꢀface of the paper plane to form the (4S,5S)ꢀepoxide 7. With the chiral epoxide 7 in
hand, the desired S 2 ringꢀopening reaction of (4S,5S)ꢀepoxide 7 with bromide was thoroughly studied
N
and the reaction conditions optimised.
The S 2 ring-opening reaction of (4S,5S)-epoxide 7
N
We have investigated the ringꢀopening reaction of (4S,5S)ꢀepoxide 7 with respect to the following four
key variables: (1) bromide, (2) additive (loading), (3) solvent and (4) temperature. The bromination of
(
4S,5S)ꢀepoxide 7 using sodium bromide in DMF/H O was initially attempted, but only the starting material
2
was recovered even after heating to 120 °C for 24 h (Table 1, entry 1). We then examined some other
sources of bromide such as KBr, LiBr and even the more reactive and nucleophilic KI. Unfortunately,
neither produced the desired product (Table 1, entry 2ꢀ4). An enhancement in the conversion to 8 was
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achieved with the use of 2 eq. of HBr as the bromide source (Table 1, entry 5), revealing that an acidic
environment could promote the desired ringꢀopening reaction.
Therefore, a series of acids such as Brφnstded acids (Table 1, entry 6ꢀ8), acidic resin (Table 1, entry 9)
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and Lewis acid (Table 1, entry 10) were used as an acidic additive. Mg(ClO ) proved to be the best acidic
4
2
additive (Table 1, entry 10). After screening of the solvent and the reaction temperature, THF was finally
chosen as the reaction solvent at 80 ºC (Table 1, entry 16). We then found that an increased amount of
LiBr and Mg(ClO ) could further improve the yield. Consequently, 5 equiv of LiBr / 10 equiv of Mg(ClO )
4 2
4
2
was used (Table 1, entry 18), considering the cost and the fact that adding more LiBr and Mg(ClO ) made
4 2
the reaction mixture too viscous to be stirred smoothly (Table 1, entry 19). With the optimized conditions,
enantiopure compound 8 was obtained in 82% yield and 99% d.e. after simple workꢀup.
a
Table 1. The ringꢀopening reaction of (4S,5S)ꢀepoxide 7 to give bromide 8.
b
Bromide
eq.)
Additive
(eq.)
Temp.
(°C)
Yield
%
Entry
solvent
(
c
c
c
c
1
2
3
4
5
6
7
NaBr (2)
KBr (2)
ꢀ
DMF/H O
120
120
120
120
20
ꢀ
2
ꢀ
DMF/H
DMF/H
DMF/H
DCM
2
2
2
O
O
O
ꢀ
d
LiBr (2)
ꢀ
ꢀ
ꢀ
KI (2)
ꢀ
e
HBr (2)
ꢀ
12
trace
6
LiBr (2)
LiBr( 2)
H SO (2)
DCM
20
2
4
HCl (3)
DCM
20
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LiBr (2)
LiBr (2)
LiBr (2)
LiBr (2)
LiBr (2)
LiBr (2)
LiBr (2)
LiBr (2)
LiBr (2)
LiBr (3)
LiBr (5)
LiBr (7.5)
H PO (3)
DCM
DCM
DCM
20
20
20
20
80
80
80
80
80
80
80
80
10
15
3
4
Amberlyst 15 (3)
0
Mg(ClO ) (3)
21
4
2
11
Mg(ClO ) (3)
CH CN
28
4
2
3
12
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Mg(ClO ) (3)
CH CN
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53
54
55
56
57
58
59
60
4 2
3
Mg(ClO ) (3)
DMF
<10
<10
25
4
2
Mg(ClO ) (3)
DMSO
Acetone
THF
4 2
Mg(ClO ) (3)
4
2
16
Mg(ClO ) (3)
55
4
2
17
Mg(ClO ) (5)
THF
68
4
2
f
18
Mg(ClO ) (10)
THF
82
4
2
g
19
Mg(ClO ) (15)
THF
85
4
2
a
All reactions were carried out under the following conditions unless stated otherwise: 7 (1 mmol), bromide,
b
c
d
catalyst, solvent (6 mL), temperature, 24 h. Yields calculated by HPLC. DMF : H O = 2:1. 5 eq. LiBr was
2
e
f
added and no reaction product was observed. 47% aqueous HBr solution. Yield after purification by
g
crystallization. The reaction mixture was too viscous to be stirred smoothly.
Azidation of bromide 8 to give 9
Then, the (R)ꢀbromide 8 was reacted with NaN to fulfill the second nucleophilic substitution reaction
3
with inversion of configuration at C4 (Scheme 6).
At the beginning, the reaction of bromide 8 with 2 eq. of NaN at 25 ºC in DMF gave only a small
3
amount of desired product with the starting material 8 being largely recovered (Table 2, entry 1). An
increase of reaction temperature and the amount of NaN (3 eq.) accelerated the conversion of starting
3
material, but the eliminated byꢀproducts 9a and 9b were formed preferentially. The formation of 9a and 9b
was caused by the alkaline reaction conditions used (Table 2, entry 2). In order to reduce the basicity of the
reaction system, a series of quaternary ammonium salts were screened as a buffer reagent (Table 2, entry
3ꢀ7). We found that (nꢀC H ) NMeCl gave the best results and promoted the azidation reaction to give 9 in
8 17 3
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9
5% yield without any byꢀproduct formation (Table 2, entry 6). 0.1 equiv of (nꢀC H ) NMeCl with 2 equiv of
8
17 3
NaN was enough for the reaction and 9 was formed in high yield without 9a and 9b (Table 2, entries 8 and
3
9). However, less (nꢀC H ) NMeCl had a slight negative effect on the reaction resulting in lower yield of
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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9
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9
0
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2
3
4
5
6
7
8
9
0
8 17 3
desired product along with 3% of the byꢀproducts 9a and 9b being detected (Table 2, entry 10).
Scheme 6. Azidation of bromide 8
a
Table 2 Azidation of bromide 8 to give azide 9.
b
NaN3
Additive
(eq.)
Temp
(°C)
Yield (%)
Entry
Solvent
(
eq.)
2
9
9a+9b
1
2
3
4
5
6
7
8
9
ꢀ
ꢀ
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
25
80
80
80
80
80
80
80
80
80
11
35
58
69
75
95
89
95
/
63
38
28
22
/
3
3
NH Cl (1.0)
4
3
(nꢀBu) NCl (1.0)
4
3
(nꢀBu) NBr (1.0)
4
3
(nꢀC H ) NMeCl (1.0)
8
17 3
c
3
[BMIM]BF (1.0)
9
4
3
(nꢀC H ) NMeCl (0.2)
/
8
17 3
d
2
(nꢀC H ) NMeCl (0.1)
94
/
8
17 3
10
2
(nꢀC H ) NMeCl (0.05)
90
3
8
17 3
a
All reactions were carried out under the following reaction conditions unless stated otherwise: 8 (1
b
mmol), NaN , additive, DMF (5 mL), temperature, 24 h. Yields calculated by HPLC.
c
3
d
1
ꢀButylꢀ3ꢀmethylimidazolium tetrafluoroborate. After workꢀup and recrystallization, a white powder
was obtained in 87% yield and 99% d.e.
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Tandem reduction-cyclization reaction of 9
Finally, lactam 10 was constructed from azide 9, presumably through the intermediate γꢀamine, with
oxazolidinone 2 being disconnected and recovered. Then, transformation of compound 10 with Boc O
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2
finished the process to produce the target molecule Segment B (Scheme 7). The NMR spectra and HPLC
retention time for Segment B was in accordance with those obtained with a commercially available
sample.
Scheme 7. Synthesis of Segment B from 9.
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5
5
6
CONCLUSIONS:
A
facile, sixꢀstep process for the synthesis of (3S,5S)ꢀ3ꢀisopropylꢀ5ꢀ((2S,4S)ꢀ4ꢀisopropylꢀ
5ꢀoxotetrahydroꢀfuranꢀ2ꢀyl)ꢀ2ꢀoxopyrrolidineꢀ1ꢀcarboxylic acid tertꢀbutyl ester was developed from
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
S)ꢀ4ꢀbenzyloxazolidinꢀ2ꢀone 2 in an overall 50% yield. The key transformations include: a highly efficient
diastereoselective epoxidation of 6, Mg(ClO ) promoted ringꢀopening of 7 with LiBr, a stereospecific S 2
4
2
N
reaction using NaN and a tandem reductionꢀcyclization reaction. This process allowed us to conveniently
3
produce Segment B on a multiꢀkilogram scale. Further improvement to the synthesis of the API of aliskiren
(
1) is currently under investigation in our group.
EXPERIMENTAL SECTION:
All compounds were purchased from commercial sources and used directly unless stated otherwise. NMR
spectra were recorded using an Avance 500 MHz spectrometer. ESIꢀMS were recorded on a Waters
Quatro Premier XE Mass Spectrometer. High resolution mass spectra were recorded on a Brucker Solaril
X70 mass spectrometer. HPLC was carried out on a Dionex Ultimate 3000 spectrometer. Melting points
were determined with a SGW Xꢀ4 micro melting point apparatus. Optical rotations were obtained on a
PerkinꢀElmer 241 Autopol polarimeter.
(
S)ꢀ4ꢀBenzylꢀ3ꢀ(3ꢀmethylꢀbutanoyl)oxazolidinꢀ2ꢀone (4): In an argonꢀpurged reactor, compound 2 (500 g,
2.82 mol) was dissolved in THF (5.5 L) at ꢀ30 – ꢀ25 °C. Then, nꢀBuLi (2.4 M, 1.2 L, 2.88 mol) was added to
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this solution over 30 minutes. After stirring for 1 h at ꢀ30 – ꢀ25 ºC, compound 3 (355.3 g, 2.96 mol) in THF
(1 L) was added and the reaction mixture stirred for another 1.5 h at ꢀ25 ºC. The reaction mixture was
diluted with 5 L of saturated ammonium chloride solution and 5 L of EtOAc, the organic phase was
separated. After washing the organic layer with water the solvent was removed by evaporation. The crude
material was dissolved in 500 mL of ethyl ether and 1 L of heptane at reflux until a clear solution was
obtained. Then, the solution was allowed to cool down to room temperature. The crystallization starts
almost immediately and was completed by stirring for a further 5 h at 10 °C. After filtration, the cake was
10
11
12
13
14
15
16
17
18
19
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23
24
25
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28
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
washed with 3 L of a cold heptane and dried under vacuum at 40 ºC to give product 4 as a white solid
1
(
693.1 g, 94%). H NMR (500 MHz, CDCl ) δ 7.31ꢀ7.18 (m, 5H), 4.66 (ddd, J = 10.7, 7.0, 3.3 Hz, 1H),
3
4.18ꢀ4.10 (m, 2H), 3.27 (dd, J = 13.4, 3.3 Hz, 1H), 2.88 (dd, J = 16.1, 6.7 Hz, 1H), 2.79ꢀ2.72 (m, 2H), 2.21
13
(
dp, J = 13.5, 6.7 Hz, 1H), 1.01 (dd, J = 8.2, 6.7 Hz, 6H). C NMR (125 MHz, CDCl ) δ 172.54, 153.40,
3
135.41, 129.40, 128.89, 127.26, 66.07, 55.08, 43.95, 37.91, 24.99, 22.55, 22.44. ESIꢀMS m/z: 262.2
+
+
(
M+1) . HRMS calcd for C H NNaO (M+Na) requires 284.1263, found 284.1270.
15 19 3
(
2S,7S,E)ꢀ1,8ꢀBis((S)ꢀ4ꢀbenzylꢀ2ꢀoxooxazolidinꢀ3ꢀyl)ꢀ2,7ꢀdiisopropyloctꢀ4ꢀeneꢀ1,8ꢀdione
(6):
In
an
argonꢀpurged reactor, compound 4 (2690 g,10.3 mol) and 1.0 M LiHMDS (11 L, 11 mol) was dissolved in
THF (8 L) at ꢀ50 ºC and the solution stirred for 1 h before DMPU (2900 g, 22.6 mol) was added. After
stirring for 2 h at ꢀ50 ºC, 1,4ꢀdibromoꢀ2ꢀbuten 5 (877 g, 4.1 mol) in anhydrous tetrahydrofuran (1.8 L) was
added and the reaction mixture kept at ꢀ50 ºC for 1 h and allowed to warm up to 0 ºC. After stirring at 0 ºC
for 1 h and at 5–10 ºC for 1.5 h, the solution was quenched with 5 L of saturated ammonium chloride
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2
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6
solution. The resulting solution was extracted with ethyl acetate (3 x 3 L). The combined ethyl acetate
extracts were washed with 1 M HCl (3 x 3 L), dried over anhydrous MgSO , filtered and concentrated. The
4
crude material was dissolved in 1.5 L of MeOH at reflux until a clear solution was obtained. The solution
was allowed to cool down to room temperature. The crystallization was completed by stirring for further 5 h
at 10 °C. After filtration, the cake was washed with 2 L of a cold MeOH and dried under vacuum at 40 ºC to
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
20
1
give product 6 as a white solid (5210 g, 88 %). [α]D = 79.1 (c 1.0, CH Cl ). M.p. 108 ꢀ 111 ºC. H NMR
2
2
(500 MHz, CDCl ) δ 7.36ꢀ7.18 (m, 10H), 5.54 (t, J = 3.8 Hz, 2H), 4.66 (ddt, J = 10.2, 6.8, 3.3 Hz, 2H),
3
4.37ꢀ4.06 (m, 4H), 3.79 (ddd, J = 9.8, 7.1, 4.2 Hz, 2H), 3.32 (dd, J = 13.3, 3.2 Hz, 2H), 2.70 (dd, J = 13.3,
10.1 Hz, 2H), 2.42ꢀ2.40 (m, 2H), 2.31ꢀ2.29 (m, 2H), 1.97 (dq, J = 13.6, 6.8 Hz, 2H), 0.94 (dd, J = 10.8, 6.8
13
Hz, 12H). C NMR (125 MHz, CDCl ) δ 175.58, 153.22, 135.70, 129.43, 128.88, 127.19, 65.76, 55.55,
3
+
4
8.65, 37.92, 31.95, 30.11, 20.80, 19.15. ESIꢀMS m/z: 575.2 (M+1) . HRMS calcd for C H N NaO
34
42
2
6
+
(M+Na) requires 597.2941, found 597.2933.
(
4S,4'S)ꢀ3,3'ꢀ((2S,2'S)ꢀ2,2'ꢀ((2S,3S)ꢀOxiraneꢀ2,3ꢀdiylbisꢀ(methylene))bis(3ꢀmethylbutanoyl))bis(4ꢀbenzylox
azolidinꢀ2ꢀone) (7): In a reactor, substrate 6 (3200 g, 5.57 mol) and mꢀCPBA (980 g, 5.68 mol) were
dissolved in DCM (15 L).The reaction mixture was stirred for 1.5 h at 0 ºC. The reaction was quenched
with 5 L of saturated sodium carbonate solution. The DCM phase was dried over anhydrous MgSO4,
filtered and concentrated to give a pale yellow oil (2990 g, 91%), which could be used directly without any
1
further purification in next reaction. H NMR (500 MHz, CDCl ) δ 7.41ꢀ7.11 (m, 10H), 4.63 (ddt, J = 10.5,
3
7.4, 2.9 Hz, 2H), 4.20ꢀ4.03 (m, 4H), 3.83 (ddd, J = 10.8, 6.4, 3.0 Hz, 2H), 3.47 (dd, J = 13.4, 3.2 Hz, 2H),
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2
.89 (t, J = 4.1 Hz, 2H), 2.77 (dd, J = 13.4, 10.5 Hz, 2H), 2.27 (ddd, J = 14.5, 11.1, 3.7 Hz, 2H), 1.95 (dq, J
13
= 13.4, 6.7 Hz, 2H), 1.71 (ddd, J = 14.2, 4.8, 3.1 Hz, 2H), 1.00ꢀ0.86 (m, 12H). C NMR (125 MHz, CDCl3)
δ 175.49, 153.27, 136.00, 129.48, 128.82, 127.01, 65.86, 55.82, 44.59, 37.52, 30.56, 30.24, 20.57, 19.01.
10
11
12
13
14
15
16
17
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19
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
+
ESIꢀMS m/z: 591.3(M+1) . HRMS calcd for C H N NaO (M+Na) requires 613.2890, found 613.2881.
34
42
2
7
(
S)ꢀ4ꢀBenzylꢀ3ꢀ((2S,4R)ꢀ4ꢀbromoꢀ2ꢀisopropylꢀ4ꢀ((2S,4S)ꢀ4ꢀisopropylꢀ5ꢀoxotetrahydrofuranꢀ2ꢀyl)butanoyl)o
xazolidinꢀ2ꢀone (8): In an argonꢀpurged reactor, substrate 7 (171 g, 0.29 mol), anhydrous LiBr (126 g, 1.45
mol) and anhydrous Mg(ClO ) (648 g, 2.9 mol) was dissolved in anhydrous THF (3 L) .The reaction
4 2
mixture was stirred for 3 h at 80 °C. The reaction was quenched with 5 L of saturated sodium carbonate
solution and extracted with ethyl acetate (3 × 5 L) and the combined organic layers evaporated. The crude
material was dissolved in 400 mL of MeOH at reflux until a clear solution was obtained. The solution was
allowed to cool down to room temperature. After filtration the cake was washed with 300 mL of cold MeOH
20
and dried under vacuum at 40 ºC to give product 8 as a white solid (494 g, 82%). [α]D = 45.4 (c 1.0,
1
CH Cl ). M.p. 92 ꢀ 95 ºC. H NMR (500 MHz, CDCl ) δ 7.52ꢀ7.09 (m, 5H), 4.64 (tt, J = 9.7, 3.6 Hz, 1H),
2
2
3
4
.48 (dt, J = 8.0, 5.9 Hz, 1H), 4.21ꢀ4.05 (m, 3H), 4.05ꢀ3.87 (m, 1H), 3.41 (dd, J = 13.3, 3.1 Hz, 1H),
.78ꢀ2.54 (m, 2H), 2.45 (dt, J = 14.9, 9.5 Hz, 1H), 2.34ꢀ2.06 (m, 4H), 1.94 (dq, J = 13.4, 6.7 Hz, 1H), 0.95
2
13
(ddd, J = 10.9, 9.7, 5.5 Hz, 12H). C NMR (125 MHz, CDCl ) δ 177.71, 174.75, 153.27, 135.56, 129.40,
3
1
28.93, 127.25, 79.29, 65.97, 57.25, 55.84, 46.89, 45.52, 37.53, 33.31, 31.41, 29.26, 27.32, 20.28, 20.13,
+
+
1
8.70, 18.43. ESIꢀMS m/z: 494.3 (M+1) . HRMS calcd for C H BrNNaO (M+Na) requires 516.1362,
24 32 5
found 516.1351.
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1
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1
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2
2
2
2
2
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(
S)ꢀ3ꢀ((2S,4S)ꢀ4ꢀAzidoꢀ2ꢀisopropylꢀ4ꢀ((2S,4S)ꢀ4ꢀisopropylꢀ5ꢀoxotetrahydrofuranꢀ2ꢀyl)butanoyl)ꢀ4ꢀbenzylox
azolidinꢀ2ꢀone (9): In an argonꢀpurged reactor, substrate 8 (1630 g, 3.3 mol), methyl trioctyl ammonium
chloride (133 g, 0.33 mol) and NaN (429 g, 6.6 mol) were dissolved in DMF (16 L). After stirring for 24 h at
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
7
5 ºC, the reaction was quenched with 10 L of water and extracted with ethyl acetate (3 × 20 L). The
combined ethyl acetate layers were dried over anhydrous MgSO , filtered and concentrated. The crude
4
material was dissolved in 7 L of heptane and 7 L of methyl tertꢀbutyl ether at reflux until a clear solution
was obtained. The solution was allowed to cool down to room temperature. After filtration the cake was
washed with 10 L of heptane and dried under vacuum at 40 ºC to give product 9 as a white solid (1309 g,
20
1
8
7%). [α]D = 36.0 (c 1.0, CH Cl ). M.p. 96 ꢀ 98 ºC. H NMR (500 MHz, CDCl ) δ 7.44ꢀ7.11 (m, 5H), 4.70
2
2
3
(
ddd, J = 13.4, 6.8, 3.3 Hz, 1H), 4.44 (dt, J = 8.0, 5.9 Hz, 1H), 4.25ꢀ4.12 (m, 2H), 4.02 (ddd, J = 11.4, 5.0,
2
.8 Hz, 1H), 3.31 (dd, J = 13.3, 3.7 Hz, 1H), 3.13 (ddd, J = 10.4, 5.2, 2.8 Hz, 1H), 2.76 (dd, J = 13.3, 9.7 Hz,
1H), 2.67ꢀ2.58 (m, 1H), 2.22ꢀ2.09 (m, 3H), 2.09ꢀ1.93 (m, 2H), 1.75 (ddd, J = 13.8, 9.2, 3.9 Hz, 1H), 1.02
1
3
(
dd, J = 6.8, 2.9 Hz, 6H), 0.92 (d, J = 10.0 Hz, 3H), 0.90 (d, J = 10.0 Hz, 3H). C NMR (125 MHz, CDCl ) δ
3
1
77.71, 175.01, 153.00, 135.28, 129.39, 128.98, 127.35, 80.59, 77.37, 77.11, 76.86, 66.13, 64.01, 55.64,
+
4
5.32, 45.07, 38.09, 30.89, 29.22, 28.01, 27.08, 20.75, 20.31, 18.49, 18.17. ESIꢀMS m/z: 457.1 (M+1) .
+
HRMS calcd for C H N NaO (M+Na) requires 479.2270, found 479.2258.
24
32
4
5
(
3S,5S)ꢀtertꢀButylꢀ3ꢀisopropylꢀ5ꢀ((2S,4S)ꢀ4ꢀisopropylꢀ5ꢀoxotetrahydrofuranꢀ2ꢀyl)ꢀ2ꢀoxopyrrolidineꢀ1ꢀcarbox
ylate (11): Compound 9 (3000 g, 6.57 mol) was dissolved in 10 L of toluene. The reactor was transferred
under 20 bar of H pressure and hydrogenated by addition of 150 g of Pd/C (5 %). After 24 h the
2
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suspension was then filtered. 2N NaOH (3.8 L, 7.6 mol) was adding to the filtrate at 0 ºC and the mixture
stirred for 1 h. A white solid (compound 2) was precipitated and was collected by filtration and the filtrate
was extracted with toluene (3 X 3 L). The combined organic layers were concentrated and another part of
compound 2 could be recovered. The aqueous layer was acidified with 2N HCl to pH = 3, a white solid was
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formed and the suspension stirred for another 30 min and filtered. The white powder was dissolved in
.
toluene (15 L) again and to this solution pꢀTsOH H O (126 g, 0.66 mol) was added and stirred overnight at
2
room temperature, then washed with saturated NaHCO and brine, dried, filtered and concentrated to give
3
compound 10 as a pale yellow solid. Compound 10 and DMAP (7.3 g, 0.06 mol) was dissolved in 10 L of
ethyl acetate. To this solution was added Et N (587 g, 5.88 mol). This solution was warmed at 50 °C. At
3
this temperature a solution of (Boc) O (1540 g, 7.04 mol) was added over 10 min. The reaction solution
2
was stirred for 12 h at 50 °C. After this time, the reaction solution was cooled down to 0–5 ºC and stirring
continued at this temperature for 5 h. After filtration the product cake was washed with 5 L of cold ethyl
20
acetate/heptane and dried under vacuum at 40 ºC to give product 11 as a white solid (1930 g, 93 %). [α]D
1
=
4
ꢀ36.3 (c 1.0, CH Cl ). M.p. 142 ꢀ 146 ºC. H NMR (500 MHz, CDCl ) δ 4.49 (dd, J = 7.2, 2.4 Hz, 1H),
2 2 3
.35ꢀ4.24 (m, 1H), 2.64 (d, J = 1.8 Hz, 1H), 2.51 (d, J = 5.3 Hz, 1H), 2.21 (s, 1H), 2.17ꢀ2.06 (m, 3H), 1.98
(
d, J = 9.1 Hz, 1H), 1.84ꢀ1.73 (m, 1H), 1.51 (s, 9H), 1.00 (dd, J = 9.9, 6.9 Hz, 6H), 0.91 (d, J = 6.8 Hz, 3H),
13
0.84 (d, J = 6.8 Hz, 3H). C NMR (125 MHz, CDCl ) δ 177.27, 174.68, 150.31, 83.55, 78.82, 77.32, 77.07,
3
+
7
6.81, 56.79, 47.39, 44.74, 28.53, 27.85, 26.34, 22.92, 20.41, 18.42, 17.61. ESIꢀ MS m/z: 354.2(M+1) .
+
HRMS calcd for C H NNaO (M+Na) requires 376.2100, found 376.2089.
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ASSOCIATED CONTENT
Supporting Information:
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H NMR, C NMR and MS spectra for these products. This material is available free of charge via the
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AUTHOR INFORMATION
Corresponding Author
School of Perfume and Aroma Technology, Shanghai Institute of Technology, 100 Haiquan Rd., Shanghai
201418, P.R. China.
Eꢀmail: liufeng@sit.edu.cn.
Present Addresses
†
Suzhou No.4 Pharmaceutical Factory, 171 Baiyangwang Street, Suzhou, 215008, P.R. China .
Author Contributions
The manuscript was written with contributions from all the authors. All authors have given approval to the
final version of the manuscript.
‡
These authors contributed equally.
Notes:
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the National Natural Science Foundation of China (Grant No 21302126) and
the Shanghai Engineering Technology Research Center of Fragrance and Flavor (12DZ2251400).
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