Concise synthesis of chiral N -Benzyl-α,α-Diarylprolinols through shi asymmetric epoxidation

Article abstract of DOI:10.1055/s-0033-1340825

A concise and practical synthesis of chiral N-benzyl-α,α- diaryl-2-prolinols was developed through Shi asymmetric epoxidation, followed by double nucleophilic substitution of bromo-containing olefins. A series of enantioenriched N-benzyl-α,α-diaryl-2-prolinols were obtained with excellent enantioselectivities (96% ee) in moderate to good yields (40-76% yield). For the first time, enantiopure N-benzyl-α,α-diphenyl-2- prolinol was obtained from bromo-containing olefin using this methodology. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1340825

LETTER
▌805
lCettoerncise Synthesis of Chiral N-Benzyl-α,α-Diarylprolinols through Shi Asym-
metric Epoxidation
Synthesis of Chiral N-Benzyl-α,α-Diarylprolinols
Jie Li,a Hai Zhou,a Jiangsen Weng,a Mingwen Wang,b Chengsheng Ge,*a Wujie Tua
a
College of Chemistry and Materials Engineering, Quzhou University, Quzhou 324000, P. R. of China
Fax +86(570)8015339; E-mail: gechengsheng@qzu.zj.cn
b
ACS Scientific Inc., Metuchen, NJ 08840, USA
Received: 05.12.2013; Accepted after revision: 22.01.2014
In many literatures, the enantiopure α,α-diaryl-2-prolinols
Abstract: A concise and practical synthesis of chiral N-benzyl-α,α-
were synthesized from naturally occurring L-proline via
diaryl-2-prolinols was developed through Shi asymmetric epoxida-
tion, followed by double nucleophilic substitution of bromo-con-
taining olefins. A series of enantioenriched N-benzyl-α,α-diaryl-2-
double Grignard addition.6,7 Alternatively, the coupling
reaction of benzophenone with N-Boc-pyrroline gave chi-
prolinols were obtained with excellent enantioselectivities (96% ee) ral or racemic α,α-diphenyl-2-prolinol promoted by a chi-
ral lithium reagent or SmI2 in good yield.8 However, the
in moderate to good yields (40–76% yield). For the first time, enan-
tiopure N-benzyl-α,α-diphenyl-2-prolinol was obtained from bro-
mo-containing olefin using this methodology.
procedures of the coupling reactions used relatively ex-
pensive (–)-sparteine or other chiral resolution reagents to
make chiral α,α-diaryl-2-prolinols. A concise and practi-
cal protocol for the catalytic asymmetric synthesis of α,α-
Key words: synthesis, chiral N-benzyl-α,α-diaryl-2-prolinols,
asymmetric epoxidation
diaryl-2-prolinols is still of importance. To develop a gen-
eral strategy, Lin et al.9 found that the pyrroline moiety
The enantiopure α,α-diaryl-2-prolinols are widely used as
the source of chirality in asymmetric transformation.1 Ini-
tially, the Corey group reported preparing oxazaboro-
lidines using α,α-diphenyl-2-prolinol as catalyst.2 Since
then, the enantiopure α,α-diaryl-2-prolinols were success-
fully applied to metallo- and organocatalyzed reactions
for various asymmetric transformations.3a–g As a widely
used catalyst in organocatalysis, the enantiopure α,α-
diphenyl-2-prolinol silyl ether has been defined as
Jørgensen–Hayashi catalyst.4 Recently, as a highly efficient
catalyst in industry, the α,α-diphenyl-2-prolinol silyl ether
has been successfully used in the asymmetric synthesis of
chiral drugs.5
can be constructed by a four-step reaction sequence of
Sharpless asymmetric dihydroxylation, monomesylation,
epoxidation, and intramolecular aminolysis of epoxida-
tion. We envisaged to construct N-benzyl-α,α-diaryl-2-
prolinols in a concise route via Shi asymmetric epoxida-
tion and double nucleophilic substitution (Scheme 1).
Quite recently, Chein and co-workers10 reported that en-
antiopure (thiolan-2-yl)diphenylmethanol could be syn-
thesized using Shi asymmetric epoxidation as key step.
Initially, we attempted to synthesize enantioenriched 4a.
The R configuration of 3a (96% ee) was easily prepared
via Shi asymmetric epoxidation. With 3a in hand, we in-
vestigated the double nucleophilic substitution of benzyl
O
O
O
O
O
BnNH2
O
Br
Br
Ar
Ar
1 (50 mol%)
Ar
Ar
Ar
Ar
N
Oxone
H2O–MeCN
K2CO3, 4 Å MS, MeCN, reflux
Bn
HO
O
2
3
4a Ar = Ph
4b Ar = 4-FC6H4
4c Ar = 4-MeOC6H4
4d Ar = 4-MeC6H4
4e Ar = 3-MeC6H4
4f Ar = 4-EtC6H4
4g Ar = 4-ClC6H4
Scheme 1 Enantioselective construction of N-benzyl-α,α-diaryl-2-prolinols using Shi asymmetric epoxidation and double nucleophilic sub-
stitution
SYNLETT 2014, 25, 0805–0808
Advanced online publication: 11.03.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340825; Art ID: ST-2013-W1114-L
© Georg Thieme Verlag Stuttgart · New York

806
J. Li et al.
LETTER
trasonication. Meanwhile THF and toluene (Table 1, entry
2 and 3) did not promote the double nucleophilic substitu-
tion, and an unknown mixture was obtained. Furthermore,
a mixture of 3a and two equivalents of benzyl amine in
acetonitrile (Table 1, entry 4) was refluxed for 12 hours.
It was exciting that 4a was isolated in 20% yield with 96%
enantiomeric excess. Encouraged by this discovery, our
effort was to optimize the reaction conditions. Finally po-
tassium carbonate and the combination of potassium car-
bonate and 4 Å molecular sieves (Table 1, entries 5 and 6)
were found to be able to significantly increase the yield.
The combination of potassium carbonate and 4 Å molec-
ular sieves gave the best result. Prolonging the reaction
time (Table 1, entry 7) improved the yield slightly. All of
these reactions resulted in excellent enantiomeric excess.
The absolute configuration of 4a was confirmed by com-
paring with that of a standard sample. To overcome the
difficulty of separating 3a via silica gel chromatography,
we reacted crude 3a with benzyl amine directly. Interest-
ingly, 4a could be obtained in 76% yield over two steps.
In order to develop a practical synthesis method to prepare
enantiopure N-benzyl-α,α-diphenyl-2-prolinol, further re-
crystallization in hot petroleum ether afforded 4a with
greater than 99% enantiomeric excess.
Table 1 Solvent, Base, and Additive Screening for Double Nucleo-
philic Substitution
BnNH2
base or combination of
base and additive
Br
Ph
Ph
Ph
Ph
N
solvent, reflux
Bn
HO
O
3a
4a
Entry Solvent Base or combination Time
of base and additive (h)
Yield
(%)c
ee
(%)d,e
1
2
3
4
5
6
7
EtOH
THF
nonea,b
12
12
12
12
12
12
24
0
0
none
PhMe
MeCN
MeCN
MeCN
MeCN
none
0
none
20
50
96
96
K2CO3
K2CO3, 4 Å MS
K2CO3, 4 Å MS
85 (76)f 96
86 96
a Without ultrasonication.
b Under ultrasonication.
c Isolated yield.
d The ee was determined by HPLC analysis with Chiralcel AD-H col-
umn.
Various bromo-containing olefins reacting with different
substituents of the aromatic ring were tested via Shi asym-
metric epoxidation and double nucleophilic substitution
to give N-benzyl-α,α-diarylprolinols in moderate to good
yields (40–76% yield) with excellent enantioselectivities
(96% ee) (Scheme 2). Olefins with 4-methoxyphenyl and
3-methylphenyl gave moderate yields (40–45% yield).
e Racemic sample was prepared via Shi epoxidation using acetone as
catalyst.
f Crude 3a was reacted as raw material.
amine with 3a. As shown in Table 1, ethanol (entry 1) was
first tried as a polar solvent, unfortunately, the desired
compound could not be found either under or without ul-
Br
Br
Ar
1 (50 mol%)
BnNH2
Ar
Ar
Ar
Ar
N
Ar
Oxone
H2O–MeCN
K2CO3, 4 Å MS, MeCN, reflux
Bn
HO
O
3a–g
2a–g
4a–g
-----------------------------------------------------------------------------------------------------------------------------------------------------
O
F
N
N
N
N
Bn
HO
O
Bn
Bn
Bn
HO
HO
HO
F
4a 76% yield
4b 70% yield
4c 40% yield
4d 75% yield
96% ee
96% ee
96% ee
96% ee
Cl
N
N
Bn
HO
Bn
N
HO
Bn
HO
Cl
4e 45% yield
4f 77% yield
4g 68% yield
96% ee
96% ee
96% ee
Scheme 2 Substrate scope. a Yield is based on isolated product over two steps. b The ee of the product was determined by HPLC analysis with
Chiralcel AD-H column. c Racemic sample was prepared via Shi epoxidation using acetone as catalyst. d The absolute configuration of the prod-
uct was deduced by that of 4a.
Synlett 2014, 25, 805–808
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Chiral N-Benzyl-α,α-Diarylprolinols
807
Br
Br
Ph
Ph
1 (50 mol%)
BnNH2
Ph
Ph
Ph
Ph
N
Oxone
H2O–MeCN
K2CO3, 4 Å MS, MeCN, reflux
Bn
HO
O
6
5
7
74% yield
96% ee
Scheme 3 Asymmetric synthesis of (S)-(1-benzylpiperidin-2-yl) diphenylmethanol
The further investigation on this phenomenon will be ad- epoxidation followed by double nucleophilic substitution
dressed in the upcoming paper.
of bromo-containing olefins was developed.11 It was the
first time that enantiopure N-benzyl-α,α-diphenyl-2-proli-
nol was obtained in high yield from a bromo-containing
olefin using this methodology.
To extend the application scope of this protocol, we fur-
ther examined the construction of six-membered piperi-
dine
(S)-(1-benzylpiperidin-2-yl)diphenylmethanol
(Scheme 3). As anticipated, 96% enantiomeric excess of
7 was synthesized in 74% yield from bromo-containing
olefin 5, and >99% enantiomeric excess of 7 could be ob-
tained in 85% yield via recrystallization in hot petroleum
ether from 96% enantiomeric excess of 7.
Acknowledgment
We are grateful to the National Natural Science Foundation of Chi-
na (No 21306104).
Then we turned our attention to develop a practical meth-
odology to produce enantiopure N-benzyl-α,α-diphenyl-
2-prolinol for industrial purpose. It is well known that the
Shi catalyst and the Shi pyranose catalyst were prepared
from D-fructose and L-fructose via alcohols 8 and 9 fol-
lowed by the oxidation reaction. When the oxidation was
involved, it is still problematic to scale up the synthesis.
We found that the Shi catalyst and the Shi pyranose cata-
lyst can be synthesized via IBX oxidation in ethyl acetate
(Scheme 4). The great advantage is that (a) it is very easy
to separate the products from ethyl acetate and we can pre-
pare pure products in 90% yield in an oxidation step on a
100 g scale; (b) IBA, the IBX reducing product can be
converted into IBX in 80% yield for reuse.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SupInpfioomgrattr
o
nSupprigI
o
tnnofrmat
References and Notes
(1) (a) Erkkila, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007,
107, 5416. (b) Mukherjee, S.; Yang, J. W.; Hoffmann, S.;
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2159.
(2) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc.
1987, 109, 5551. (b) Corey, E. J.; Shibata, S. J.; Bakshi,
R. K. J. Org. Chem. 1988, 53, 2861. (c) Corey, E. J.; Helal,
C. J. Angew. Chem. Int. Ed. 1998, 37, 1985.
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Soc. 1987, 109, 7111. (b) Trost, B. M.; Christoph, M. C.
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(d) Marigo, M.; Franzen, J.; Poulsen, T. B.; Zhuang, W.;
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(e) Franzen, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.;
Kjaersgaard, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005,
With the Shi pyranose catalyst in hand, we further synthe-
sized the R configuration of enantiopure N-benzyl-α,α-di-
phenyl-2-prolinol in 65% yield with 99% enantiomeric
excess from a bromo-containing olefin.
In summary, a concise and practical synthesis of chiral
N-benzyl-α,α-diaryl-2-prolinols through Shi asymmetric
OH
O
O
O
OH
IBX, EtOAc
reflux
O
O
O
O
O
O
O
HO
OH
p-TsOH, acetone
O
O
OH
O
OH
O
8
Shi catalyst
D-fructose
OH
O
O
O
O
O
OH
O
IBX, EtOAc
reflux
O
O
O
HO
OH
p-TsOH, acetone
O
O
OH
O
OH
O
O
9
Shi pyranose catslyst
L-fructose
Scheme 4 Scale-up synthesis of the Shi catalyst and the Shi pyranose catalyst
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 805–808

808
J. Li et al.
LETTER
127, 18296. (f) Palomo, C.; Antonia, M. A. Angew. Chem.
Int. Ed. 2006, 45, 7876. (g) Sunden, H.; Rios, R.; Cordova,
A. Tetrahedron Lett. 2007, 48, 7865.
δ = 7.70–7.65 (m, 2 H), 7.56–7.51 (m, 2 H), 7.28 (m, 3 H),
7.08 (m, 6H), 3.96–3.92 (m, 1 H), 3.29 (d, J = 16 Hz, 1 H),
3.10 (d, J = 16 Hz, 1 H), 2.98–2.95 (m, 1 H), 1.99–1.90 (m,
1 H), 1.75 (m, 3 H). 13C NMR (100 MHz, CDCl3): δ = 128.2,
128.0, 127.0, 126.9, 126.9, 126.8, 126.8, 115.0, 114.8,
114.8, 114.6, 77.3, 70.6, 60.6, 55.5, 29.8, 24.1. HRMS: m/z
calcd for C24H24F2NO: 380.1820 [M + H]+; found: 380.1797.
Compound 4c: yield 40%; 96% ee. [α]D22 +101.1 (c 1.0,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.58 (d, J = 8 Hz,
2 H), 7.45 (d, J = 8 Hz, 2 H), 7.24–7.21 (m, 3 H), 7.06 (d,
J = 8 Hz, 2 H), 6.83–6.78 (m, 4 H), 4.85 (br, 1 H), 3.89–3.86
(m, 1 H), 3.75 (s, 1 H), 3.69 (s, 3 H), 3.30 (d, J = 12 Hz, 1
H), 3.02 (d, J = 12 Hz, 1 H), 2.37–2.30 (m, 1 H), 1.97–1.87
(m, 1 H), 1.78–1.71 (m, 1 H), 1.65–1.57 (m, 2 H).
(4) Jensen, K. L.; Dickmeiss, G.; Jiang, H.; Albrecht, L.;
Jørgensen, K. A. Acc. Chem. Res. 2012, 45, 248.
(5) Xu, F.; Zacuto, M.; Yoshikawa, N.; Desmond, R.; Hoerrner,
S.; Itoh, T.; Journet, M.; Humphrey, G. R.; Cowden, C.;
Strotman, N.; Devine, P. J. Org. Chem. 2010, 75, 7829.
(6) (a) Trost, B. M.; Ngai, M. Y.; Dong, G. B. Org. Lett. 2011,
13, 1900. (b) Alvarez, I. C.; Collados, L. J. F.; Quiroga, F.
M. L. Tetrahedron: Asymmetry 2010, 21, 2334.
(7) Mathre, D. J.; Jones, T. K.; Xavier, L. C.; Blacklock, T. J.;
Reamer, R. A.; Mohan, J. J.; Jones, E. T. T.; Hoogsteen, K.;
Baum, M. W.; Grabowski, E. J. J. J. Org. Chem. 1991, 56,
751.
(8) (a) Nikolic, N. A.; Beak, B. Org. Synth. 1997, 74, 23.
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Lett. 2008, 10, 3021.
(9) Wang, B.; Fang, K.; Lin, G. Q. Tetrahedron Lett. 2003, 44,
7981.
Compound 4d: yield 75%; 96% ee. [α]D22 +94.5 (c 1.0,
CHCl3). IR (KBr): ν = 3290, 3027, 2965, 2919, 2806, 1507,
1454, 1381, 1099, 1038, 803, 699 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 7.61 (d, J = 8 Hz, 2 H), 7.47 (d, J = 12 Hz, 2 H),
7.28–7.21 (m, 3 H), 7.13–7.08 (m, 6 H), 3.98–3.93 (m, 1 H),
3.33 (d, J = 16 Hz, 1 H), 3.04 (d, J = 16 Hz, 1 H), 2.96–2.90
(m, 1 H), 2.41–2.32 (m, 1 H), 2.30 (s, 3 H), 2.24 (s, 3 H),
2.04–1.94 (m, 1 H), 1.91–1.73 (m, 1 H), 1.69–1.59 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 145.1, 143.9, 139.6, 135.5,
135.3, 128.7, 128.7, 128.5, 127.9, 126.6, 125.2, 77.6, 70.6,
60.6, 55.5, 29.8, 24.1, 20.9. HRMS: m/z calcd for C26H30NO:
372.2322 [M + H]+; found: 372.2292.
(10) (a) Wu, H. Y.; Chang, C. W.; Chein, R. J. J. Org. Chem.
2013, 78, 5788. (b) Huang, M. T.; Wu, H. Y.; Chein, R. J.
Chem. Commun. 2014, 50, 1101.
(11) General Experimental Procedure for the Synthesis of
4a–g
A mixture solution of 5,5-diphenyl-4-pentenyl bromide (2a,
1 g, 3.3 mmol) in MeCN–DMM (1:2, v/v, 24 mL), and
Na2B4O7·10H2O (0.62 g, 1.6 mmol), tetrabutylammonium
hydrogen sulfate (45 mg, 0.13 mmol), and Shi catalyst (0.42
g, 1.65 mmol) in a buffer solution [4·10–4 M aq Na2(EDTA),
16 mL] was cooled to 0 °C in an ice bath. A solution of
Oxone (5.06 g, 8.25 mmol) in 4·10–4 M aq Na2(EDTA)
solution (20 mL) and a solution of K2CO3 (5 g, 36 mmol) in
deionized water were, respectively, added dropwise through
two separate addition funnels over a period of 3 h at 0 °C.
After addition, the reaction was stirred for another 3 h at this
temperature and then diluted with H2O (150 mL). The
resulting solution was extracted with PE (2 × 150 mL), dried
over Na2SO4, and concentrated to afford the crude 3a (1.56
g, >95% purity), which was applied to next step without
purification. The mixture solution of the above obtained
crude 3a (1.56 g, ca. 3.3 mmol), benzyl amine (0.706 g, 6.6
mmol), K2CO3 (0.91 g, 6.6 mmol), and freshly activated 4 Å
MS (1.56 g) in MeCN (10 mL) was refluxed for 12 h. The
resulting solution was filtered and evaporated to give the
crude product which was purified over silica gel chroma-
tography (EtOAc–PE = 1:20 to 1:10) to afford 0.86 g of 4a
as a white solid.
Compound 4e: yield 76%; 96% ee. [α]D22 +90.8 (c 1.0,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.55 (s, 1 H), 7.47
(d, J = 8 Hz, 1 H), 7.41 (s, 1 H), 7.36 (d, J = 8 Hz, 1 H), 7.30–
7.13 (m, 5 H), 7.04 (d, J = 6 Hz, 1 H), 6.98 (d, J = 8 Hz, 1
H), 6.90 (d, J = 8 Hz, 1 H), 3.94–3.90 (m, 1 H), 3.18 (d, J =
12 Hz, 1 H), 3.02 (d, J = 12 Hz, 1 H), 2.93–2.91 (m, 1 H),
2.38–2.35 (m, 7 H), 2.03–1.94 (m, 1 H), 1.81–1.56 (m, 3 H).
Compound 4f: yield 77%. 96% ee. [α]D22 +88.8 (c 1.0,
CHCl3). IR (KBr): ν = 3426, 2964, 2930, 1652, 1607, 1452,
1414, 1261, 1099, 1030, 818, 699 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 7.61 (d, J = 12 Hz, 2 H), 7.47 (d, J = 8 Hz, 4 H),
7.17–7.03 (m, 9 H), 4.85 (br s, 1 H), 3.96–3.91 (m, 1 H), 3.27
(d, J = 16 Hz, 1 H), 3.02 (d, J = 16 Hz, 1 H), 2.92–2.89 (m,
1 H), 2.62–2.51 (m, 4 H), 1.94–1.93 (m, 1 H), 1.76–1.74 (m,
1 H), 1.61–1.54 (m, 2 H), 1.21–1.10 (m, 6 H). 13C NMR (100
MHz, CDCl3): δ = 145.3, 144.1, 141.8, 141.6, 139.7, 128.5,
127.9, 127.4, 127.3, 126.6, 125.4, 125.2, 77.7, 70.8, 60.6,
55.6, 29.9, 28.4, 28.3, 24.2, 14.4, 15.4. HRMS: m/z calcd for
C26H30NO: 400.2635 [M + H]+; found: 400.2611.
Compound 4g: yield 68%. 96% ee. [α]D22 +94.8 (c 1.0,
CHCl3). IR (KBr): ν = 3333, 3061, 3028, 2963, 2871, 2804,
1488, 1403, 1092, 1012, 809, 699 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 7.66 (d, J = 12 Hz, 2 H), 7.51 (d, J = 12 Hz, 2
H), 7.30–7.22 (m, 7 H), 7.06 (d, J = 8 Hz, 2 H), 5.07 (br s, 1
H), 3.95–3.91 (m, 1 H), 3.33 (d, J = 20 Hz, 1 H), 3.10 (d, J =
16 Hz, 1 H), 2.98–2.94 (m, 1 H), 2.43–2.37 (m, 1 H), 1.98–
1.92 (m, 1 H), 1.74–1.62 (m, 3 H). 13C NMR (100 MHz,
CDCl3): δ = 146.6, 145.2, 139.4, 132.7, 132.5, 128.7, 128.7,
128.6, 128.5, 127.3, 127.3, 127.2, 77.4, 70.6, 60.8, 55.7,
30.0, 24.2. HRMS: m/z calcd for C24H24Cl2NO: 412.1229
[M + H]+; found: 412.1209.
Compound 4a: yield 76%; 96% ee. [α]D22 +91.5 (c 1.0,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.75 (d, J = 8 Hz,
2 H), 7.61 (d, J = 8 Hz, 2 H), 7.35–7.06 (m, 11 H), 4.03–3.99
(m, 1 H), 3.26 (d, J = 16 Hz, 1 H), 3.06 (d, J = 16 Hz, 1 H),
2.98–2.93 (m, 1 H), 2.43–2.35 (m, 1 H), 2.03–1.93 (m, 1 H),
1.84–1.63 (m, 3 H).
Compound 4b: yield 70%; 96% ee. [α]D22 +98.4 (c 1.0,
CHCl3). IR (KBr): ν = 3400, 2975, 2887, 2808, 1649, 1600,
1502, 1223, 1037, 836 cm–1. 1H NMR (400 MHz, CDCl3):
Synlett 2014, 25, 805–808
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