New proline analogues for organocatalysis

Article abstract of DOI:10.1016/j.tetasy.2010.05.005

This paper describes an anomalous behaviour of the Sharpless dihydroxylation of a terminal olefin. The synthesis of a new chiral pyrrolidine and its application as an organocatalyst in the Michael addition of cyclohexanone into nitrostyrenes are described

Full text of DOI:10.1016/j.tetasy.2010.05.005

Tetrahedron: Asymmetry 21 (2010) 786–793
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
New proline analogues for organocatalysis
*
David Díez , Ana B. Antón, Javier Peña, Pilar García, Narciso M. Garrido, Isidro S. Marcos, F. Sanz ,
Pilar Basabe, Julio G. Urones
Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad de Salamanca. Plaza de los Caidos 1-5, 37008 Salamanca, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
This paper describes an anomalous behaviour of the Sharpless dihydroxylation of a terminal olefin. The
synthesis of a new chiral pyrrolidine and its application as an organocatalyst in the Michael addition of
cyclohexanone into nitrostyrenes are described.
Received 19 February 2010
Accepted 23 February 2010
Available online 1 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Dedicated to Professor S.G. Davies on the
occasion of his 60th birthday
1. Introduction
COOH
N
H
N
H
N
H
In the last few years, there has been an enormous development in
organocatalysis,1 with proline being the catalyst of reference for
many reactions, since the seminal paper of List, Lerner and Barbas
in 2000.2 One of the reactions that has caused more interest in this
area is the Michael addition.3 There have been many proline ana-
logues4 developed for the Michael addition of carbonyl compounds
to trans-b-nitrostyrene, which can be usually classified as analogues
with an acidic or hydrogen bonding substituent I or analogues with a
highly sterically demanding substituent such as II.5 In recent years
our group has been involved in developing new proline analogues
of type I and III6 and of type II and IV7 and 23 to be used in the Mi-
chael addition of cyclohexanones to trans-b-nitrostyrene
(Fig. 1).8 Herein, we report the synthesis of new organocatalyst dia-
stereoisomers of 23 and 24. The catalytic asymmetric dihydroxyla-
tion (AD) developed by Sharpless et al.9 has been used with many
different compounds, with excellent diastereoselectivities although
several investigators such as Gardiner,10a Kishi10b, Krysan10c and Sal-
vadori10d have observed a low degree of asymmetric induction with
terminal olefins. In our case we have disclosed a similar finding as
the authors mentioned above and studied closely the dihydroxyla-
tion. The X-ray of a derivative 20 was obtained, which allowed us
to determine the diastereoselectivity.
Proline
H
I
II
O
O
O
O
H
H
OBn
OBn
N
H
N
H
IV
N
H
III
SO2Ph
NHSO2CF3
23
Figure 1.
protected proline as described by other authors.11 The enantio-
meric purity of 1 was corroborated by comparison with the
described specific rotation of previously synthesised 1 and by chi-
ral HPLC, see Section 4.
In order to evaluate the dihydroxylation of 1, the reaction was
carried out under achiral catalytic conditions and using either
a
dihydroxylation (AD-mix , containing (DHQ)2PHAL), or b dihydr-
a
oxylation (AD-mix b, containing (DHQD)2PHAL as a chiral ligand).
The diastereomeric ratio was measured by 1H NMR spectroscopy.
As can be observed, (Table 1) the same diastereoselectivity was
obtained with both chiral inductors. Hence, it was decided to
change to PYR-based ligands and we observed in these cases that
only with chiral ligand (DHQD)2PYR was it possible to obtain the
diol on the b side as the major product. This type of selectivity is
in agreement with the one observed by Gardiner et al.10a
In order to establish the stereochemistry of 2 and 3, they were
protected separately as their acetonides to give compounds 4 and 5
(Scheme 1). Moreover, compounds 11 and 12 were obtained for
comparison with 2 and 4 and 19 with 5 following two different
routes, Schemes 2 and 3.
2. Results and discussion
First of all we decided to study the Sharpless dihydroxylation of
the important olefin 1 previously obtained in our lab from N-Boc-
* Corresponding author. Tel.: +34 923 294474; fax: +34 923 294574.
E-mail address: ddm@usal.es (D. Díez).
Servicio de Rayos X, Facultad de Ciencias Químicas. Universidad de Salamanca.
37008 Salamanca, Spain
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.05.005

D. Díez et al. / Tetrahedron: Asymmetry 21 (2010) 786–793
787
Table 1
Dihydroxylation of compound 1
O
O
NBn
H
H
H
H
H
OH
OH
OH
OH
+
13
N
Boc
N
Boc
N
Boc
a
1
2
3
Entry
Conditions
Chiral ligand
2/3
O
O
1
2
3
4
5
a
b
c
d
e
None
57/43
68/32
70/30
65/35
15/85
OTBS
OTBS
15
O
(DHQ)2PHAL
(DHQD)2PHAL
(DHQ)2PYR
(DHQD)2PYR
O
+
14
NHBn
b
NHBn
Reagents: (a) OsO4, NMO, t-BuOH/H2O/THF, 95%; (b) AD-mix-a, MeSO2NH2, t-BuOH/
H2O, 92%; (c) AD-mix-b, MeSO2NH2, t-BuOH/H2O, 92%; (d) (DHQ)2PYR, MeSO2NH2,
K2CO3, K3[Fe(CN)6], K2SO4ꢂ2H2O, t-BuOH/ H2O, 90%; (e) (DHQD)2PYR, MeSO2NH2,
K2CO3, K3[Fe(CN)6], K2SO4ꢂ2H2O, t-BuOH/ H2O, 85%.
O
O
c
d
O
O
OTBS
OH
H
H
H
H
NHBn
NHBn
O
O
OH
OH
a
N
Boc
16
N
Boc
17
H
H
H
H
4
2
e
O
O
O
O
N
N
Bn
H
H
Boc
H
b
H
OH
OH
O
N
19
18
N
Boc
Boc
O
Scheme 3. Reagents: (a) 3-(t-butyldimethylsilyloxy)prop-1-ynyllithium, Et2O, 90%
(14:15, 1:1); (b) H2, PtO2, AcOEt, 93%; (c) TBAF, THF, 69%; (d) CBr4/PPh3, then NEt3,
15%; (e) H2, Boc2O, Pd(OH)2, AcOEt, 30%.
3
5
Scheme 1. Reagents and conditions: (a) acetone, 2,2-dimethoxypropane, anhy-
drous CuSO4, 96%; (b) acetone, 2,2-dimethoxypropane, anhydrous CuSO4, 89%.
9 was treated with first generation Grubbs’16 catalyst (bis(tricyclo-
hexylphosphine)benzylidine ruthenium(IV) chloride) at 40 °C. The
pyrroline 1015b was obtained and without isolation was submitted
to hydrogenation under the usual conditions to give 11. Protection
of the last compound as an acetonide led to 12. Compound 9 was
protected as its acetonide 9a, which was made to react under sim-
ilar conditions as mentioned above (first generation Grubbs’ cata-
lyst and hydrogenation) to obtain compound 12. Compounds 11
O
a)
b)
OH
O
OH
OH
6
7
8
c)
½
a 2D0
ꢀ
¼ þ26:0 (c 0.95, CHCl3) and 12 ½a D20
¼ þ48:2 (c 0.95, CHCl3)
ꢀ
OH
H
H
H
H
have the same spectroscopic properties and opposite specific rota-
OH
OH
OH
OH
OH
e)
tions to 2 ½a 2D0
ꢀ
¼ ꢁ42:7 (c 1.1, CHCl3) and 4 ½a D20
¼ ꢁ60:2 (c 1.25,
ꢀ
d)
N
Boc
N
Boc
CHCl3), respectively.
N
Boc
O
11
Route 2: In order to determine the configuration of compounds
3 and 5, a different methodology for synthesising the enantiomer
of 5 was followed, as shown in Scheme 3.
10
9
f)
g)
Imine 13 has been previously coupled with the lithium deriva-
tive of the silyl-protected propargyl alcohol by Diaz-de-Villegas
and Gálvez17 to obtain compounds 14 and 15 whose stereochemis-
try was established by the authors. After separation by column
chromatography, diastereomer 14 was hydrogenated to give 16,
which after silyl deprotection gave alcohol 17. When this com-
pound was submitted to cyclisation conditions,18 the protected
pyrrolidine 18 was obtained in low yield. It was then transformed
H
H
H
H
O
O
O
O
O
i)
h)
N
N
Boc
10b
N
Boc
Boc
12
9a
Scheme 2. Reagents and conditions: (a)
L
-(+)-DET, Ti(i-OPr)4, TBHP, DCM, ꢁ20 °C;
49%.; (b) NaOH 0.5 N, 89%; (c) allylamine, Ti(iOPr)4, DCM then Boc2O, 65% (two
steps); (d) Grubbs’ catalyst, DCM, 40 °C, 36%; (e) H2, PtO2, EtOAc, 71%; (f) acetone,
2,2-dimethoxypropane, anhydrous CuSO4, 96%; (g) acetone, 2,2-dimethoxypropane,
anhydrous CuSO4, 57%; (h) Grubbs’ catalyst, DCM; (i) H2, PtO2, EtOAc, 65% in two
steps.
into pyrrolidine 19 ½a D20
¼ þ58:9 (c 0.45, CHCl3) in a one-pot reac-
ꢀ
tion by hydrogenation in the presence of Boc2O. This compound
showed identical spectroscopical properties as 5 ½a D20
¼ ꢁ84:3 (c
ꢀ
1.14, CHCl3) but the sign of the rotation was opposite.
With these experiments the stereochemistries of 2 and 3 were
established. In order to corroborate these results, compound 2 was
treated under basic conditions to give 20 (Scheme 4). The existence
of a band in the IR spectrum at 1690 cmꢁ1 indicates the presence of a
six-membered ring as observed in other similar compounds
Route 1: The commercially available compound 6 (Scheme 2)
was submitted to Sharpless epoxidation12 to obtain epoxide 713
that under Payne rearrangement14 conditions gave epoxide 8.13
This compound was treated with allylamine followed by protection
under the same conditions used by Riera et al.15a Compound 9
(1686 cmꢁ1 19 over a five-membered ring (1750 cmꢁ1).20 The cou-
)
½
a 2D0
ꢀ
¼ þ25:9 (c 1.15, CHCl3), is the enantiomer of the one de-
pling constant for the H-4 with H-4a J = 4.7 Hz is in agreement with
similar compounds and with trans stereochemistry for the two
hydrogens.19b The structure and configuration were determined
scribed by Riera15a {½a D20
¼ ꢁ22:6 (c 1.0, CHCl3)}. This compound
ꢀ
was transformed into 12 in two different ways. Firstly, compound

788
D. Díez et al. / Tetrahedron: Asymmetry 21 (2010) 786–793
by X-ray analysis (Fig. 2).21 All cyclisation attempts of compound 3
under different basic conditions were unsuccessful.
addition of cyclohexanone to trans-b-nitrostyrene following the
usual procedure.
First, we studied the influence of the solvent (Table 2), and it
can be seen that the reaction yields varied significantly. The less
polar solvents gave higher yields and better enantioselectivities.
We then decided to test the addition of an acid in order to increase
the enantiomeric excess and the reaction rate using toluene as the
chosen solvent.
H
H
H
4
H
4a
N
a
OH
OH
OH
N
Boc
O
O
20
2
The best reaction conditions are in either toluene or hexane and
using benzoic acid as an additive (Table 2, entry 13).
With the optimal reaction conditions in hand, we probed the
scope of the reaction with a variety of nitroolefins and cyclohex-
anone (Table 3) in the presence of 15% of catalyst 24, using tol-
uene as the solvent at room temperature (21 °C) and benzoic
acid as an additive, obtaining yields that vary from good to
excellent showing in all cases good diastereo and
enantioselectivity.
Scheme 4. Reagents: (a) NaH, THF, 59%.
3. Conclusions
The conditions for a- and b-dihydroxylation of the important vi-
nyl derivative of proline 1 have been found. Another example of
anomalous Sharpless dihydroxylation is reported. Two organocata-
lysts 23 and 24 have been obtained and the stereochemistry of one
of them, 23, has been corrected. Both catalysts work better in non-
polar solvents in the Michael additions of cyclohexanones to
nitrostyrenes and are easily tunables; these can be the starting
materials for future analogous organocatalysts.
Figure 2. Representation of the X-ray crystal structure of compound 20.
Herein, we can conclude that the stereochemistries of 2 and 3
are those ones shown in Table 1.22 Taking these results into ac-
count, the Sharpless dihydroxylation of compound 1 behaves
according to Gardiner’s model for an analogous compound.10a
Once the configurations of compounds 2 and 3 were estab-
lished, we decided to obtain the corresponding organocatalysts
as shown in Scheme 5.
When compounds 2 and 3 were submitted to the usual benzy-
lation conditions, the corresponding dibenzylderivatives 21 and 22
were obtained, respectively. These compounds were deprotected
under acidic conditions to give 23 and 24.
4. Experimental
4.1. General
Unless otherwise stated, all chemicals were purchased as the
highest purity commercially available and were used without
further purification. IR spectra were recorded on a BOMEM 100
FT-IR or an AVATAR 370 FT-IR Thermo Nicolet spectrophotome-
ters. 1H and 13C NMR spectra were performed in CDCl3 and ref-
erenced to the residual peak of CHCl3 at d 7.26 ppm and d
77.0 ppm, for 1H and 13C, respectively, using Varian 200 VX
and Bruker DRX 400 instruments. Chemical shifts are reported
in d ppm and coupling constants (J) are given in hertz. MS were
performed in a VG-TS 250 spectrometer at 70 eV ionising volt-
age. Mass spectra are presented as m/z (% rel int.). HRMS were
recorded on a VG Platform (Fisons) spectrometer using chemical
ionisation (ammonia as gas) or Fast Atom Bombardment (FAB)
technique. For some of the samples, QSTAR XL spectrometer
was employed for electrospray ionisation (ESI). Optical rotations
were determined on a Perkin–Elmer 241 polarimeter in 1 dm
cells. Diethyl ether and THF were distilled from sodium, and
dichloromethane was distilled from calcium hydride under an
argon atmosphere.
The properties of 23 as an organocatalyst have been described
previously.8,22 With compound 24 in hand, we studied the Michael
H
H
H
b
H
OH
OH
OH
OH
N
Boc
N
Boc
3
2
a
H
H
H
H
OBn
OBn
OBn
OBn
N
Boc
N
Boc
22
21
4.1.1. (2S)-N-tert-Butoxycarbonyl-2-vinylpyrrolidine, 1
This compound was obtained as in the literature11a and the
enantiomeric excess was determined by measurement of the
c
d
½
a 2D0
ꢀ
¼ ꢁ13:0 (c 0.91, CHCl3), in literature ½a D20
¼ ꢁ13:4 (c 1.0,
ꢀ
CHCl3),11d
½
a 2D0
ꢀ
¼ ꢁ12:1 (c 2.15, CHCl3),11f for an enantiomeric ex-
H
H
H
H
cess of 99%. Ee was measured by chiral stationary phase HPLC on
a CHIRALCEL™ OD-H column [cellulose tris(3,5-dimethylphenyc-
arbamate)] on silica gel, er 92/8. It was transformed into its for-
OBn
OBn
OBn
OBn
N
H
N
H
24
23
mate derivative according to the literature11e
½
a 2D0
ꢀ
¼ ꢁ23:3 (c 1.0,
EtOH), for an er 83/17 in our case ½a D20
ꢀ
¼ ꢁ26:2 (c 1.0, EtOH),
Scheme 5. Reagents: (a) NaH, BnBr, TBAI, THF, 95%; (b) NaH, BrBn, TBAI, THF, 54%;
(c) HCl 6 M, MeOH, 70%; (d) HCl 6 M, MeOH, 87%.
means an er of 92/8.

D. Díez et al. / Tetrahedron: Asymmetry 21 (2010) 786–793
789
Table 2
Solvent and acid effects on the asymmetric Michael addition of cyclohexanone to trans-b-nitrostyrene using compound 24 as a catalyst
Ph
O
O
NO2
NO2
Cat. 24 (15%)
+
21ºC, solvent
25
Ph
Entrya
Solv.
Additive
t (h)
Yieldb (%)
drc (%)
eed (%)
1
2
3
4
5
6
7
8
9
10
11
12
10
11
12
13
14
15
16
DMSO
168
96
168
96
168
96
168
96
24
24
24
24
23
23
23
21
23
15
24
—
—
—
—
—
—
—
10
10
10
36
13
—
—
—
62
—
—
—
—
—
—
—
—
—
>95
>95
>95
>95
>95
—
—
—
90
—
—
—
—
—
—
—
—
—
14
51
27
38
50
—
—
—
76
—
—
DMSO
TsOH
TsOH
TsOH
TsOH
iPrOH
iPrOH
MeOH
MeOH
THF
THF
CH2Cl2
CHCl3
n-Hexane
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene[e]
TsOH
CF3COOH
CSA
Benzoic Acid
2,4-Dinitrobenzoic Acid
Salicylic Acid
Toluic Acid
38
>95
77
a
b
c
For conditions see Section 4.
Yield of the isolated product.
Determined by 1H NMR spectroscopic analysis.
d
e
Determined by chiral high-performance liquid chromatography (HPLC) analysis (Chiralpak AD).
Reaction done at 0 °C.
4.1.2. (2S)-N-tert-Butoxycarbonyl-2-[(10S)-10,20-dihydroxyethyl]-
pyrrolidine, 2 and (2S)-N-tert-butoxycarbonyl-2-[(10R)-10,20-
dihydroxyethyl]-pyrrolidine, 3
(a) To a solution of olefin 1 (33 mg, 0.17 mmol) in 1 mL of a mix-
ture of tert-BuOH/THF/H2O (7/2/1) were added NMO (69 mg,
and K2OsO4ꢂ2H2O previously prepared. Methanesulfonamide
(37 mg, 0.38 mmol) was added, then stirred magnetically at 21 °C
for 20 min. The ensuing mixture was cooled to 0 °C (ice-water
bath), treated with olefin 1 (76 mg, 0.38 mmol) and then stirred
vigorously for 72 h. The reaction was quenched, at 0 °C, by addition
of excess Na2SO3, warmed to 21 °C, stirred at this temperature for
30 min and then extracted with ethyl acetate (3 ꢃ 15 mL). The
combined organic extracts were dried over Na2SO4, filtered and
concentrated under reduced pressure. The product was purified
by column chromatography (hexane/EtOAc 1:1) to yield 54 mg
(0.23 mmol, 90%, 65/35) of the mixture of 2 and 3.
0.51 mmol) and OsO4 4% (w/v) (4 lL). After 22 h, 5 mL of Na2SO3
satd was added and then extracted with ethyl acetate
(3 ꢃ 15 mL). The combined organic extracts were dried over
Na2SO4, filtered and concentrated under reduced pressure to yield
30 mg (0.13 mmol, 95%, 57/43) of 2 and 3.
(b) To a solution of tert-BuOH (14 mL) and water (7 mL) were
added AD-mix
a
(4.40 g) and methanesulfonamide (298 mg,
(e) To a solution of tert-BuOH (35 mL) and water (35 mL) were
added K2CO3 (3.00 g, 21.60 mmol), K3[Fe(CN)6] (7.10 g,
21.60 mmol), (DHQD)2PYR (635 mg, 0.72 mmol), K2OsO4ꢂ2H2O
(107 mg, 0.29 mmol) and methanesulfonamide (686 mg,
7.21 mmol), then stirred magnetically at 21 °C for 20 min. The
ensuing mixture was cooled to 0 °C (ice-water bath), treated with
olefin 1 (1.40 g, 7.21 mmol) and then stirred vigorously for 72 h.
The reaction was quenched, at 0 °C, by addition of Na2SO3
(10.10 g), warmed to 21 °C, stirred at this temperature for 30 min
and then extracted with ethyl acetate (3 ꢃ 60 mL). The combined
organic extracts were dried over Na2SO4, filtered and concentrated
under reduced pressure. The product was purified by column chro-
matography (hexane/EtOAc 1:1) to yield 1.40 g (6.7 mmol, 85%, 15/
85) of the mixture of 2 and 3.
3.13 mmol), then it was stirred magnetically at 21 °C for 20 min.
The ensuing mixture was cooled to 0 °C (ice-water bath), treated
with olefin 1 (617 mg, 3.13 mmol) and then stirred vigorously for
72 h. The reaction was quenched, at 0 °C, by addition of Na2SO3
(5.00 g), warmed to 21 °C, stirred at this temperature for 30 min
and then extracted with ethyl acetate (3 ꢃ 20 mL). The combined
organic extracts were dried over Na2SO4, filtered and concentrated
under reduced pressure. The product was purified by column chro-
matography (hexane/EtOAc 6:4) to yield 623 mg (2.90 mmol, 92%,
68/32) of 2 and 3.
(c) To a solution of tert-BuOH (28 mL) and water (14 mL) were
added AD-mix
b (9.72 g) and methanesulfonamide (593 mg,
6.24 mmol), and it was stirred magnetically at 21 °C for 20 min.
The ensuing mixture was cooled to 0 °C (ice-water bath), treated
with olefin 1 (1.23 g, 6.24 mmol) and then stirred vigorously for
72 h. The reaction was quenched, at 0 °C, by addition of Na2SO3
(10.10 g), warmed to 21 °C stirred at this temperature for 30 min
and then extracted with ethyl acetate (3 ꢃ 20 mL). The combined
organic extracts were dried over Na2SO4, filtered and concentrated
under reduced pressure. The product was purified by column chro-
matography (hexane/EtOAc 6:4) to yield 1.32 g (5.70 mmol, 92%,
70/30) of 2 and 3.
Compound 2: ½a 2D0
ꢀ
¼ ꢁ42:7 (c 1.1, CHCl3), IR (film)
m
(cmꢁ1):
3600–3200, 2975, 2883, 1666, 1478, 1453, 1405, 1367, 1168,
1112, 1066; 1H NMR (CDCl3, 200 MHz, rotamers) d (ppm): 4.08
(2H, m), 3.84 (1H, m), 3.57 (2H, m), 3.30–3.15 (3H, m), 2.05–1.60
(4H, m), 1.47 (9H, s); 13C NMR (CDCl3, 50 MHz)
d (ppm):
157.2(CO), 81.0(C), 73.1 (CH), 64.4 (CH2), 58.8 (CH), 47.5 (CH2),
28.8 (3CH3), 27.9 (CH2), 23.5 (CH2). HRMS (ESI): calcd for
C11H21NO4Na, [M+Na]+: 254.1368 found: 254.1376.
Compound 3: ½a 2D0
ꢀ
¼ ꢁ74:1 (c 0.63, CHCl3), IR (film)
m
(cmꢁ1):
(d) To a solution of tert-BuOH (1 mL) and water (1 mL) was
added 539 mg of the mixture of K2CO3, K3[Fe(CN)6], (DHQ)2PYR
3600–3100, 2975, 2933, 2883, 1655, 1478, 1385, 1367, 1163,
1108; 1H NMR (CDCl3, 400 MHz, 60 °C, rotamers) d (ppm): 4.02–

790
D. Díez et al. / Tetrahedron: Asymmetry 21 (2010) 786–793
1H NMR (CDCl3, 200 MHz, 60 °C, rotamers) d (ppm): 4.25–4.10
(1H, m), 3.99 (1H, dd, J = 6.5 and 13.0 Hz), 3.95–3.85 (1H, m),
3.78 (1H, dd, J = 7.0 and 8.4 Hz), 3.40–3.22 (2H, m), 2.10–1.65
(4H, m), 1.44 (9H, s), 1.39 and 1.31 (3H each, 2s); 13C NMR (CDCl3,
50 MHz, 60 °C) d (ppm): 155.1 (CO), 109.2 (C), 79.6 (C) 77.1 (CH),
67.9 (CH2), 59.3 (CH), 47.0 (CH2), 28.7 (3CH3), 26.6 (CH3), 26.4
(CH2), 25.5 (CH3), 24.2 (CH2). HRMS (ESI): calcd for C14H25NO4Na,
[M+Na]+: 294.1676 found: 294.1671.
Table 3
Substrate scope of the Michael addition of cyclohexanone to trans-b-nitrostyrenes
using catalyst 24
O
Ar
O
Cat. 24 (15%)
NO2
NO2
benzoic acid (15%)
+
Ar
21ºC, Toluene
Entrya
Ar
t (h)
Yieldb (%)
drc (%)
eed (%)
4.1.4. (2S)-N-tert-Butoxycarbonyl-2-[(10R)-10,20(isopropylid-
enedioxy)ethyl]-pyrrolidine, 5
To a solution of 3 (16 mg, 0.07 mmol) in 1 mL acetone under Ar
were added 2,2-dimethoxypropane (62 mg, 0.6 mmol) and CuSO4
in excess. After 15 h, the mixture was filtered through Celite and
concentrated under reduced pressure to yield 18 mg (0.06 mmol,
O
O
O
1
21
62
90
93
90
76
78
93
NO2
25
26
27
89%) of 5. ½a 2D0
ꢀ
¼ ꢁ84:3 (c 1.14, CHCl3), IR (film)
m
(cmꢁ1): 2980,
2885, 1697, 1478, 1458, 1384, 1254, 1158, 1102, 1057, 857; 1H
NMR (CDCl3, 200 MHz, 60 °C, rotamers) d (ppm): 4.40–4.28 (1H,
m), 4.10–4.00 (1H, m), 3.93 (1H, dd, J = 6.4 and 8.4 Hz), 3.76 (1H,
dd, J = 7.8 and 8.4 Hz), 3.60–3.42 (1H, m), 3.38–3.18 (1H, m),
2.05–1.65 (4H, m), 1.46 (9H, s), 1.37 and 1.33 (3H each, 2s); 13C
NMR (CDCl3, 50 MHz, 60 °C) d (ppm): 155.3 (CO), 109.0 (C), 79.6
(C) 78.2 (CH), 66.2 (CH2), 57.5 (CH), 47.6 (CH2), 28.7 (3CH3), 28.1
(CH2), 26.4 (CH3), 25.6 (CH3), 24.1 (CH2). HRMS (ESI): calcd for
C14H25NO4Na, [M+Na]+: 294.1676 found: 294.1686.
NO2
NO2
2
3
21
21
93
OMe
NO2
>95
Br
4.1.5. (2R,3S)-1,2-Epoxy-4-pentene-3-ol, 7
To a solution of L-(+)-DET (14.70 g, 71.28 mmol) in 594 mL of
DCM at ꢁ20 °C under argon was added Ti(iPrO)4 (16.90 g,
59.40 mmol). After stirring for 15 min, 6 and a solution of TBHP
5.5 M in n-decane (26.1 mL) were added and the mixture was kept
in a freezer at ꢁ20 °C for 4 days. The reaction was monitored by
TLC and stopped when 6 had disappeared. The solution was
warmed to ꢁ10 °C and, with vigorous stirring, the reaction was
quenched with 75 mL of 30% aqueous tartaric acid. Stirring was
continued for 15 min at 0 °C. The water phase was extracted with
Et2O (3 ꢃ 50 mL) and the combined organic phases were dried
(Na2SO4) and concentrated. The remaining contents were distilled
through a Vigreux column to give 7 (2.91 g, 49%). For the spectro-
scopic properties of 7 see Ref. 13c.
4
21
99
87
86
O
O
O
NO2
NO2
NO2
28
29
30
O
S
5
6
21
21
95
96
86
81
84
93
4.1.6. (2S,3S)-2,3-Epoxy-4-pentenol, 8
Crude 7 (1.46 g, 14.6 mmol) was added to 8 mL of 0.5 M NaOH
and stirred for 30 min at room temperature. Extraction with DCM
(3 ꢃ 35 mL), drying of the combined organic phases (Na2SO4) and
evaporation gave 8 (1.30 g, 13 mmol, 89%). For spectroscopic prop-
erties see Ref. 13c.
a
b
c
For conditions see Section 4.
Yield of the isolated product.
Determined by 1H NMR spectroscopic analysis.
d
Determined by chiral high-performance liquid chromatography (HPLC) analysis
(Daicel Chiralpak AD).
4.1.7. (2R,3R)-3-(N-Allyl-N-tert-butoxycarbonylamino)-4-
penten-1,2-diol, 9
3.95 (1H, m), 3.65–3.47 (4H, m), 3.33–3.25 (1H, m), 2.07–1.97 (1H,
m), 1.97–1.85 (1H, m), 1.83–1.70 (2H, m), 1.48 (9H, s); 13C NMR
(CDCl3, 100 MHz, 60 °C) d (ppm): 155.1 (CO), 80.5(C), 75.8 (CH),
64.4 (CH2), 59.7(CH), 47.4 (CH2), 28.7 (CH2), 28.3 (3CH3), 24.0
(CH2). HRMS (ESI): calcd for C11H21NO4Na, [M+Na]+: 254.1368
found: 254.1376.
To a solution of epoxide 8 (1.00 g, 10 mmol) in DCM (44 mL)
were added allylamine (3 mL, 40 mmol) and titanium isopropoxide
(6 mL, 20 mmol) under Ar. The reaction was monitored by TLC.
After 48 h, 5 mL of 10% NaOH was added, and stirring was main-
tained for 24 h. The suspension was filtered, and the aqueous phase
was extracted with DCM (3 ꢃ 15 mL). The organic phases were
dried over Na2SO4. The solvent was evaporated, and the resulting
residue was dissolved in THF (25 mL). Boc2O (2.20 g, 10 mmol)
was then added, and the mixture was heated at 70 °C for 15 h.
Evaporation of the solvent followed by chromatographic purifica-
tion yielded 1.68 g (6.5 mmol, 65%) of 9. See Ref. 15.
4.1.3. (2S)-N-tert-Butoxycarbonyl-2-[(10S)-10,20(isopropylidene-
dioxy)ethyl]-pyrrolidine, 4
To a solution of 2 (146 mg, 0.63 mmol) in 4 mL acetone under Ar
were added 2,2-dimethoxypropane (526 mg, 5.05 mmol) and
CuSO4 in excess. After 6 h, the mixture was filtered through Celite
and concentrated under reduced pressure. The product was puri-
fied by column chromatography (hexane/EtOAc 9:1) to yield
½
a 2D0
ꢀ
¼ þ25:9 (c 1.15, CHCl3), IR (film)
m
(cmꢁ1): 3600–3100,
2976, 2930, 1691, 1671, 1458, 1406, 1367, 1252, 1168, 1095; 1H
NMR (CDCl3, 400 MHz) d (ppm): 6.21–6.02 (1H, m) 5.86–5.72
(1H, m) 5.31–5.22 (2H, m), 5.15–5.05 (2H, m), 4.10–4.04 (1H, m),
3.92–3.75 (3H, m), 3.65–3.50 (2H, m), 1.46 (9H, s); 13C NMR (CDCl3,
163 mg (0.60 mmol, 96%) of 4. ½a D20
¼ ꢁ60:2 (c 1.25, CHCl3), IR
ꢀ
(film)
m
(cmꢁ1): 2981, 1697, 1390, 1367, 1254, 1170, 1106, 1060;

D. Díez et al. / Tetrahedron: Asymmetry 21 (2010) 786–793
791
100 MHz) d (ppm): 157.5 (CO), 134.8 (CH), 133.6 (CH), 118.8 (CH2),
116.6 (CH2), 80.7 (C), 72.6 (CH), 63.4 (CH2), 61.7 (CH), 49.6 (CH2),
28.3 (3CH3). HRMS (ESI): calcd for C13H23NO4Na, [M+Na]+:
280.1519 found: 280.1516.
(CH2), 26.9 (CH3), 26.2 (3CH3), 25.7 (CH3), 18.5 (CH2), 14.7 (CH2),
ꢁ5.0 (2CH3). HRMS (ESI): calcd for C22H40NO3Si, [M+H]+:
394.2772 found: 394.2769.
4.1.13. (4R,5S)-4-Benzylamino-5,6-isopropylidenedioxy-1-
hexanol, 17
4.1.8. (2R)-N-tert-Butoxycarbonyl-2-[(10R)-10,20-dihydroxy-
ethyl]-pyrrolidine, 11
To a stirred solution of 9 (200 mg, 0.83 mmol) in DCM (56 mL)
was added a solution of Grubbs’ catalyst (bis(tricyclohexylphos-
phine)benzylidine ruthenium(IV) chloride) (85 mg, 0.12 mmol) in
DCM (40 mL) under Ar. The solution was heated at 40 °C for 6 h.
Evaporation of the solvent followed by chromatographic purifica-
To a solution of 16 (409 mg, 1.04 mmol) in THF under an Ar
atmosphere was added TBAF 1 M in THF (2 mL). After 3 h, 5 mL
of H2O was added, and the aqueous phase was extracted with
EtOAc (3 ꢃ 20 mL). The combined organic layers were dried over
anhydrous Na2SO4, filtered and concentrated under reduced pres-
sure to give the product which was purified by column chromatog-
raphy (hexane/EtOAc 6:4) to yield 200 mg (0.71 mmol, 69.0%) of
´
tion yielded product 10 with Grubbs catalyst as an impurity. This
mixture was submitted to the next reaction. To a solution of 10
(69 mg, 0.30 mmol) in EtOAc (4 mL) was added PtO2 10% (34 mg,
0.15 mmol). The mixture was left to stir under hydrogen for 12 h.
It was then filtered through Celite. Evaporation of the solvent in va-
cuo followed by chromatographic purification yielded the product
17. ½a 2D0
ꢀ
¼ ꢁ11:0 (c 0.93, CHCl3), IR (film)
m
(cmꢁ1): 3600–3100,
2985, 2934, 2870, 1455, 1380, 1370, 1252, 1213, 1158, 1058,
857, 739; 1H NMR (CDCl3, 200 MHz) d (ppm): 7.39–7.21 (5H, m),
4.30–3.50 (8H, m), 3.78–3.62 (1H, m), 1.80–1.40 (4H, m), 1.36
and 1.34 (3H each, 2s); 13C NMR (CDCl3, 50 MHz) d (ppm): 139.5
(C), 128.8 (2CH), 128.6 (2CH), 127.5 (C), 109.5 (C), 77.4 (CH), 67.2
(CH2), 62.9 (CH2), 59.5 (CH), 50.8 (CH2), 29.1 (CH2), 28.1 (CH2),
27.0 and 25.8 (2CH3). HRMS (ESI): calcd for C16H26NO3, [M+H]+:
280.1907 found: 280.1905.
11 (49 mg, 0.21 mmol, 71%). ½a D20
¼ þ26:0 (c 0.95, CHCl3). The
ꢀ
spectroscopic data were the same as 2.
4.1.9. (2R)-N-tert-Butoxycarbonyl-2-[(10R)-10,20(isopropylid-
enedioxy)ethyl]-pyrrolidine, 12
To a solution of 11 (38 mg, 0.16 mmol) in 2 mL acetone under Ar
were added 2,2-dimethoxypropane (138 mg, 1.33 mmol) and
CuSO4 in excess. After 15 h, the mixture was filtered through Celite
and concentrated under reduced pressure to yield 42 mg
4.1.14. (2R)-N-Benzyl-2-[(10S)-10,20(isopropylidenedioxy)ethyl]-
pyrrolidine, 18
To a solution of 17 (200 mg, 0.72 mmol) in DCM (7 mL) under
an Ar atmosphere were added PPh3 (207 mg, 0.79 mmol) and
CBr4 (262 mg, 0.79 mmol). The mixture was left to stir for 30 min
before the addition of Et3N (0.3 mL, 2.3 mmol). The solution was
stirred for 15 h. It was then diluted with DCM and washed with
HCl 2 M solution (ꢃ2), sodium bicarbonate (5%) solution (ꢃ2),
water and saturated brine. The organic phase was dried with anhy-
drous Na2SO4, filtered and the solvent was removed in vacuo. The
product was purified by column chromatography (hexane/EtOAc
(0.15 mmol, 96%) of 12. ½a D20
¼ þ48:2 (c 0.95, CHCl3). The spectro-
ꢀ
scopical data were the same as 4.
4.1.10. (2R,3R)-3-(N-Allyl-N-tert-butoxycarbonylamino)-4-
penten-1,2-diol acetonide, 9a
To a solution of 9 (40 mg, 0.16 mmol) in 2 mL acetone under Ar
were added 2,2-dimethoxypropane (133 mg, 1.3 mmol) and CuSO4
in excess. After 15 h, the mixture was filtered through Celite and
concentrated under reduced pressure to yield 27 mg (0.09 mmol,
95:5) to yield 28 mg (0.11 mmol, 15%) of 18. ½a D20
¼ þ29:3 (c
ꢀ
0.96, CHCl3), IR (film)
m
(cmꢁ1): 2983, 2935, 1685, 1670, 1654,
57%) of 9a. ½a 2D0
ꢀ
¼ þ12:5 (c 0.95, CHCl3). The spectroscopic proper-
1647, 1637, 1491, 1458, 1383, 1259, 1211, 1155, 1124; 1H NMR
(CDCl3, 200 MHz) d (ppm): 7.43–7.18 (5H, m), 4.28 (1H, d,
J = 13.6 Hz), 4.25 (1H, q, J = 7.0 Hz), 3.99 (1H, dd, J = 7.0 and
8.0 Hz), 3.70 (1H, t, J = 7.6 Hz), 3.44 (1H, d, J = 13.6 Hz), 3.02–2.90
(1H, m), 2.88–2.75 (1H, m), 2.55 (1H, q, J = 8.0 Hz), 1.92–1.45
(4H, m), 1.43 and 1.35 (3H each, 2s); 13C NMR (CDCl3, 50 MHz) d
(ppm): 140.0 (C), 129.2 (2CH), 128.3 (2CH), 127.1 (C), 109.5 (C),
79.1 (CH), 67.0 (CH2), 65.7 (CH), 59.5 (CH2), 54.5 (CH2), 26.9
(CH3), 26.7 (CH2), 25.5 (CH3), 23.3 (CH2). HRMS (ESI): calcd for
C16H24NO2, [M+H]+: 262.1802 found: 262.1799.
ties of this compound were described in Ref. 15c.
4.1.11. (2R)-N-tert-Butoxycarbonyl-2-[(10R)-10,20(isopropylidene-
dioxy)ethyl]-pyrrolidine, 12
To a stirred solution of 9a (24 mg, 0.08 mmol) in DCM (2.7 mL)
was added Grubbs’ catalyst (bis(tricyclohexylphosphine)benzyli-
dine ruthenium(IV) chloride) (7 mg, 0.008 mmol) under Ar. After
23 h, evaporation of the solvent followed by chromatographic puri-
fication yielded product 10b with Grubbs’ catalyst as an impurity.
This mixture without purification was dissolved in EtOAc (1 mL)
and added to PtO2 10% (6.4 mg, 0.028 mmol). The mixture was left
to stir under hydrogen for 14 h. It was then filtered through Celite.
Evaporation of the solvent in vacuo followed by chromatographic
purification yielded product 12 (14 mg, 0.051 mmol), 65%, in two
steps.
4.1.15. (2R)-N-tert-Butoxycarbonyl-2-[(10S)-10,20(isopropylidene-
dioxy)ethyl]-pyrrolidine, 19
To a solution of 18 (25 mg, 0.1 mmol) in EtOAc (1 mL) were
added Boc2O (33 mg, 0.15 mmol) and Pd(OH)2 as catalyst. The
reaction was stirred for 5 h under H2. After that, the mixture was
filtered through Celite and concentrated under reduced pressure
to give the product, which was purified by column chromatogra-
phy (hexane/EtOAc 9:1) to yield 7.4 mg (0.03 mmol, 30%) of 19.
4.1.12. (4R,5S)-4-Benzylamino-5,6-isopropylidenedioxy-1-hexyl-
tert-butyldimethylsilylether, 16
To a solution of 14 (437 mg, 1.12 mmol) in EtOAc was added
PtO2 (10%). The mixture was left to stir under hydrogen for 12 h.
It was then filtered through Celite and the solvent was evaporated
½
a 2D0
ꢀ
¼ þ58:9 (c 0.45, CHCl3). The spectroscopic data were identical
to compound 5.
in vacuo to yield 409 mg (1.04 mmol, 93%) of 16. ½a D20
ꢀ
¼ þ0:6 (c
4.1.16. (4S,4aS)-4-Hydroxy-perhydropyrrolo[1,2-c]-1,3-oxazin-
1-one, 20
1.05, CHCl3), IR (film)
m
(cmꢁ1): 2985, 2954, 2930, 2858, 1462,
1453, 1382, 1370, 1255, 1213, 1157, 1096, 1062, 836; 1H NMR
(CDCl3, 200 MHz) d (ppm): 7.40–7.17 (5H, m), 4.19–3.48 (8H, m),
2.62 (1H, bs), 1.75–1.20 (4H, m), 1.40 and 1.35 (3H each, 2s),
To a solution of 2 (93 mg, 0.43 mmol) in THF (2 mL) under an Ar
atmosphere at 0 °C was added NaH (23 mg, 0.95 mmol). After 24 h,
3 mL of water was added and the aqueous phase was extracted
with EtOAc (3 ꢃ 20 mL). The combined organic layers were dried
over anhydrous Na2SO4, filtered and concentrated under reduced
pressure giving the product, which was purified by column
0.90 (9H, s), 0.05 (6H, s); 13C NMR (CDCl3, 50 MHz)
d
(ppm):141.1 (C), 128.5 (2CH), 128.4 (2CH), 127.1 (C), 109.2 (C),
78.5 (CH), 67.2 (CH2), 63.3 (CH2), 59.0 (CH), 51.4 (CH2) 28.9

792
D. Díez et al. / Tetrahedron: Asymmetry 21 (2010) 786–793
chromatography (hexane/EtOAc 3:7) to yield 40 mg (0.25 mmol,
evaporated in vacuo to afford after column chromatography (hex-
59%) of 20. ½a 2D0
ꢀ
¼ ꢁ33:7 (c 0.87, CHCl3), IR (film)
m
(cmꢁ1):
ane/EtOAc 9:1) 218 mg (0.70 mmol, 70%) of 23. ½a D20
¼ ꢁ34:6 (c
ꢀ
3600–3100, 2960, 2919, 1676, 1481, 1438, 1142, 1085; 1H NMR
(CDCl3, 400 MHz) d (ppm): 4.26 (1H, dd, J = 4.7 and 10.4 Hz), 3.94
(1H, t, J = 10.4 Hz), 3.72 (1H, dt, J = 4.7 and 10.4 Hz), 3.55–3.43
(2H, m), 3.36 (1H, dt, J = 5.3 and 10.4 Hz), 2.40–2.30 (1H, m),
2.05–1.95 (1H, m), 1.88–1.73 (1H, m), 1.62–1.50 (1H, m); 13C
NMR (CDCl3, 100 MHz) d (ppm): 152.6 (CO), 69.8 (CH2), 66.7
(CH), 61.9 (CH), 47.2 (CH2), 31.6 (CH2), 22.8 (CH2). HRMS (ESI):
calcd for C7H11NO3Na, [M+Na]+: 180.0611 found: 180.0641.
0.60, CHCl3). IR (film) m
(cmꢁ1): 3600–3100, 3029, 2922, 2875,
2749, 1453, 1094, 1028, 739. 1H NMR (CDCl3, 400 MHz) d (ppm):
7.35–7,26 (10H, m,- Ph), 4.77 (1H, d, J = 11.7 Hz, –CH2Ph), 4.60
(1H, d, J = 11.7 Hz, –CH2Ph), 4.55 (2H, s, –CH2Ph), 3.67 (2H, m,
CH2O), 3.64 (1H, m, CHO), 3.28 (1H, m, CHN), 2.96 (1H, m, HA-5),
2.86 (1H, m, HB-5), 1.85 (1H, m, HA-3), 1.75 (2H, m, CH2-4), 1.65
(1H, m, HB-3). 13C NMR (CDCl3, 100 MHz) d (ppm): 138.7 and
138.2 (Cipso-Ph), 128.4 and 128.3 (4Cortho-Ph), 127.8 and 127.6
(4Cmeta-Ph), 127.5 (2Cpara-Ph), 80.3 (CH-10), 73.4 (OCH2Bn), 72.6
(OCH2Bn), 71.3 (OCH2), 59.9 (NCH), 46.7 (NCH2), 27.3 (CH2-4),
25.5 (CH2-3). HRMS (ESI): calcd for C20H26NO2, [M+H]+: 312.1958
found: 312.1956.
4.1.17. (2S)-N-tert-Butoxycarbonyl-2-[(10S)-10,20-dibenzyloxy-
ethyl]-pyrrolidine, 21
A suspension of NaH (69 mg, 2.85 mmol) in THF (1 mL) was stir-
red under an Ar atmosphere. Then a mixture of 2 (300 mg,
1.30 mmol), tert-butylammonium iodide (97 mg, 0.26 mmol) and
BnBr (0.61 mL, 5.19 mmol) was added to the previous solution by
canula and left to stir at room temperature for 12 h. The reaction
was quenched by the addition of H2O and then the reaction mixture
was extracted with EtOAc (3 ꢃ 70 mL). The organic layers were com-
bined, washedwith brineand driedover anhydrousNa2SO4. Afterfil-
tering and evaporating the solvents, the crude extract was purified
by flash chromatography (hexane/EtOAc, 9:1–7:3) to obtain
4.1.20. (2S)-2-[(10R)-10,20-Dibenzyloxyethyl]-pyrrolidine, 24
A solution of 22 (497 mg, 1.21 mmol) in 12 mL of EtOH was stir-
red at 0 °C. Then HCl 6 M (1.6 mL) was added and the mixture was
warmed to 21 °C. The solvent was evaporated and the reaction
mixture was dissolved in CH2Cl2. The resulting mixture was
washed with NaHCO3 concd, extracted with CH2Cl2 (3 ꢃ 50 mL)
and dried over anhydrous Na2SO4. After filtering, the solvent was
evaporated in vacuo affording after column chromatography (hex-
536 mg (1.2 mmol, 95%) of 21. ½a D20
ꢀ
¼ ꢁ70:1 (c 0.72, CHCl3). IR (film)
ane/EtOAc 1:1) 328 mg (1.05 mmol, 87%) of 24. ½a D20
¼ þ7:3 (c 0.9,
ꢀ
m
(cmꢁ1): 2974, 2930, 2873, 1692, 1454, 1394, 1365, 1168, 1101. 1H
CHCl3). IR (film) m
(cmꢁ1): 3600–3100, 3087, 3062, 3029, 2867,
NMR (CDCl3, 200 MHz, rotamers) d (ppm): 7.34–7.30 (10H, m), 4.69
and 4.60 (1H each, 2d, J = 11.8 Hz), 4.55 (2H, d, J = 4.8 Hz), 4.30 (1H,
m), 4.05 (1H, m), 3.90 (1H, m), 3.58–3.20 (3H, m), 2.18–1.54 (4H, m),
1.47 (9H, s). 13C NMR (CDCl3, 50 MHz) d (ppm): 154.8 (CO), 138.6
(2C), 128.6 (4CH), 128.0 (4CH), 127.7 (2CH), 79.6 (C), 78.0 (CH),
74.0 (CH2), 73.5 (CH2), 71.9 (CH2), 59.0 (CH), 47.3 (CH2), 28.8
(3CH3), 26.4 (CH2), 25.7 (CH2). HRMS (ESI): calcd for C25H33NO4Na,
[M+Na]+: 434.2302 found: 434.2314.
1496, 1453, 1385, 1365, 1276, 1206, 1094, 1028. 1H NMR (CDCl3,
400 MHz) d (ppm): 7.38–7,26 (10H, m, –2Ph), 4.80 and 4.60 (1H
each, 2d, J = 11.4 Hz, –CH2Ph), 4.55 (2H, s, –CH2Ph), 3.72–3.52
(3H, m, 1H-10 and 2H-20), 3.23–3.15 (1H, m, H-2), 3.02–2.4 (1H,
m, HA-5), 2.85–2.75 (1H, m, HB-5), 1.83–1.65 (3H, m, HA-4 and
2H-3), 1.51–1.40 (1H, m, HB-4). 13C NMR (CDCl3, 100 MHz) d
(ppm): 138.7 and 138.2 (2Cipso-Ph), 128.3 (4Cortho-Ph), 127.8
(2Cpara-Ph), 127.5 (4Cmeta-Ph), 81.1 (CH-10), 73.4 (–CH2Ph), 73.0
(–CH2Ph), 71.6 (CH2-20), 60.2 (CH-2), 46.1 (CH2-5), 27.6 (CH2-4),
24.9 (CH2-3). HRMS (ESI): calcd for C20H26NO2, [M+H]+: 312.1958
found: 312.1960.
4.1.18. (2S)-N-tert-Butoxycarbonyl-2-[(10R)-10,20-dibenzyloxy-
ethyl]-pyrrolidine, 22
A suspension of NaH (85 mg, 3.51 mmol) in THF (5 mL) was stir-
red in an Ar atmosphere. Then a mixture of 3 (343 mg, 1.60 mmol),
tert-butylammonium iodide (120 mg, 0.32 mmol) and BnBr
(0.75 mL, 6.4 mmol) was added to the previous solution by cannula
and left to stir at room temperature for 4 h. The reaction was
quenched by addition of H2O and then the reaction mixture was
extracted with EtOAc (3 ꢃ 70 mL). The organic layers were com-
bined, washed with brine and dried over anhydrous Na2SO4. After
filtering and evaporating the solvents, the crude extract was puri-
fied by flash chromatography (hexane/EtOAc, 9:1) to obtain
4.1.21. Typical procedure for Michael addition reaction
To a mixture of catalyst 24 (8.5 mg, 0.027 mmol, 15%), benzoic
acid (3.3 mg, 0.027 mmol, 15%) and trans-b-nitrostyrene (27 mg,
0.18 mmol) were added 0.8 mL of toluene and 0.34 mL
(3.62 mmol) of cyclohexanone. The resulting mixture was allowed
to stir at room temperature for 12 h, whereupon the reaction was
quenched with saturated aqueous ammonium chloride (2 mL) and
the aqueous layers were extracted with ethyl acetate. The com-
bined organic layers were washed with brine, dried over Na2SO4,
filtered and evaporated in vacuo and the resulting residue was
purified by flash column chromatography using hexane/EtOAc.
Compounds 25,23 26,24 27,25 28,26 2924 and 3025 are reported in
the literature.
357 mg (0.87 mmol, 54%) of 22. ½a D20
¼ ꢁ31:7 (c 0.93, CHCl3). IR
ꢀ
(film)
m
(cmꢁ1): 2974, 2930, 2872, 1692, 1454, 1391, 1366, 1254,
1168, 1098, 1028. 1H NMR (CDCl3, 200 MHz, rotamers) d (ppm):
7.41–7.22 (10H, m), 4.82 and 4.70 (1H each, 2d, J = 11.8 Hz), 4.55
(2H, s), 4.20–4.00 (2H, m, H-2 and HA-20), 3.73–3.19 (2H, m, H-2
and HB-20), 3.58 (1H, m, HA-5), 3.35 (1H, m, HB-5), 2.02–1.63 (4H,
m), 1.47 (9H, s). 13C NMR (CDCl3, 50 MHz) d (ppm): 155.0 (CO),
139.4 (C), 138.8 (C), 128.5 (2CH), 128.4 (2CH), 127.8 (2CH), 127.7
(2CH), 127.6 (CH), 127.5 (CH), 79.8 (CH), 79.5 (C), 73.6 (CH2),
73.1 (CH2), 71.6 (CH2), 58.1(CH), 47.4 (CH2), 28.7 (3CH3), 27.4
(CH2), 24.2 (CH2). HRMS (ESI): calcd for C25H33NO4Na, [M+Na]+:
434.23018 found: 434.2307.
Acknowledgements
The authors gratefully acknowledge the help of A. Lithgow
(NMR) and C. Raposo (MS) of Universidad de Salamanca and MCeI
(CTQ2006-08296), CTQ2009-11172, FSE and Junta Castilla y León
GR178, SA001A09 for financial support. Ana B. Antón and J. Peña
are grateful to the University of Salamanca and Junta de Castilla
y León for their fellowships.
4.1.19. (2S)-2-[(10S)-10,20-Dibenzyloxyethyl]-pyrrolidine, 23
A solution of 21 (410 mg, 1 mmol) in 10 mL MeOH was stirred
at 0 °C. Then HCl 6 M (1.34 mL) was added over the mixture and
warmed to 21 °C. The solvent was evaporated and the reaction
mixture was dissolved in CH2Cl2. The resulting mixture was
washed with NaHCO3 concd, extracted with CH2Cl2 (3 ꢃ 30 mL)
and dried over anhydrous Na2SO4. After filtering, the solvent was
References
1. (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 116, 5138; (b) Gaunt, M.
J.; Johansson, C. C. C.; McNally, A.; Vo, N. T. Drug Discovery Today 2007, 12, 8;
(c)Asymmetric Organocatalysis. From Biomimetic Concepts to Applications in
Asymmetric Synthesis; Berkessel, A., Gröger, H., Eds.; Wiley-VCH: Weinheim,
2005.

D. Díez et al. / Tetrahedron: Asymmetry 21 (2010) 786–793
793
2. List, B.; Lerner, A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122, 2395.
3. (a) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1877; (b)
Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719; (c) Zhu, M.-K.; Cun, L.-F.; Mi,
A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. Tetrahedron: Asymmetry 2006, 17, 491; (d) Terada,
M.; Ube, H.; Yaguchi, Y. J. Am. Chem. Soc. 2006, 128, 1454; (e) Huang, H.;
Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170; (f) Mosseé, S.; Laars, M.; Kriis,
K.; Kanger, T.; Alexakis, A. Org. Lett. 2006, 8, 2559; (g) Lattanzi, A. Tetrahedron:
Asymmetry 2006, 17, 837; (h) Luo, S.; Mi, X.; Zhang, L.; Liu, S.; Xu, H.; Cheng, J.-
P. Angew. Chem., Int. Ed. 2006, 45, 3093; (i) Almasí, D.; Alonso, D. A.; Nájera, C.
Tetrahedron: Asymmetry 2007, 18, 299; (j) Tsogoeva, A. B. Eur. J. Org. Chem. 2007,
1701; (k) Pellisier, H. Tetrahedron 2007, 63, 9267.
13. (a) Jäger, V.; Hümmer, W.; Stahl, U.; Gracza, T. Synthesis 1991, 769; (b) Jäger, V.;
Stahl, U.; Hümmer, W. Synthesis 1991, 776; (c) Jäger, V.; Schröter, D.;
Koppenhoefer, B. Tetrahedron 1991, 47, 2195; (d) Hanson, R. M. Org. React.
2002, 60, 1. page 39.
14. Payne, G. B. J. Org. Chem. 1962, 27, 3819.
15. (a) Murruzzu, C.; Riera, A. Tetrahedron: Asymmetry 2007, 18, 149; (b) Madhan,
A.; Rao, B. V. Tetrahedron Lett. 2003, 44, 5641; (c) Chandrasekhar, B.; Madhan,
A.; Rao, B. V. Tetrahedron 2007, 63, 8746.
16. (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413; (b) Grubbs, R. H.; Miller,
S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446; (c) Schuster, M.; Blechert, S. Angew.
Chem., Int. Ed. 1997, 36, 2036; (d) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1
1998, 371; (e) Ivin, K. J. J. Mol. Catal. A: Chem. 1998, 133, 1.
4. Kotsuki, H.; Ikishima, H.; Okuyama, A. Heterocycles 2008, 75(493), 757.
5. (a) Palomo, C.; Mielgo, A. Angew. Chem., Int. Ed. 2006, 45, 7876; (b) Mielgo, A.;
Palomo, C. Chem. Asian J. 2008, 3, 922.
17. Díez, R.; Badorrey, R.; Diaz-de-Villegas, M. D.; Gálvez, J. A. Eur. J. Org. Chem.
2007, 2114.
6. Díez, D.; Gil, M. J.; Moro, R. F.; Marcos, I. S.; García, P.; Basabe, P.; Garrido, N. M.;
Broughton, H. B.; Urones, J. G. Tetrahedron 2007, 63, 740.
7. Díez, D.; Nuñez, M. G.; Benéitez, A.; Moro, R. F.; Marcos, I. S.; Basabe, P.;
Broughton, H. B.; Urones, J. G. Synlett 2009, 390.
8. Díez, D.; Antón, A. B.; García, P.; Garrido, N. M.; Marcos, I. S.; Basabe, P.; Urones,
J. G. Tetrahedron: Asymmetry 2008, 19, 2088.
18. Díez, D.; Antón, A. B.; García, P.; Nuñez, M. G.; Garrido, N. M.; Moro, R. F.;
Marcos, I. S.; Basabe, P.; Urones, J. G. Tetrahedron: Asymmetry 2006, 17, 2260.
19. (a) Wu, P.-L.; Chung, T.-H.; Chou, Y. J. Org. Chem. 2001, 66, 4287; (b) Tayama, E.;
Otoyama, S.; Isaka, W. Chem. Commun. 2008, 4216.
´
20. (a) Parker, K. A.; OFee, R. J. Am. Chem. Soc. 1983, 105, 654; (b) Gleave, D. M.;
Brickner, S. J. J. Org. Chem. 1996, 61, 6470.
9. For a review on this subject, see: (a) Kolb, H. C.; VanNieuwenhze, M. S.;
Sharpless, K. B. Chem. Rev. 1994, 94, 2483; See too: (b) Bodkin, J. A.; McLeod, M.
D. J. Chem. Soc., Perkin Trans. 1 2002, 2733; (c) Donohoe, T. J.; Johnson, P. D.; Pye,
R. J. Org. Biomol. Chem. 2003, 2025; (d) Johnson, R. A.; Sharpless, K. B. Catalytic
Asymmetric Dihydroxylation: Discovery and Development. In Catalytic
Asymmetric Synthesis;; Ojima, I., Ed.; Wiley: VCH, 2000; p 357; (e) Bolm, C.;
Hildebrand, J. P.; Muniz, K. Recent Advances in Asymmetric Dihydroxylation
and Aminohydroxylation. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.;
Wiley: VCH, 2000; p 398; (f) Sharpless, B. H.; Sharpless, K. B. Asymmetric
Dihydroxylation in Asymmetric Oxidation Reactions. In A Practical Approach in
Chemistry; Katsuki, T., Ed.; Oxford University Press: New York, 2001; p 81; (g)
Sharpless, K. B. Angew. Chem., Int. Ed 2002, 41, 2024.
21. A single crystal of compound 20 was mounted on glass fibre for data collection
on a Bruker Kappa APEX II CCD diffractometer. Data were collected at 293 K
using Cu
Ka radiation (k = 1.54178 Å) and x scan technique and were
corrected for Lorentz and polarisation effects. Crystal data for 20: C7H11NO3,
M = 157.17, orthorhombic, space group P212121 (no 19), a = 7.11310(10) Å,
b = 8.65750(10) Å, c = 8.65750(10) Å,
Dcalcd = 1.401 Mg/m3, m = (Cu
reflections were collected at 6.29 6 2h 6 59.81 and merged to give 933
unique reflections (Rint = 0.0126), of which 881 with >2 (I) were
a
= b =
c
= 90°, V = 745.052(18) Å3, Z = 4,
K
a
) = 0.924 mmꢁ1
,
F(0 0 0) = 336. 1914
I
r
considered to be observed. Structure solution, refinement and data output
were carried out with the SHELXTL™ program package. The structure was
solved by direct methods combined with difference Fourier synthesis and
refined by full-matrix least-squares procedures, with anisotropic thermal
parameters in the last cycles of refinement for all non-hydrogen atoms. H
atoms of SP3 hybridized carbons were located directly in a difference Fourier
map and freely refined. The rest of the hydrogen atoms were positioned
10. (a) Gardiner, J. M.; Bruce, S. E. Tetrahedron Lett. 1998, 39, 1029; (b) Yang, Y.-R.;
Kim, D.-S.; Kishi, Y. Org. Lett. 2009, 11, 4516; (c) Krysan, D. J. Tetrahedron Lett.
1996, 37, 1375; (d) Salvadori, P.; Superchi, S.; Minutolo, F. J. Org. Chem. 1996,
61, 4190.
11. (a) Poon, Ch. Y.; Chiu, P. Tetrahedron Lett. 2004, 45, 2985; (b) Dieter, R. K.; Chen,
N.; Watson, R. T. Tetrahedron 2005, 61, 3221; (c) Dieter, R. K.; Oba, G.;
Chandupatla, K. R.; Topping, C. M.; Lu, K.; Watson, R. T. J. Org. Chem. 2004, 69,
3076; (d) Moriwake, T.; Hamano, S.-I.; Saito, S.; Torii, S. Chem. Lett. 1987, 2085;
(e) Serino, C.; Stehle, N.; Park, Y. S.; Florio, S.; Beak, P. J. Org. Chem. 1999, 64,
1160; (f) Sobrio, F.; Quentin, T.; Dhilly, M.; Bourdier, T.; Tymciu, S.; Debruyne,
D.; Barre, L. Nucl. Med. Biol. 2008, 35, 377.
geometrically. The final R factors were R1 = 0.0240 and xR2 = 0.0617 for a total
of 111 parameters.
Crystallographic data (excluding structure factors) for the structure reported in
this paper have been deposited at the Cambridge Crystallographic Data Centre
as supplementary material number CCDC 739299.
22. In Ref. 8 the stereochemistry of compounds 13, 14 and 15 should be changed
for the ones of 2, 21 and 23 of this paper, respectively.
12. For a recent review of asymmetric epoxidation, see: (a) Xia, Q.-H.; Ge, H.-Q.; Ye,
C.-P.; Liu, Z.-M.; Su, K.-X. Chem. Rev. 2005, 105, 1603; See also: (b) Johnson, R.
A.; Sharpless, K. B.. In Comprehensive Organic Synthesis; Trost, B. M., Ed.;
Pergamon: New York, 1991; Vol. 7, p 389; (c) Jacobsen, E. N.; Wu, M. H. In
Comprehensive Asymmetric Catalysis II; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds.; Springer: Berlin, 1999; p 649; See also: (d) Gao, Y.; Hanson, R. M.;
Klunder, J. M.; Ki, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987,
109, 5765.
23. Juaristi, E.; Beck, A.; Hansen, J.; Matt, T.; Mukhopadhay, T.; Simson, M.;
Seebach, D. Synthesis 1993, 1271.
24. Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol.
Chem. 2005, 3, 84.
25. Ishi, T.; Fujioka, S.; Sekiguchi, Y.; Kotsuki, H. J. Am. Chem. Soc. 2004, 126, 9558.
26. Seebach, D.; Lyapkalo, I. M.; Dahinden, R. Helv. Chim. Acta 1999, 11, 1829.