Boron trifluoride etherate-assisted ring opening of ethylene oxide by a chiral organolithium: Enantioselective synthesis of (R)-N-Boc-2-(2-hydroxyethyl) pyrrolidine

Article abstract of DOI:10.1016/j.tetasy.2004.11.083

A practical synthesis of (R)-N-Boc-2-(2-hydroxyethyl)pyrrolidine in high enantiomeric purity is described. The synthesis involves BF₃· Et₂O-assisted ring opening of ethylene oxide by a homochiral carbanion (R)-3, which is derived from sparteine-mediated asymmetric deprotonative lithiation of 1-Boc-pyrrolidine.

Full text of DOI:10.1016/j.tetasy.2004.11.083

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 661–664
Boron trifluoride etherate-assisted ring opening of ethylene oxide
by a chiral organolithium: enantioselective synthesis of
(
R)-N-Boc-2-(2-hydroxyethyl)pyrrolidine
Xiaohu Deng and Neelakandha S. Mani*
Johnson & Johnson Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA
Received 13 October 2004; accepted 18 November 2004
Available online 21 January 2005
Abstract—A practical synthesis of (R)-N-Boc-2-(2-hydroxyethyl)pyrrolidine in high enantiomeric purity is described. The synthesis
involves BF
ated asymmetric deprotonative lithiation of 1-Boc-pyrrolidine.
2005 Elsevier Ltd. All rights reserved.
3 2
ÆEt O-assisted ring opening of ethylene oxide by a homochiral carbanion (R)-3, which is derived from sparteine-medi-
ꢀ
1
. Introduction
ethylpyrrolidine. Although Lewis acid-assisted ring
opening of epoxides by achiral organolithiums is well
1
4,15
(À)-Sparteine-mediated asymmetric deprotonative lithi-
ation has emerged as a powerful synthetic tool to gener-
ate ꢀchiral carbanionsꢁ, thanks to the pioneering work by
Hoppe and Hense and Beak et al. Capturing the chiral
information from these organolithium species through
alkylations, or by addition to carbonyl compounds,
has resulted in numerous applications in asymmetric
precedented,
to the best of our knowledge, investiga-
tions into the configurational stability of chiral organo-
lithiums under such alkylation conditions have not been
reported.
1
2
2. Results and discussion
3
–9
synthesis. A recent paper introduced a readily accessi-
1
0
ble (+)-sparteine surrogate, allowing preparation of
these chiral organolithiums in both enantiomeric forms;
considerably expanding the scope of this methodology.
One remaining limitation of this chemistry is that the di-
pole-stabilized chiral organolithiums are configuration-
ally stable only at very low temperature (À78 to
À40 ꢁC) and in select solvents (diethyl ether, THF,
In connection with one of our drug discovery projects,
we needed multi-gram quantities of (R)-Boc-2-hydroxy-
ethylpyrrolidine, (R)-1, in good enantiomeric purity
(Fig. 1). Compound 1 is a versatile precursor used in
the construction of natural products such as anthramy-
1
6
17
18
19
cin, lydicamycin, halosaline, and cuscohygrine,
as well as many bioactive molecules such as Clemastine
1
1,12
20
and hydrocarbon solvents).
Under these conditions,
(antihistamine),
1
antagonist).
and SB-269970 (5HT7 receptor
2
alkylations using less reactive electrophiles, such as
epoxides, alkyl bromides, or alkyl chlorides, do not pro-
ceed efficiently. Electrophiles that are suitable for this
chemistry are thus limited to strong electrophiles such
The most commonly used methods to synthesize com-
pound (R)-1 involved multi-step sequences from expen-
as TMSCl, Bu SnCl, alkyl iodides, aldehydes, and
3
sive, chiral starting materials such as D-prolinol or D-
21–24
1
3
ketones. Herein, we report the first example of an
intermolecular alkylation of a chiral organolithium with
an epoxide activated by BF ÆEt O, resulting in an effi-
proline, which are not suitable for large-scale syn-
thesis. Shown in Scheme 1 is a typical example.
3
2
cient, enantioselective synthesis of (R)-Boc-2-hydroxy-
Use of asymmetric deprotonative lithiations mediated
by commercially available (À)-sparteine and (+)-sparte-
ine surrogate have allowed access to chiral carbanions in
either enantiomeric form. Reference methodologies
generally rely on reaction of the chiral carbanions with
1
0,11
*
Corresponding author. Tel.: +1 858 784 3289; fax: +1 858 784
267; e-mail: nmani@prdus.jnj.com
3
0
957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.11.083

662
X. Deng, N. S. Mani / Tetrahedron: Asymmetry 16 (2005) 661–664
N
HO
S
O
N
O
O
OH
N
N
Boc
Cl
SB-269970
Clemastine
1
Figure 1.
Boc O, H O
1. (COCl) , DMF-CH Cl
2
2
2
2
2
COOH
COOH
N
Boc
N
H
2. CH N , Et O
2
2
2
94%
3. PhCOOAg, MeOH
60%
LiAlH , Et O
COOMe
4
2
N
Boc
OH
N
Boc
95%
Scheme 1.
strong electrophiles. Alternatively, epoxide electrophiles
may be used in intramolecular processes in the absence
of epoxide activation by a Lewis acid. In contrast, we
envisioned that an intermolecular alkylation of (R)-3
with a strained cyclic ether in the presence of a Lewis
acid would provide (R)-1. We investigated this approach
first using conventional methodology, by applying stan-
dard s-BuLi/(À)-sparteine conditions as described by
BF ÆEt O has proven to be the most efficient Lewis acid
3 2
suitable for activation of epoxides towards alkyl/aryl-
1
4,15
lithiums at low temperature (À78 ꢁC).
In theory,
strongly basic sparteine could compete with an epoxide
for the Lewis acid and thus potentially compromise the
configurational integrity of the chiral organolithium (R)-
3. However, we reasoned that a fast epoxide ring open-
ing must be the decisive event and an equilibrium con-
taining some epoxide–Lewis acid complex should drive
the reaction forward before epimerization of (R)-3
might occur. Results from our experiments indicate that
this indeed is the case.
1
3
Beak (Scheme 2). To that end, (R)-3 was prepared
and the ethereal solution was treated with less reactive
electrophiles such as ethylene oxide 4 and protected 2-
bromoethanol 5. No reaction was observed in either
case, and unreacted starting materials were recovered.
Modifying the reactivity of the chiral organolithium/
The chiral organolithium/sparteine complex (R)-3 was
generated in diethyl ether using the standard conditions,
and the complex was treated with ethylene oxide, fol-
lowed by 1 equiv of BF ÆEt O (Scheme 3). The reaction
2
5,26
sparteine complex by transmetallation to copper
2
or
magnesium, also failed to yield any desired alkylation.
7
3
2
Lewis acids are known to activate epoxides for nucleo-
2
philic attack by coordinating to the oxygen atom.
proceeded smoothly to afford the desired (R)-Boc-2-
hydroxyethylpyrrolidine (R)-3 in very good yield (83%)
8
O 4
or
s-BuLi, (-)-Sparteine,
Et O, -78 C, 4 h
2
N
Boc
No reaction
o
Li/sparteine
N
OTHP
5
Br
Boc
R)-3
2
(
Scheme 2.
s-BuLi, (-)-Sparteine,
o
Et O, -78 C, 4 h
2
OR
N
N
ethylene oxide,
Boc
Boc
2
o
BF ·Et O, -78 C, 2 h
3
2
(
R)-1 R=H
(R)-6 R=4-NO PhCO
2
Yield: 83%
ee: 82%
Scheme 3.

X. Deng, N. S. Mani / Tetrahedron: Asymmetry 16 (2005) 661–664
663
1
3
and enantioselectivity (ee = 82%). The enantiomeric ex-
cess (ee) was determined by chiral HPLC analysis of
the p-nitrobenzoate derivative (R)-6, which was pre-
pared from (R)-1 upon treatment with p-nitrobenzoyl
chloride. We observed that the order of reagent addition
in the reaction as described above is the most preferred
in obtaining good results. For example, addition of the
epoxide, pre-complexed with BF ÆEt O, to the organoli-
thium gave lower yields and eeꢁs. Reverse addition of the
chiral organolithium to the pre-complexed epoxide also
gave very low yields, presumably due to premature
breakdown of the organolithium/sparteine complex.
1.50 (m, 6H), 1.43 (s, 9H). C NMR (CDCl ) d
3
154.39, 77.72, 57.01, 51.43, 44.37, 36.30, 29.09, 26.36,
21.46. IR (neat) 2970.0 (w), 1668.4 (s), 1397.2 (s),
1365.4 (s), 1166.3 (s). EI-MS (70 eV): m/z (%): 215 (2,
+
+
+
M ); 170 (17, M ÀCH CH OH), 158 (8, M ÀC H ),
2
2
4
9
+
+
142 (15, M ÀC H O), 114 (100, M ÀC H OCO).
4
9
4
9
+
HRMS (ES) Calcd for C H NO [M +H], 216.1600;
1
1
22
3
Found,
216.1610.
GC
(HP-5MS
30 m · 0.25
3
2
mm · 0.25 m column; oven temp 55 ꢁC; ramp 10 ꢁC/
min; final temp 270 ꢁC; mass selective detector)
R = 12.1 min.
T
3.2. (+)-(2R)-1-Boc-2-[2-(4-Nitro-benzoyloxy)-ethyl]-pyr-
rolidine (R)-6
In conclusion, an efficient, one-step method was devel-
oped to synthesize compound (R)-1, a versatile precur-
sor of many bioactive molecules. High yield and ee
were obtained from inexpensive starting materials.
Nucleophilic ring opening of an epoxide by a chiral
organolithium, promoted by BF ÆEt O, in high effi-
A solution of compound (R)-1 (crude product before
distillation, 100 mg, 0.46 mmol, 1 equiv), Et N (71 mg,
3
0.70 mmol, 1.5 equiv) and 4-nitrobenzoyl chloride
(0.13 g, 0.70 mmol, 1.5 equiv) in 10 mL of CH Cl was
stirred at rt for 16 h. The organic layer was washed with
3
2
2
2
ciency and enantioselectivity, expands the scope of this
methodology and should find many useful applications.
brine, dried over MgSO , filtered, and evaporated. Col-
4
umn chromatography of the crude product with EtOAc/
hexanes as eluent afforded the title compound as a white
solid (100 mg, 0.27 mmol, 59%). The racemic sample
3. Experimental
1
was prepared in the same way. H NMR (CDCl ) d
3
Proton and carbon NMR spectra were recorded at
8.30–8.2 (m, 3, 2H), 8.21–8.16 (m, 2H), 4.50–4.30 (m,
2H), 4.10–3.85 (m, 1H), 3.50–3.20 (m, 2H), 2.40–1.60
1
13
Bruker 500 NMR spectrometer ( H, 500 MHz; C,
25 MHz). Infrared spectroscopy was performed on a
1
3
1
(m, 6H), 1.44 (s, 9H). C NMR (CDCl ) d 144.21,
3
Nicolet Avatar 360 FT-IR. Flash column chromatogra-
phy was performed using Merck silica gel 60. 1-Boc-pyr-
152.52, 133.59, 128.98, 128.62, 121.46, 77.58, 61.82,
52.59, (44.45, 44.02), (31.87, 31.26), (29.06, 28.24),
26.45, (21.78, 20.96). IR (neat): 2966.6 (w), 1724.9 (s),
1688.4 (s), 1528.7 (s), 1392.9 (s), 1275.3 (s). HRMS
2
9
rolidine and racemic (±)-1-Boc-2-(2-hydroxy-ethyl)-
3
pyrrolidine were prepared according to literature pro-
0
+
cedures. s-BuLi, (À)-sparteine, ethylene oxide, BF ÆEt O
(ES) Calcd for C H N O [M +H], 365.1713; Found,
18 25
3
2
2
6
and 4-nitrobenzoyl chloride were purchased from
Aldrich and used without further purification. All glass-
ware was flame dried prior to use.
365.1716. Chiral HPLC analysis was performed on a
Hewlett Packard 1100 (Chiralpak AD column,
4.6 · 50 mm, mobile phase EtOH/hexanes = 85/15, Flow
rate 1 mL/min). Retention times were 4.94 min (R-enan-
tiomer) and 5.87 min (S-enantiomer), respectively. The
ee of the product, determined by area integration was
found to be 82%.
3
.1. (+)-(2R)-1-Boc-2-(2-hydroxy-ethyl)-pyrrolidine (R)-1
(
À)-Sparteine (24.7 g, 105 mmol, 1.2 equiv) in 250 mL of
Et O was cooled to À78 ꢁC under N and then 1-Boc-
2
2
pyrrolidine (15 g, 88 mmol, 1.0 equiv) was added by syr-
inge. After stirring at À78 ꢁC for 10 min, s-BuLi (81 mL,
Acknowledgements
1
.3 mol/L, 1.2 equiv) was added dropwise and the result-
ing mixture was stirred at À78 ꢁC for 4 h. A solution of
We wish to thank Dr. Nicholas Carruthers for helpful
discussions.
ethylene oxide (5.8 g, 130 mmol, 1.5 equiv) in 20 mL of
Et O, which was pre-cooled to À78 ꢁC, was transferred
2
to the previous flask via cannula under N and then
2
BF ÆEt O (18.7 mL, 130 mmol, 1.5 equiv) was added
3
2
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