Asymmetric synthesis of N-substituted (R)-2-[(pyrrolidin-1-yl)methyl]pyrrolidines

Article abstract of DOI:10.1081/SCC-100103998

The preparation of (R)-2[(pyrrolidin-1-yl)methyl] pyrrolidine and (R)-1-methyl-2-[(pyrrolidin-1-yl)methyl]pyrrolidine (both in 85% ee) is reported. The key step in the synthesis involves the sparteine-mediated asymmetric functionalization of N-Boc pyrrolidine and subsequent trapping with 1-pyrrolidine-carbonyl chloride.

Full text of DOI:10.1081/SCC-100103998

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ASYMMETRIC SYNTHESIS
OF N-SUBSTITUTED
(R)-2-[(PYRROLIDIN-1-
YL)METHYL]PYRROLIDINES
a
b
Justin R. Harrison & Peter O'Brien
a
Department of Chemistry, University of York,
Heslington, York, YO10 5DD, UK
b
Department of Chemistry, University of York,
Heslington, York, YO10 5DD, UK
Published online: 09 Nov 2006.
To cite this article: Justin R. Harrison & Peter O'Brien (2001) ASYMMETRIC
SYNTHESIS OF N-SUBSTITUTED (R)-2-[(PYRROLIDIN-1-YL)METHYL]PYRROLIDINES,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 31:8, 1155-1160, DOI: 10.1081/SCC-100103998
To link to this article: http://dx.doi.org/10.1081/SCC-100103998
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SYNTHETIC COMMUNICATIONS, 31(8), 1155–1160 (2001)
ASYMMETRIC SYNTHESIS OF
N-SUBSTITUTED (R)-2-[(PYRROLIDIN-
1
-YL)METHYL]PYRROLIDINES
Justin R.Harrison and Peter O’Brien *
Department of Chemistry, University of York,
Heslington, York YO10 5DD, UK
ABSTRACT
The preparation of (R)-2[(pyrrolidin-1-yl)methyl] pyrro-
lidine and (R)-1-methyl-2-[(pyrrolidin-1-yl)methyl]pyrrolidine
(both in 85% ee)is reported. The key step in the synthesis
involves the sparteine-mediated asymmetric functionalization
of N-Boc pyrrolidine and subsequent trapping with 1-pyrro-
lidine-carbonyl chloride.
Diamines such as (S)-1-4 prepared in just a few steps from natural (S)-
proline are extremely useful chiral reagents and ligands for asymmetric syn-
thesis (vide infra). In addition, there is biological interest in the synthesis of
structurally related compounds: compounds like 1-4 are prolyl endopepti-
1
2
dase inhibitors and ligands for central nervous system receptors.
3
The lithium amide of (S)-1, introduced by Asami, is a popular chiral
–5
6
–8
base.
enriched allylic alcohols, and asymmetric syntheses of (ꢀ)-carbovir and
It can be used to rearrange meso-epoxides to enantiomerically
9
1
0
(
þ)-faranal utilize chiral base (S)-1. A computational study on the reac-
1
1
tion of lithiated (S)-1 with cyclohexene oxide has recently been completed.
*
Corresponding author.
1
155
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

1
156
HARRISON AND O’BRIEN
However, since only (S)-1 is readily available, its use in synthesis is limited.
Asami addressed this problem by preparing (S)-proline-derived diamines
that gave, with limited success, enantiocomplementary results to diamine
1
2
(
expensive (R)-proline in their synthesis of lasiol.
S)-1. In contrast, Mori et al. chose to prepare diamine (R)-1 from
1
3
1
4
Diamines (S)-2-4, introduced by Mukaiyama and Kobayashi, have
proven to be very useful reagents for asymmetric Mukaiyama aldol reac-
tions. Recently, such methodology was used on two separate occasions in
the total asymmetric synthesis of Taxol reported by Mukaiyama and co-
1
5
workers. Kobayashi and Horibe have extended the methodology so that,
by suitable choice of proline-derived diamine, it is possible to prepare either
1
6
enantiomer of syn-adol products. Nevertheless, ready access to the
enantiomeric ligands (R)-2-4 would be advantageous for synthetic chemists.
The need for chiral diamines (R)-1-4 prompted us to explore a new
approach for their synthesis. We recognized that the required stereochem-
istry could be set up by asymmetric functionalization of N-Boc pyrrolidine 5
1
7–20
using (ꢀ)-sparteine as reported by Beak et al.
. Using this approach, we
have completed the synthesis of (R)-1 and (R)-2 and this is the subject of the
present communication.
Lithiation of N-Boc pyrrolidine 5 at ꢀ78 C using s-butyllithium and
ꢁ
(
rolidinecarbonyl chloride. The reaction was quenched with acetic acid after
ꢀ)-sparteine was followed by reaction with commercially available 1-pyr-
ꢁ
just 5–10 min at ꢀ78 C. Work-up and purification by chromatography
1
afforded amide (R)-6 {[ꢀ] þ 36.6 (c 0.9 in MeOH); lit., [ꢀ] þ 37.1 (c 1.0
D
D
in MeOH)} in 57% yield and 85% ee (established by conversion into dia-
mines (R)-1 and (R)-2 and determination of their enantiomeric excesses, vide
infra). If the reaction was left any longer than 10 min before quenching, we
observed a compromise in the enantiomeric excess obtained.
Amide (R)-6 was converted into diamine (R)-1 {[ꢀ] ꢀ 6.0(c 0.8 in
D
3
EtOH); lit., [ꢀ] þ 8.2 (c 2.4 in EtOH)for ( S)-1} by N-Boc deprotection
D
using TFA and subsequent lithium aluminium hydride reduction. Diamine
(
R)-1 generated in this way had 85% ee as shown by conversion into
diastereomeric Mosher’s amides. Alternatively, diamine (R)-2 {[ꢀ] þ 66.8
D

ASYMMETRIC DIAMINE SYNTHESIS
1157
Scheme 1.
1
4
(
c 0.8 in EtOH); lit., [ꢀ] ꢀ84.5 (c 0.5 in EtOH)for ( S)-2} was obtained by
D
direct lithium aluminium hydride reduction of amide (R)-6. The enantio-
1
meric excess (85%)of diamine ( R)-2 was verified by H NMR spectroscopy
in the presence of the chiral shift reagent (R)-2,2,2-trifluoro-1-(9-anthryl)
ethanol.
Scheme 2.
In summary, we have reported a simple way of preparing diamines
R)-1 and (R)-2 in good enantiomeric excess. Extension of the methodology
(
to include the preparation of other useful diamines such as (R)-3 and (R)-4
and related compounds of biological interest is possible by simple variation
of the carbonyl chloride and subsequent synthetic manipulations of the
intermediate N-Boc amide.
EXPERIMENTAL
THF was dried over sodium-benzophenone and distilled before use.
CH Cl was dried over calcium hydride and distilled before use. N-
2
2
2
1
Butyllithium was titrated against N-benzylbenzamide before use. All reac-
tions were carried out under oxygen-free nitrogen using over-dried glass-
ware. For Kugelrohr distillations, the temperatures quoted correspond to
the oven temperatures. Melting points were measured on an Electrothermal
IA 9100 digital melting point apparatus. Optical rotations were recorded on

1
158
HARRISON AND O’BRIEN
ꢁ
a Jasco DIP-370 polarimeter (using the sodium D line; 589 nm)at 20 C and
ꢀ
1
2
ꢀ1
[
ꢀ]D values are given in units of 10 deg cm g
.
(
R)-1-[N-(tert-Butoxycarbonyl)prolinamido]pyrrolidine (R)-8
3
s-Butyllithium (1.8 cm of a 1.28 M solution in cyclohexane, 2.3 mmol)
was added dropwise over 5 min to a stirred solution of N-Boc pyrrolidine 5
3
(
269 mg, 1.5 mmol)and freshly distilled ( ꢀ)-sparteine (0.58 cm , 2.5 mmol)
3
ꢁ
ꢁ
in Et O (10 cm )at ꢀ78 C under nitrogen. After stirring at ꢀ78 C for 5 h, 1-
2
3
pyrrolidinecarbonyl chloride (Lancaster Synthesis, 0.34 cm , 3.0 mmol)was
added dropwise over 5 min, followed by the immediate dropwise addition of
3
acetic acid (0.43 cm , 7.5 mmol). After allowing to warm to room tempera-
3
ture, water (4 cm )was added and the reaction mixture was extracted with
3
EtOAc (3ꢂ10 cm ). The combined organic extracts were washed with 5%
3
3
phosphoric acid (H PO ; 2 ꢂ 4 cm )and brine (10 cm ), dried (MgSO ), and
3
4
4
evaporated under reduced pressure to give the crude product as an oil.
Purification by flash chromatography with EtOAc as eluent gave amide
(
R)-8 (235 mg, 57%)as a white solid identical spectroscopically to that
ꢁ
ꢁ
ꢁ
2
ꢁ
previously reported, m.p. 79 –81 C (lit., 83 –84 C); [ꢀ] þ36.6 (c 0.9 in
D
1
MeOH); lit., [ꢀ] þ37.1 (c 1.0 in MeOH).
D
(
R)-2-[(Pyrrolidin-1-yl)methyl]pyrrolidine (R)-1
3
Trifluoroacetic acid (0.7 cm , 9.1 mmol)was added dropwise to a
3
stirred solution of amide (R)-8 (210 mg, 0.8 mmol)in CH Cl (1.4 cm )at
2
2
ꢁ
0 C under nitrogen. After stirring at room temperature for 30 min, 10%
3
aqueous sodium hydroxide solution (10 cm )was added and the mixture
3
was extracted with CH Cl (3ꢂ10 cm ). The combined organic extracts
2
2
were dried (K CO )and evaporated under reduced pressure. The residue
2
3
3
was dissolved in THF (13 cm )under nitrogen. Then lithium aluminium
hydride (140 mg, 3.7 mmol)was added and the resulting suspension was
heated at reflux for 17 h. After cooling to room temperature, Et O
2
3
(
20 cm )and excess solid hydrated sodium sulfate were added. The mixture
was stirred for 1 h and the solids were removed by filtration through Celite.
The filtrate was evaporated under reduced pressure to give the crude prod-
uct as a brown oil. Purification by Kugelrohr distillation gave diamine (R)-1
(
68 mg, 56%)as a colorless oil identical spectroscopically to that previously
ꢁ
3
reported, b.p. 95–105 C/14 mm Hg; {[ꢀ] ꢀ 6.0 (c 0.8 in EtOH); lit.,
D
[
ꢀ] þ 8.2 (c 2.4 in EtOH)for ( S)-1}.
D

ASYMMETRIC DIAMINE SYNTHESIS
R)-1-Methyl-2-[(pyrrolidin-1-yl)methyl]pyrrolidine (R)-2
1159
(
Lithium aluminium hydride (150 mg, 3.9 mmol)was added dropwise
3
to a stirred solution of amide (R)-8 (213 mg, 0.8 mmol)in THF (8 cm )at
room temperature under nitrogen. The resulting suspension was stirred at
room temperature for 48 h. Then excess solid hydrated sodium sulfate was
added. The mixture was stirred for 1 h and the solids were removed by
filtration through Celite. The filtrate was evaporated under reduced pressure
to give the crude product as a brown oil. Purification by Kugelrohr distilla-
tion gave diamine (R)-2 (100 mg, 75%)as a colorless oil identical spectro-
ꢁ
ꢁ
scopically to that previously reported, b.p. 100 –110 C/14 mm Hg;
4
1
{
[ꢀ] þ 66.8. (c 0.8 in EtOH); lit., {[ꢀ] ꢀ 84.5 (c 0.5 in EtOH)for ( S)-2}.
D
D
ACKNOWLEDGMENTS
We thank The Leverhulme Trust for the award of a fellowship
(
to JRH).
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Received May 5, 2000