Synthesis of enantiopure 3,5-disubstituted pyrrolidines by ring-opening/cross-metathesis reaction of 2-azanorbornene derivatives

Article abstract of DOI:10.3987/COM-06-10825

A concise method for the synthesis of enantiopure 3,5-disubstituted pyrrolidines from 2-azanorbornene derivatives is described. The method is also applied to the synthesis of 3,5-disubstituted prolines.

Full text of DOI:10.3987/COM-06-10825

HETEROCYCLES, Vol. 68, No. 10, 2006
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HETEROCYCLES, Vol. 68, No. 10, 2006, pp. 2079 - 2086. © The Japan Institute of Heterocyclic Chemistry
Received, 22nd June, 2006, Accepted, 28th July, 2006, Published online, 1st August, 2006. COM-06-10825
SYNTHESIS OF ENANTIOPURE 3,5-DISUBSTITUTED PYRROLIDINES
BY
RING-OPENING/CROSS-METATHESIS
REACTION
OF
2-AZANORBORNENE DERIVATIVES
Odón Arjona,* Mª José Cabas, José Nieto-Rubio, and Ana Querejeta
Department of Organic Chemistry, Faculty of Chemistry, Complutense University,
E-28040, Madrid, Spain. e-mail: arjonao@quim.ucm.es
Abstract – A concise method for the synthesis of enantiopure 3,5-disubstituted
pyrrolidines from 2-azanorbornene derivatives is described. The method is also
applied to the synthesis of 3,5-disubstituted prolines.
Ring-opening/cross-metathesis (ROM-CM) of bicyclic substrates is an important task in organic
synthesis1,2 by two main reasons: a) the sequence results in the rapid generation of complex skeletons from
relatively simple starting materials and, b) the chiral information inherent in the ring system is transferred
into the stereochemistry of the cyclic product. Despite this synthetic potential that has been largely
considered in norbornene and 7-oxanobornene3 (the group of Rainier3d,e also considered with the
7-oxanobornene system its 7-aza analogue) the metathesis of 2-azanorbornene systems has received less
attention. Thus, the metathesis of N-substituted 2-azabicyclo[2.2.1]hept-5-en-3-one (1) (Figure 1) has been
studied by three different groups. The groups of Blechert4 and Ishikura5 reported the regiochemistry of the
ROM-CM sequence of 1a-d with allylsilanes in the presence of Grubbs' first or second generation catalyst
(A or B respectively), resulting in general with fair regioselectivity except in the case of large N-trialkylsilyl
substituted derivatives.
O
O
O
PCy
3
3
N
N
H
Cl
Cl
Ar
Ar
H
N
Ru
N
N
Cl
R
Ph
n
Ru
n
PCy
Cl
Ph
1a R=H
PCy
3
1b R=Boc
1c R=Ac
1d R=benzyl or silyl derivative
2
3
B
Ar=2,4,6-trimethylphenyl
A
Figure 1

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HETEROCYCLES, Vol. 68, No. 10, 2006
On the other hand, the domino metathesis, ROM-CM-RCM sequence, has been described by our group6
as new enantioselective synthesis of 1-azabicyclic systems of different ring sizes, starting from N-alkenyl
or N-alkynyl derivatives of (-)-1a (Figure 1). In both cases the 1-azabicyclic system was obtained besides
the pyrrolidinones (ROM-CM) depending on the structure of the starting materials and the reaction
conditions.
In this context and following with our general interest in applying ring opening metathesis of strained
systems in synthesis, we decided to applied the ROM-CM sequence to 2-azanorbornene derivatives
(1a-b), (4) and (5), (6)7 (Figure 2) with ethylene using Grubbs' catalysts (A) or (B) as a convenient
method to prepare enantiomerically pure substituted pyrrolidines or prolines.
X
CO Et
2
N
Y
R
N
R
1a R= H; X,Y= O
1b R= Boc; X,Y= O
4 R= Boc; X=Y= H
5 R= CHMePh
6 R= Boc
Figure 2
The synthesis of the substrates has been achieved following literature procedures describe for racemic
derivatives. Thus, the commercially available (R)-(-)-2-azabicyclo[2.2.1]hept-5-en-3-one [(-)-1a] was
protected as its Boc carbamate8 and resulted in (-)-1b. Selective reduction of the lactam carbonyl group in
(-)-1a with LiAlH4 followed by in situ protection as Boc carbamate yielded (+)-4.9 The derivatives of
2-azabicycle[2.2.1]heptane-3-carboxylic acid ethyl esters 5 and 6 were obtained, following literature
procedures, by aza-Diels-Alder of imine, derived from the condensation of 1-phenylethylamine with ethyl
glyoxylate, and cyclopentadiene for 510 or aza-Wittig, aza-Diels-Alder sequence for 6.11The reactions of
compounds (-)-1b, (+)-4 and (-)-1a with ethylene (1 atm) in the presence of the Grubbs' second
generation catalyst (B)12 afforded pyrrolidines (7-9) in variable amounts depending on the structure of the
starting materials and the reaction conditions (Scheme 1, Table 1).
[Ru] (5%)
R
X
X
CH2=CH2
N
+
X
N
R
N
R
CH2Cl2
Y
Y
Y
(-)-7a R= H; X,Y= O
(+)-8a R= Boc; X=Y= H
(+)-9a R= Boc; X,Y= O
(-)-1a R= H; X,Y= O
(+)-4 R= Boc; X=Y= H
(-)-1b R= Boc; X,Y= O
(+)-9b R= Boc; X,Y= O
Scheme 1

HETEROCYCLES, Vol. 68, No. 10, 2006
2081
Table 1. Metathesis reactions of compounds [(-)-1a, (+)-4 and (-)-1b] with ethylenea
Entry
Compound
(-)-1a
Time (h)
12
Product (isolated yield)
(-)-7a (30%)
1
2
(-)-1a
2.5
(-)-7a (70%)
3b
(+)-4
2.5
(+)-8a (60%)
4
(-)-1b
2.5
(+)-9a (15%); (-)-9b (65%)
(-)-9b (80%)
5c
(-)-1b
2.5
a
Reaction conditions: All the reactions were performed in CH2Cl2, 5 mol % of catalyst (B), 1 atm ethylene and room
temperature.
b In this case double dilution was required and catalyst (A) showed better yield than catalyst (B) (45%).
c Purification using a basic silica gel.
The results in Table 1 show that the conversion of the bicycle system to the 3,5-disubstituted pyrrolidines
(7-9) proceeded stereospecifically in fair to good yields. The transformation appears with better results in
a shorter time of reaction and with the presence of a carbonyl function in position C-3 of the bicycle. It
should be pointed out that in the case of compound [(-)-1b] the reaction allowed, after chromatography,
as a minor component the expected (+)-9a and as a major one the isomerised compound [(-)-9b] (Entry 4,
Table 1). A similar product was obtained by Ishikura et al5a,b as a minor component in the reaction of 1b
with allyltrimethylsilane. They assume that the initial ring-opening/cross-metathesis products isomerize
through double bond migration during silica gel column chromatography. This isomerized pyrrolidine
[(-)-9b] could be obtained as the only product and with good yield by column chromatography using a
basic silica gel (Entry 5, Table 1). This isomerisation requires an N-Boc substituent that increases the
acidity of protons in C-3, since in the other cases it does not take place. The isomerisation was
stereoselective and the E-diastereomer was obtained selectively.13 This process allows to differentiate
both positions, C-3 and C-5,14 from simple way and can be a good alternative to the cross-metathesis with
substituted terminal alkenes because the usual regio- and stereoselective problems founded in these
reactions.
We next undertook the reaction of 2-azabicyclo[2.2.1]heptane-3-carboxilic acid ethyl ester derivatives (5)
and (6) in the same conditions as before (Scheme 2, Table 2).
[Ru] (5%)
CH2=CH2
CO Et
2
CO Et
2
N
R
N
CH2Cl2
R
5 R= CHMePh
6 R= Boc
10 R= CHMePh
11 R= Boc
Scheme 2

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HETEROCYCLES, Vol. 68, No. 10, 2006
Table 2. Metathesis reactions of compounds (5) and (6) with ethylenea
Entry
Compound
Catalyst
Time (h)
12
Product (isolated yield)
1
2
3
4
5
5
6
6
A
B
B
B
10 (15%)
10 (30%)
11 (70%)
--
12
2.5
12
a Reaction conditions: All the reactions were performed in CH2Cl2, 5 mol % of catalyst, 1 atm ethylene and room temperature.
Ring opening metathesis of derivative (5) with Grubbs first generation catalyst (A) gave poor results and
83% of starting material was recovered (Entry 1, Table 2). The use of the catalyst (B) only increases to
30% the yield of 10. This result can be due to the nature of the nitrogen (amine)15 in compound (5) since
when changing the protecting group by a Boc, compound (6), (carbamate vs amine) the yield increase up
to 70% of the 3,5-divynil proline derivative (11)(Entry 3, Table 2). Longer reaction time fails to increase
the yield of the reaction due to the polymerization of the product.
In summary, we have developed a useful synthesis of enantiopure cis-3,5-disubstituted pyrrolidines
bearing unsaturated side chains. The reaction also allows the differentiation of both positions and the
application to the synthesis of cis-3,5-divinylprolines derivatives. Other applications of these
transformations are being investigated and will be reported in due course.
ACKNOWLEDGEMENTS
We are grateful to the Ministry of Education and Science of Spain (Project nº BQU2003-04967) for
financial support. José Nieto-Rubio thanks Complutense University of Madrid for a predoctoral
fellowship.
EXPERIMENTAL
All starting materials were commercially available research-grade chemicals and used without further
purification. CH2Cl2 was distilled after refluxing over CaCl2 under Ar. Silica gel 60 F254 was used for
1
13
TLC. Flash column chromatography was carried out on silica gel 60. H and C NMR spectra were
recorded at 200 MHz or 300MHz and 50.5 MHz or 75 MHz respectively in CDCl3 solution with TMS as
internal reference. Melting points are uncorrected. Elemental analyses were performed at the
Complutense University of Madrid.

HETEROCYCLES, Vol. 68, No. 10, 2006
2083
tert-Butyl (1R,4S)-(-)-3-oxo-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate [(-)-1b]. To a solution of
(-)-1a (570mg, 5.2 mmol) in CH2Cl2 (20 ml) were added NEt3 (0.7 ml, 5.2 mmol),
di-tert-butyldicarbonate (2.27 g, 10.4 mmol) and DMAP (630 mg, 5.2 mmol) at rt. After stirring for 24h
at the same temperature, the mixture was evaporated in vacuo and the residue was diluted with water and
extracted with Et2O. The organic extract was dried over MgSO4 and evaporated in vacuo. The residue was
purified by flash chromatography on silica gel (hexane:AcOEt, 5:1) to give (-)-1b (980 mg, 90%) as
white solid, mp 56-57 ºC. [α]D = -189.1(c = 2.0, CHCl3). IR (neat) 1790, 1755 cm-1. 1H NMR (200 MHz,
25
CDCl3): δ = 1.44 (s, 9H), 2.08 (d, 1H), 2.28 (d, 1H), 3.33 (m, 1H), 4.89 (m, 1H), 6.60 (m, 1H), 6.83 (m,
13
1H). C NMR (50.5 MHz, CDCl3): δ = 176.0, 150.2, 139.8, 138.0, 82.4, 62.2, 54.7, 54.3, 27.9. Anal.
Calcd for C11H15NO3: C, 63.14; H, 7.23; N, 6.69. Found: C, 62.92; H, 7.35; N, 6.80
tert-Butyl (1R,4S)-(+)-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate [(+)-4]. A solution of (-)-1a (320
mg, 2.95 mmol) in Et2O (20 ml) and THF (5 ml) was added dropwise to a suspension of LiAlH4 (420 mg,
11 mmol) in Et2O with stirring under argon at rt, and the mixture was refluxed for 7 h. It was cooled in an
ice bath, then water (2 ml) was added dropwise with vigorous stirring, and the precipitate was filtered off.
Di-tert-butyl dicarbonate (647 mg, 3.3 mmol) was added to the filtrate, and the mixture was stirred for 14
h at rt. After addition of benzene (40 ml) the mixture was dried over anhydrous MgSO4, and concentrated
under reduced pressure. The residual was purified by flash chromatography on silica gel (hexane:AcOEt,
25
9:1) to give (+)-4 (300 mg, 52%) as a colorless oil (two rotamers). [α]D = +198.4 (c = 1.75, CHCl3). IR
1
(neat) 1700 cm-1. H NMR (200 MHz, CDCl3) δ = 1.44 (s, 9H), 1.51-1.60 (m, 2H), 2.55-2.71 (m, 1H),
3.16 (br s, 1H), 3.30 (dd, 1H, J=9.2, 2.9 Hz), 4.57 (br s, 1H), 4.71 (br s, 1H), 6.27 (s, 1H), 6.38 (s, 1H).
13C NMR (50.5 MHz, CDCl3) δ = 155.9, 136.1, 134.4, 133.7, 79.0, 61.1, 59.9, 48.1, 46.3, 45.9, 43.4, 42.9,
28.5. Anal. Calcd for C11H17NO2: C, 67.66; H, 8.78; N, 7.17. Found: C, 67.35; H, 8.65; N, 7.05.
General procedure for the metathesis reactions. A solution of the 2-azanorbornene derivative in
CH2Cl2 (39 ml/mmol 2-azanorbornene derivative) was saturated with ethylene and left under ethylene
atmosphere (1 atm). [Ru] catalyst dissolved in CH2Cl2 (12 ml/mmol 2-azanorbornene derivative) was
added and the mixture was stirred for the time showed in Tables 1 and 2. The solvent was removed under
reduced pressure, and the residue was purified by flash chromatography (hexane:AcOEt, 5:1).
25
(3S,5R)-(-)-3,5-divinylpyrrolidin-2-one [(-)-7a], white solid, mp 67-68°C (hexane:AcOEt). [α]D -7.6 (c
1
= 0.5, CHCl3). IR (neat) 1728 cm-1. H NMR (200 MHz, CDCl3): δ = 1.60-1.80 (m, 1H), 2.41-2.62 (m,
1H), 3.01-3.20 (m, 1H), 4.02-4.20 (dd, 1H, J=7.5Hz), 5.01-5.30 (m, 4H), 5.60-6.02 (m, 2H), 6.80 (s, 1H).
13C NMR (50.5 MHz, CDCl3): δ = 177.8, 138.6, 135.2, 117.6, 116.6, 55.3, 46.2, 34.9. Anal. Calcd for
C8H11NO: C, 70.04; H, 8.08; N, 10.21. Found: C, 69.85; H, 8.16; N, 10.09.
tert-Butyl (2R,4S)-(+)-2,4-divinylpyrrolidine-1-carboxylate [(+)-8a], (two rotamers), colorless oil.
25
1
[α]D +1.71 (c = 1.4, CHCl3). IR (neat) 1782 cm-1. H NMR (200 MHz, CDCl3): δ = 1.35 (s, 9H),

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HETEROCYCLES, Vol. 68, No. 10, 2006
2.01-2.30 (m, 1H), 2.50-2.71 (m, 1H), 2.80-3.02 (m, 2H), 3.51-3.80 (br s, 1H), 3.90-4.21 (br s, 1H),
13
4.91-5.12 (m, 4H), 5.50-5.81 (m, 2H). C NMR (50.5 MHz, CDCl3): δ = 154.9 , 140.2, 132.0, 131.5,
116.2, 114.6, 114.5, 79.9, 79.8, 60.5, 60.4, 55.5, 52.3, 41.1, 40.2, 36.8, 28.9, 28.8. Anal. Calcd for
C13H21NO2: C, 69.92; H, 9.48; N, 6.27. Found: C, 69.75; H, 9.32; N, 6.12.
25
tert-Butyl (3S,5R)-(+)-2-oxo-3,5-divinylpyrrolidine-1-carboxylate [(+)-9a], pale yellow oil. [α]D
+4.0 (c = 0.7, CHCl3). IR (neat) 1780, 1730 cm-1. 1H NMR (200 MHz, CDCl3): δ = 1.44 (s, 9H), 2.07 (m,
13
2H), 3.21 (m, 1H), 4.58 (t, 1H), 5.16 (m, 4H), 5.84 (m, 2H). C RMN (50.5 MHz, CDCl3): δ = 174.0,
150.5, 136.6, 134.1, 118.4, 115.8, 83.2, 57.7, 45.6, 36.5, 28.4. Anal. Calcd for C13H19NO3: C, 65.80; H,
8.07; N, 5.90. Found: C, 65.67; H, 8.15; N, 5.78.
tert-Butyl (5R)-(-)-(3E)-3-ethylidene-2-oxo-5-vinylpyrrolidine-1-carboxylate [(-)-9b], pale yellow oil.
25
1
[α]D -13.0 (c = 1.8, CHCl3). IR (neat) 1775, 1712 cm-1. H NMR (200 MHz, CDCl3): δ = 1.44 (s, 9H),
1.73 (dt, 3H), 2.36 (br d, 1H), 2.78 (m, 1H), 4.57 (td., 1H), 5.09 (m, 2H), 5.71 (m, 1H), 6.70 (m, 1H ). 13C
NMR (50.5 MHz, CDCl3): δ = 166.6, 150.3, 137.9, 133.5, 130.7, 115.4, 82.7, 56.7, 28.6, 28.0, 14.8. Anal.
Calcd for C13H19NO3: C, 65.80; H, 8.07; N, 5.90. Found: C, 65.70; H, 8.00; N, 5.82.
Ethyl (±)-cis-1-(1-phenylethyl)-3,5-divinylpyrrolidine-2-carboxylate (10), colorless oil. IR (neat) 1725
1
cm-1. H NMR (200 MHz, CDCl3): δ = 1.22 (t, 3H, J=7.1Hz), 1.34 (d, 3H, J=6.7Hz), 1.48 (ddd, J=13.0,
4.2, 3.2), 2.55 (dt, 1H, J=13.0, 8.8 Hz), 2.66-2.76 (m, 1H), 3.54 (d, 1H, J=2.7 Hz), 3.93, (td, 1H, J=8.8,
4.3 Hz) 3.98 (q, 1H, J=6.7 Hz), 4.00 (q, 2H, J=7.1 Hz), 4.68-5.06 (m, 4H), 5.47-5.62 (m, 1H), .6.70-6.02
13
(m, 1H), 7.10-7.40 (m, 5H). C NMR (50.5 MHz, CDCl3): δ = 175.3, 145.1, 142.1, 142.0, 128.6, 128.1,
127.2, 114.4, 114.3, 68.3, 65.3, 60.6, 58.2, 46.5, 38.6, 20.2, 14.6. Anal. Calcd for C19H25NO2: C, 76.22; H,
8.42; N, 4.68. Found: C, 76.05; H, 8.30; N, 4.52.
Ethyl (±)-cis-1-tert-butoxycarbonyl-3,5-divinylpyrrolidine-2-carboxylate (11), colorless oil. IR (neat)
1772, 1739 cm-1. 1H NMR (200 MHz, CDCl3): δ = 1.24 (m, 3H), 1.34 (s, 9H), 1.56 (m, 1H), 2.22 (m, 1H),
2.76 (dd, 1H), 4.23 (m, 4H), 5.03 (m, 2H), 5.73 (m, 2H). 13C NMR (50.5 MHz, CDCl3): δ = 172.5, 140.2,
138.2, 116.0, 114.3, 80.2, 65.4, 60.9, 46.3, 38.0, 28.2. Anal. Calcd for C16H25NO4: C, 65.06; H, 8.53; N,
4.74. Found: C, 64.95; H, 8.42; N, 4.62.
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12. The use of Grubbs second generation catalyst (B) gave better results, in general, than the use of

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catalyst (A). For instance see reference 5.
13. The stereochemistry of the new double bond was determined by NOE experiments.
14. Also the isomerised product [(-)-9b] was obtained in a one pot reaction from [(-)-7a] (45% yield), by
protection with (Boc)2O, Et3N/DMAP in CH2Cl2.
15. The protection of an amine is especially important in cross-metathesis chemistry since most catalysts
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36, 93.