Stereoselective synthesis of pyrrolidines and pyrrolizidines by intramolecular carbolithiation

Article abstract of DOI:10.1055/s-2001-16074

Methods for the preparation of substituted homoallylic amines and their conversion to pyrrolidines or pyrrolizidines are described. N-Alkylation of a variety of homoallylic secondary amines with (tributylstannyl)methyl methanesulfonate and subsequent tinlithium exchange, generates organolithium species that undergo intramolecular carbolithiation (anionic cyclization). High stereoselectivities in the cyclization, particularly for the formation of 2,4-disubstituted pyrrolidines, are obtained.

Full text of DOI:10.1055/s-2001-16074

PAPER
1523
Stereoselective Synthesis of Pyrrolidines and Pyrrolizidines by Intramolecular
Carbolithiation
S
tereose
l
ective
S
ynt
i
hesis
o
n
f
Pyrrolidines and P
C
yrrolizidines oldham,* Richard Hufton, Kathy N. Price, Richard E. Rathmell, David J. Snowden, Graham P. Vennall
School of Chemistry, University of Exeter, Stocker Road, Exeter EX4 4QD, UK
Fax +44(1392)263434; E-mail: I.Coldham@exeter.ac.uk
Received 21 November 2000
one or, commonly, more than one chiral center and there-
fore stereocontrolled methods for their preparation are re-
quired.
Abstract: Methods for the preparation of substituted homoallylic
amines and their conversion to pyrrolidines or pyrrolizidines are de-
scribed. N-Alkylation of a variety of homoallylic secondary amines
with (tributylstannyl)methyl methanesulfonate and subsequent tin-
lithium exchange, generates organolithium species that undergo in-
tramolecular carbolithiation (anionic cyclization). High stereoselec-
tivities in the cyclization, particularly for the formation of 2,4-
disubstituted pyrrolidines, are obtained.
Intramolecular carbolithiation reactions refer to the cy-
clization of an organolithium species onto an unsaturated
functional group, typically an alkene or alkyne. Extensive
studies by Bailey and co-workers have established the
chemistry as a highly effective method for the formation
of, in particular, cyclopentane and cyclohexane ring sys-
tems.1 The cyclization is a high yielding process and the
initially formed cyclic organolithium species can be
trapped by a variety of electrophiles to give functionalized
products. Cyclization onto an alkene generates a product
containing a new chiral centre. It was found that the use of
a substrate, such as 1 (Scheme 1), containing a chiral cen-
tre, promoted a regioselective and stereoselective in-
tramolecular carbolithiation reaction to provide
predominantly the cis-1,3-disubstituted cyclopentane 2.2
The iodine-lithium exchange process occurs at low tem-
perature and the mixture is allowed to warm to room tem-
perature in order to effect cyclization. The predominance
of the cis-product is explained by a preference for a chair-
shaped transition state, in which the lithium atom coordi-
nates to the alkene -bond.2
Key words: amines, carbanions, cyclizations, lithiation, heterocy-
cles
The vast array of different structural arrangements within
the alkaloid class of natural products, together with their
diverse biological activity has fascinated scientists and
prompted numerous synthetic efforts worldwide towards
their preparation. Methods for the construction of simple
pyrrolidines to complex polycyclic amines have been re-
ported and allow the study of the chemical and biological
properties of many alkaloids and their analogs.
In this paper we report some of our work on the prepara-
tion of substituted pyrrolidines and pyrrolizidines using
intramolecular carbolithiation chemistry. Some represen-
tative pyrrolidine and pyrrolizidine alkaloids are shown in
Figure 1. Many biologically active compounds, natural
and synthetic, containing these ring systems are known
and new methods to access such targets are of interest and
importance, for example, in medicinal chemistry. The
pyrrolidine and pyrrolizidine target compounds contain
Scheme 1 (a) t-BuLi (2.1 equiv), pentane–Et2O (3:2), –78 °C to
r.t.., 1 h, then MeOH
To make use of this chemistry for the synthesis of pyrro-
lidines and pyrrolizidines, a nitrogen atom must be locat-
ed within the newly forming ring system. The position of
the nitrogen atom and choice of functionality is crucial in
order to allow successful formation of the organolithium
species (and its precursor) and to avoid side reactions such
as -elimination. Early examples of this chemistry to give
the pyrrolidine ring system using sulfur-lithium exchange
Figure 1 Some representative pyrrolidine and pyrrolizidine alkalo-
ids
Synthesis 2001, No. 10, 30 07 2001. Article Identifier:
1437-210X,E;2001,0,10,1523,1531,ftx,en;C05200SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1524
I. Coldham et al.
PAPER
were reported by Broka and co-workers.3 Generation of suggesting that substitution at the carbon to the nitrogen
aryl- or vinyllithium species from the corresponding ha- atom slows the rate of N-alkylation due to steric hin-
lides and cyclization to give cyclic amines is known.4 Pro- drance. An alternative procedure was therefore required in
ton abstraction and anionic cyclization has also been order to provide the stannanes 11. Treatment of secondary
reported.5 A particularly useful approach centres on tin- amines with formaldehyde and benzotriazole, followed by
lithium exchange for the formation of an -amino-organ- displacement of the benzotriazole group with tributyltin-
olithium species that can undergo the intramolecular car- lithium has been reported as an effective method for the
bolithiation reaction.6,7 The precursor
-amino- synthesis of substituted -amino-organostannanes.10c,d
organostannanes can be prepared by a number of meth- However, condensation of the amine 7 (R = Me) with
ods, such as alkylation of a secondary amine with paraformaldehyde and benzotriazole in toluene gave a
iodomethyltrialkyltin8 or (tributylstannyl)methyl meth- mixture (58%, 1:1) of the recovered amine 7 (R = Me) and
anesulfonate,9 addition of a trialkyltin metal species to an the amine 7 (R = H). The product 7 (R = H) must arise
iminium ion,10 or addition of a trialkyltin chloride to an - from the intermediate iminium ion, which can undergo a
amino-organometallic species.11 For example, the stan- [3,3] aza-Cope rearrangement, followed by hydrolysis of
nane 3 (Scheme 2) can be prepared with high optical pu- the new iminium ion. No products resulting from trapping
rity in a single step from N-Boc-pyrrolidine, using of either iminium ion with benzotriazole were observed.
asymmetric proton abstraction in the presence of (–)- The problem was solved using the more reactive alkylat-
sparteine and quench with tributyltin chloride.12 Transfor- ing agent (tributylstannyl)methyl methanesulfonate (10),9
mation of the stannane 3 to the stannane 4 and tin-lithium which can be prepared from the corresponding alcohol
exchange effects a stereoselective intramolecular carbo- and methanesulfonic anhydride. Alkylation was sluggish
lithiation reaction to give the alkaloid (+)-pseudoheliotri- but proceeded on warming to give the amines 11 in rea-
dane (5) as a single diastereomer with no loss of optical sonable to poor yields (Table 1). The yield of the
purity.13
alkylated product reduces with the increasing size of the
-substituent. This is illustrated further on attempted alky-
lation of the more hindered amine 9, which gave the cor-
responding -amino-organostannane in very poor yield
(8%).
Scheme 2 (a) -Bromocatechol borane, CH2Cl2, then but-3-enoyl
chloride; (b) AlH3, Et2O; (c) BuLi, hexane–Et2O (10:1), r. t., 1 h, then
MeOH
The stannane 4 has a chiral centre at the projected lithium-
bearing carbon atom. The presence of a substituent at oth-
er locations within the newly forming pyrrolidine ring can
also have an influence on the stereoselectivity of the cy-
clization. To investigate this stereoselectivity, we have
prepared a variety of substituted -amino-organostan-
nanes and report herein the results of their cyclization.14
Scheme 3 (a) Mg, allyl bromide, Et2O, THF, r.t., 4 h, then NH4Cl;
(b) Zn, AcOH–H2O (1:1), ultrasound, 4 h, r.t.; (c) MsOCH2SnBu3
(10), MeCN, K2CO3 or i-Pr2NEt, 55 °C, 2 d
Initial work focused on the formation of 2-substituted ho-
moallylic secondary amines. Alkylation of these amines
with iodomethyltributyltin was expected6a to provide the
-amino-organostannanes required for the investigation
of the stereoselectivity in the intramolecular carbolithia-
tion reaction. A versatile synthesis of the homoallylic
amines was required that would allow the preparation of a
variety of 2-substituted derivatives. The approach adopted
is shown in Scheme 3, using allyl Grignard addition to the
nitrones 6.15 Reduction of the product hydroxylamines us-
ing zinc and acetic acid provided the homoallylic amines
7. This chemistry could also be applied to the nitrone 8, to
give the homoallylic amine 9.
Table 1 Preparation of the Stannanes 11
Nitrone
6a
R
Yield 7 (%)
Yield 11 (%)
Me
n-Bu
i-Pr
80
61
84
57
45
14
6b
6c
The stannanes 11 were treated with butyllithium to effect
tin-lithium exchange and intramolecular carbolithiation
(Scheme 4). Using THF as the solvent at low temperature,
the stannane 11a (R = Me) gave, after quenching with
MeOH, exclusively the cis-2,4-disubstituted pyrrolidine
12a (46%), confirmed by NOE studies. This result con-
Attempted alkylation of the amines
7
with
iodomethyltributyltin8 gave only recovered starting amine
under a variety of conditions. This contrasts with the sub-
strate 7 (R = H) in which alkylation proceeds smoothly,6a
Synthesis 2001, No. 10, 1523–1531 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of Pyrrolidines and Pyrrolizidines
1525
forms with those of Bailey2 and Broka,3 in which the ma- the pyrrolizidines 15 and 16 (E = H) were isolated as their
jor product has the substituents cis to one another as picrate salts, as an inseparable (3:1) mixture of isomers.
expected from a chair-shaped transition state (Figure 2). The intermediate organolithium species was trapped with
To our surprise, the stannanes 11b and 11c did not trans- different electrophiles to give different substituted pyr-
metallate in THF, even on warming. The increased steric rolizidines (Table 3). In each case the products 15 and 16
bulk of the larger R substituent may be hindering the for- (picrate salts) were isolated as a mixture (3:1) of diastere-
mation of the intermediate stannate complex.
omers. Attempts to determine (by NMR) the identity of
the major diastereomer were unsuccessful. The preference
for a chair-shaped transition state, with a cis-fused azabi-
cyclo[3.3.0]octane ring system, suggests that the major
product would be the pyrrolizidine 15, arising from the
transition state depicted in Figure 3. X-Ray analysis of the
picrate salt of the mixture of pyrrolizidines 15 and 16 (E
= H), indicate that the major component is indeed the pyr-
rolizidine 15.19
We have found previously6 that non-polar solvents give
enhanced yields of the pyrrolidine products, and indeed,
the use of hexane–Et2O gave the desired pyrrolidines 12
in good yield (Table 2). In this solvent system, transmet-
allation and cyclization was successful for all the stan-
nanes 11a–c. Transmetallation occurs at room
temperature and may be taking place by a mechanism that
is different from that in THF, and which involves a con-
certed process.16 At this temperature, some of the pyrro-
lidines trans-12 were obtained, although the cis-isomer
remained the major product.
Scheme 4 (a) BuLi, THF or hexane–Et2O (10:1), –78 °C to r.t., 5 h
then MeOH
Scheme 5 (a) CF3CO2H, CH2Cl2, r.t.; (b) 10, MeCN, i-Pr2NEt, r.t.;
(c) BuLi, hexane–Et2O (9:1), –78 °C to r.t., 4 h, then E+, then picric
acid, EtOH
Table 2 Cyclization of the Stannanes 11 in Hexane–Et2O (10:1)
Table 3 Cyclization of the Stannane 14
Stannane
11a
R
Yield 12 (%)
cis/trans
7 :1
E+
E
Yield 15 + 16
(%)
Me
Bu
i-Pr
78
50
74
Entry
11b
6 : 1
1
2
3
4
5
MeOH
H
81
66
67
55
60
11c
6 : 1
TMSCl
SiMe3
Bu3SnCl
allyl bromide
Ph2C=O
SnBu3
CH2CH=CH2
C(OH)Ph2
Figure 2 Chair-shaped transition state of the intermediate organo li-
thium from 11
The chemistry outlined above allows an efficient and ste-
reocontrolled access to substituted pyrrolidines. We were
interested in extending this methodology to the prepara-
tion of substituted pyrrolizidines and investigating the
possibility of trapping the intermediate organolithium
species with a variety of different electrophiles. Scheme 5
outlines our approach to the pyrrolizidine ring system us-
ing the stannane 14, prepared from N-Boc-2-allylpyrroli-
dine 13.17 Acidic hydrolysis of the N-Boc group gave the
known, volatile, 2-allyl-pyrrolidine,18 which was alkylat-
ed with (tributylstannyl)methyl methanesulfonate (10).
Figure 3 Chair-shaped transition state of the intermediate lithium
salt from 14
The successful synthesis of pyrrolidines and pyrroliz-
idines by intramolecular carbolithiation of chiral (racem-
ic) organolithium compounds derived from the stannanes
11 and 14, led us to investigate the influence of a chiral
auxiliary attached to the nitrogen atom.20 Alkylation of
(R)- or (S)- -methylbenzylamine with but-3-enyl bro-
mide, followed by (tributylstannyl)methyl methane-
sulfonate (10), gave the stannanes (R)- or (S)-18
The stannane 14 was treated with butyllithium in hexane–
Et2O to effect transmetallation and cyclization. On trap-
ping the resulting organolithium species with methanol,
Synthesis 2001, No. 10, 1523–1531 ISSN 0039-7881 © Thieme Stuttgart · New York

1526
I. Coldham et al.
PAPER
(Scheme 6). Transmetallation with butyllithium effected gen lone pairs is known and the presence of a heteroatom
intramolecular carbolithiation to give, after quenching on the chiral auxiliary that would allow such coordination
with methanol, the pyrrolidines 19 and 20 (Table 4). In the could hold the chiral auxiliary in a cyclic arrangement.
non-polar hexane–Et2O solvent system at 0 °C, an equal We therefore prepared the stannanes 22 (R = H and R =
mixture (determined by 1H NMR spectroscopy) of the di- Me) from the amine 21 (R = H) itself derived from (R)-
astereomeric pyrrolidines 19 and 20 was formed (entry 1). phenylglycinol (Scheme 7).22
However, in THF at –78 °C, a 3:1 mixture in favour of the
pyrrolidine 19 was produced, as determined by hydro-
genolysis of the -methylbenzyl group and comparison of
Addition of butyllithium to the stannane 22 (R = H) in the
solvent THF resulted in tin-lithium exchange, but no pyr-
rolidine products were isolated. A mixture of the four
the sign of optical rotation with the known (R)-3-meth-
products 22 (R = H, 18%), 21 (R = H, 18%), protodestan-
ylpyrrolidine.21 Altering the conditions or amount of re-
nylated compound 23 (39%) and the oxazolidine 24
(20%) were obtained. In the less polar hexane–Et2O sol-
agents gave no significant enhancement in the ratio of
products. Addition of (–)-sparteine, did, however, give a
vent system, transmetallation was very sluggish and re-
small improvement when using the enantiomer (R)-18
covered starting material 22 (R = H) was isolated even
(entry 3). However, no influence from (–)-sparteine in
after several hours at room temperature. It is likely that
Et2O (stannane 18 in hexane–Et2O) was observed (entry
butyllithium abstracts a proton first from the alcohol
4) and using (–)-sparteine in THF gave results analogous
group and that the subsequent tin-lithium exchange then
to those in THF alone (transmetallation and cyclization at
requires a polar solvent system. The origin of the oxazoli-
dine 24 is not clear.
–78 °C, entry 5). Addition of (–)-sparteine to the enanti-
omer (S)-18 resulted in a mis-matched case and signifi-
Addition of butyllithium to the stannane 22 (R = Me) ef-
cant reduction in diastereoselectivity (entry 6). These
fected transmetallation in either THF or hexane–Et2O. In
results suggest that (–)-sparteine is coordinated to the or-
both cases a complex mixture of products was obtained
ganolithium species and can play a part in influencing the
and none of the desired pyrrolidine product was isolated.
stereochemical outcome.
It appears, therefore, that for this type of substrate at least,
the presence of an oxygen atom lone pair to coordinate to
the lithium atom inhibits the intramolecular carbolithia-
tion reaction.
Finally, we investigated the influence of (–)-sparteine
alone to promote asymmetric induction in the intramolec-
ular carbolithiation reaction.23 The stannane 256a in THF
or hexane–Et2O was treated with butyllithium/(–)-
sparteine complex to promote transmetallation and cy-
clization to N-benzyl-3-methylpyrrolidine 26 (Scheme 8).
Scheme 6 (a) 10, MeCN, i-Pr2NEt, r.t.; (b) BuLi, solvent, –78 °C to
r.t., then MeOH
Good yields of the pyrrolidine 26 were obtained, but with
low levels of optical purity (Table 5). Over a range of con-
Table 4 Cyclization of the Stannane 18
ditions, the enantioselectivity of the cyclization remained
fairly constant at approximately 28% ee. The selectivity
was measured by 1H NMR spectroscopy using the Pirkle
chiral solvating agent.24
Entry 18
Conditions
Yield
19 + 20 (%) 19/20
Ratio
1
2
3
(R)-
hexane–Et2O (10:1), 0 °C 73
50:50
74:26
79:21
(R)-
(R)-
THF, –78 °C
78
74
THF
(–)-sparteine/THF, –78 °C
4
5
6
(R)-
(R)-
(S)-
hexane–Et2O (10:1),
(–)-sparteine/Et2O, 0 °C
86
79
73
50:50
77:23
45:55
hexane–Et2O (10:1),
(–)-sparteine/THF, –78 °C
Scheme 7 (a) 10, MeCN, i-Pr2NEt, r.t.; (b) NaH, MeI, THF, r.t.
hexane–Et2O (10:1),
(–)-sparteine/THF, –78 °C
The marked stereochemical influence of the -methylben-
zyl group led us to consider preparing a substrate that
would promote greater stereoselectivity in the cyclization,
possibly through a more rigid transition state. The ability
of organolithium species to coordinate to nitrogen or oxy-
Scheme 8 (a) (–)-sparteine, BuLi, solvent, –78 °C to r.t., then
MeOH
Synthesis 2001, No. 10, 1523–1531 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of Pyrrolidines and Pyrrolizidines
1527
Table 5 Cyclization of the Stannane 25 with (–)-Sparteine in THF
Hydroxylamine from 6b and Allylmagnesium Bromide
Mp 63–65 °C.
Entry
Conditions
Yield 26 (%)
Ratio 26 (ee)
63:37 (26)
64:36 (28)
64:36 (28)
IR (film): = 3230 (OH), 3070 (CH), 3035 (CH), 2955 (CH), 1605
cm–1 (Ph).
1
2
3
THF, –78 °C
THF, –78 °Ca
74
74
84
1H NMR (CDCl3): = 0.92 (3 H, t, J = 8.0 Hz, CH3), 1.22–1.51 (5
H, m, CHCH2CH2Me), 1.60–1.71 (1 H, m, CHCH2CH2Me), 2.16–
2.26 (1 H, m, CHCH=C), 2.45–2.55 (1 H, m, CHCH=C), 2.63–2.71
(1 H, m, CHBu), 3.78 (2 H, s, CH2Ph), 5.04 (1 H, d, J = 10.0 Hz,
CH=C), 5.08 (1 H, d, J = 17.0 Hz, CH=C), 5.58 (1 H, br s, OH), 5.85
(1 H, dddd, J = 17.0, 10.0, 7.5, 6.5 Hz, CH=C), 7.20–7.40 (5 H, m,
C6H5).
hexane–Et2O
(10:1), –78 °C
4
hexane–Et2O
(10:1), 0 °Cb
82
64:36 (28)
13C NMR (CDCl3): = 14.08, 22.91, 28.93, 29.55, 34.23, 59.16,
65.61, 115.95, 127.14, 128.24, 129.53, 136.98, 138.51.
HRMS: m/z Found M+, 233.1772. C15H23NO requires M, 233.1780.
MS: m/z (%) = 233 (0.1, M+), 192 (38, M – C3H5), 91 (100, CH2Ph).
a Inverse addition.
b (–)-Sparteine in Et2O.
In conclusion, the intramolecular carbolithiation reaction
can be used as an efficient and stereoselective approach to
substituted pyrrolidines and pyrrolizidines. These targets
are present in a wide range of alkaloid and other natural
product structures and this chemistry therefore provides a
convenient method for their preparation.
Hydroxylamine from 8 and Allylmagnesium Bromide
Oil.
IR (film): = 3470 (OH), 3070 (CH), 3030 (CH), 2935 (CH), 1605
cm–1 (Ph).
1H NMR (CDCl3): = 1.35–1.86 [10 H, m, (CH2)5], 2.44 (2 H, d, J
= 7.5 Hz, CH2CH=C), 3.89 (2 H, s, CH2Ph), 4.25 (1 H, br s, OH),
5.07 (1 H, d, J = 10.0 Hz, CH=C), 5.09 (1 H, d, J = 17.0 Hz, CH=C),
5.99 (1 H, ddt, J = 17.0, 10.0, 7.5 Hz, CH=C), 7.20–7.45 (5 H, m,
C6H5).
13C NMR (CDCl3): = 21.78, 26.25, 32.38, 37.46, 54.76, 62.44,
116.67, 126.81, 128.25, 128.96, 135.75, 140.13.
Experimental information concerning solvents, spectroscopic
equipment, etc. has been reported previously.25 Light petroleum
used had bp 40–60 °C.
Homoallylic Amines 7a–c, 9; General Procedure
The nitrone 6 or 8 (6.3 mmol) in anhyd THF (15 mL) was added to
allylmagnesium bromide, prepared from allyl bromide (2.44 g, 20.2
mmol) and Mg turnings (476 mg, 19.6 mmol) in Et2O (20 mL), un-
der N2 at r.t. After 2 h, the mixture was cooled to 0 °C and was
quenched cautiously with sat. aq NH4Cl solution (50 mL), extracted
into CH2Cl2 (3 50 mL), dried (MgSO4) and evaporated. The resi-
due was purified by column chromatography [silica gel, light petro-
leum–EtOAc (10:1)] to give the intermediate hydroxylamine.
HRMS: m/z Found M+, 245.1780. C16H23NO requires M, 245.1780.
MS: m/z (%) = 245 (0.1, M+), 204 (38, M – C3H5), 91 (100, CH2Ph).
Stannanes 11; General Procedure
To the appropriate homoallylic amine 7 (2.5 mmol) in anhyd MeCN
(10 mL) was added K2CO3 (0.5 g, 3.7 mmol) and (tributylstan-
nyl)methyl methanesulfonate (10;9 1.99 g, 5.0 mmol) under N2 at
r.t. The mixture was warmed to 55–60 °C for 2 d and was cooled to
r.t. and aq NaHCO3 (20 mL) was added. The mixture was extracted
into EtOAc (3 20 mL), dried (MgSO4), evaporated and purified by
column chromatography [basic alumina, light petroleum–EtOAc
(99:1)] to give the corresponding stannanes 11.
Spectroscopic data for hydroxylamines leading to amines 7a–b and
9 are given below. Spectroscopic data for hydroxylamine leading to
amine 7c agree with that reported.15c
Zinc dust (1.18 g, 18 mmol) was added to the hydroxylamine (3.7
mmol) in glacial AcOH (5 mL) and H2O (5 mL) at r.t. and the mix-
ture was subjected to sonication. After 3 h, the mixture was filtered,
basified to pH ~10 with NaOH (2 M), extracted with CH2Cl2 (3
50 mL), dried (MgSO4) and evaporated. The residue could be puri-
fied by distillation under reduced pressure to give the homoallylic
amine 7 or 9, as an oil.
11a
Oil.
IR (film): = 3065 (CH), 3030 (CH), 2925 (CH), 1605 cm–1 (Ph).
1H NMR (CDCl3):
Sn(CH2CH2CH2CH3)3],
= 0.82–1.01 [18 H, m, NCHCH3 and
1.14–1.51 [12 H, m,
Spectroscopic data for amines 7 and 9 agree with that reported.26
Sn(CH2CH2CH2CH3)3], 1.98–2.07 (1 H, m, CHCH=C), 2.34–2.54
(3 H, m, CHCH=C and NCH2Sn), 2.65–2.75 (1 H, m, CHMe), 3.51
(2 H, ABq, J = 13.5 Hz, CH2Ph), 4.98 (1 H, d, J = 10.0 Hz, CH=C),
5.01 (1 H, d, J = 17.0 Hz, CH=C), 5.75–5.87 (1 H, m, CH=C), 7.18–
7.40 (5 H, m, C6H5).
13C NMR (CDCl3): = 9.50, 13.54, 13.60, 27.43, 37.25, 38.00,
42.07, 57.19, 57.24, 115.43, 126.49, 128.04, 128.54, 137.43,
140.90.
HRMS: m/z Found M+, 479.2577. C25H45N120Sn requires M,
479.2574.
MS: m/z (%) = 479 (0.6, M+), 188 (100, M – SnBu3), 91 (86,
Hydroxylamine from 6a and Allylmagnesium Bromide
Mp 62–64 °C.
IR (film): = 3200 (OH), 3075 (CH), 3030 (CH), 2970 (CH), 1600
cm–1 (Ph).
1H NMR (CDCl3): = 1.12 (3 H, d, J = 6.5 Hz, CH3), 2.08–2.20 (1
H, m, CHCHMe), 2.43–2.54 (1 H, m, CHCHMe), 2.78–2.90 (1 H,
m, CHMe), 3.78 (2 H, ABq, J = 13.0 Hz, CH2Ph), 5.04 (1 H, d, J =
10.0 Hz, CH=C), 5.06 (1 H, d, J = 17.0 Hz, CH=C), 5.58 (1 H, br s,
OH), 5.82 (1 H, dddd, J = 17.0, 10.0, 7.5, 6.5 Hz, CH=C), 7.21–7.42
(5 H, m, C6H5).
CH2Ph).
13C NMR (CDCl3): = 14.19, 37.82, 59.71, 60.94, 116.19, 127.18,
128.26, 129.52, 136.38, 138.25.
HRMS: m/z Found M+, 191.1311. C12H17NO requires M, 191.1310.
MS: m/z (%) = 191 (0.1, M+), 150 (28, M – C3H5), 91 (100, CH2Ph).
11b
Oil.
IR (film): = 3065 (CH), 3030 (CH), 2930 (CH), 1605 cm–1 (Ph).
Synthesis 2001, No. 10, 1523–1531 ISSN 0039-7881 © Thieme Stuttgart · New York

1528
I. Coldham et al.
PAPER
1H NMR (CDCl3): = 0.78–0.94 [18 H, m, CH(CH2)3CH3 and
Sn(CH2CH2CH2CH3)3], 1.17–1.57 [18 H, m, Sn(CH2CH2CH2CH3)3
and CH(CH2)3CH3], 1.94–2.05 (1 H, m, CHCH=C), 2.33–2.57 (4 H,
m, CHCH=C, NCHBu and NCH2Sn), 3.57 (2 H, ABq, J = 13.5 Hz,
CH2Ph), 4.94–5.05 (2 H, m, CH2=C), 5.72–5.84 (1 H, m, CH=C),
7.15–7.35 (5 H, m, C6H5).
13C NMR (CDCl3): = 9.49, 13.66, 14.11, 22.98, 27.45, 28.94,
29.32, 29.90, 33.43, 36.82, 57.63, 61.47, 115.39, 126.52, 128.40,
128.75, 137.90, 140.72.
HRMS: m/z Found M+, 521.3045. C28H51N119Sn requires M,
521.3044.
MS: m/z (%) = 521 (0.1, M+), 230 (100, M – SnBu3), 91 (72,
CH2Ph).
1H NMR (C6D6): = 0.97–1.04 [3 H, m, (CH2)3CH3], 1.05 (3 H, d,
J = 6.5 Hz, NCH2CHCH3), 1.15 [1 H, ddd, J = 12.0, 9.0, 6.5 Hz,
NCH(Bu)CH], 1.28–1.51 (5 H, m, NCHCHCH2CH2Me), 1.70–1.81
(1 H, m, NCHCHCH2CH2Me), 1.96–2.05 (1 H, m, NCH2CHMe),
2.05–2.13 [1 H, m, NCH(Bu)CH], 2.30 (1 H, dd, J = 9.5, 8.0 Hz,
NCHAHBCH), 2.35–2.44 (1 H, m, NCHBu), 2.69 (1 H, dd, J = 9.5,
3.5 Hz, NCHAHBCH), 3.61 (2 H, ABq, J = 13.0 Hz, CH2Ph), 7.16–
7.35 (5 H, m, C6H5).
NOE enhancement at = 2.39 on irradiating at = 2.01 and at 2.08;
enhancement at = 2.01 and at 2.08 on irradiating at = 2.39.
13C NMR (C6D6): = 14.16, 21.69, 23.32, 28.55, 29.96, 34.04,
40.27, 58.54, 61.53, 65.40, 126.66, 128.58, 128.76, 140.86.
HRMS: m/z Found M+, 231.1994. C16H25N requires M, 231.1987.
MS: m/z (%) = 231 (2, M+), 174 (100, M – C4H9), 91 (84, CH2Ph).
11c
Oil.
cis-12c
Oil.
IR (film): = 3065 (CH), 2925 (CH), 1605 cm–1 (Ph).
1H NMR (CDCl3):
Sn(CH2CH2CH2CH3)3],
= 0.75–1.06 [21 H, m, CH(CH3)2 and
1.22–1.60 [12 H, m,
IR (film): = 3030 (CH), 2930 (CH), 1605 cm–1 (Ph).
1H NMR (C6D6): = 0.97 (3 H, d, J = 7.0 Hz, NCH2CHCH3), 1.01
(3 H, d, J = 7.0 Hz, NCHCHCH3), 1.08 (3 H, d, J = 7.0 Hz,
NCHCHCH3), 1.17 [1 H, ddd, J = 12.5, 9.5, 6.5 Hz, NCH(Pr)CH],
1.79 [1 H, dt, J = 12.5, 7.5 Hz, NCH(Pr)CH], 1.87–2.04 (2 H, m,
NCH2CH and CHMe2), 2.30 (1 H, dd, J = 9.5, 7.5 Hz, NCHAH-
BCH), 2.38 (1 H, ddd, J = 9.5, 7.5, 4.5 Hz, NCHPr), 2.65 (1 H, dd,
J = 9.5, 4.0 Hz, NCHAHBCH), 3.54 (2 H, ABq, J = 13.0 Hz, CH2Ph),
7.17–7.34 (5 H, m, C6H5).
13C NMR (C6D6): = 15.34, 20.22, 21.03, 28.38, 29.67, 33.81,
58.75, 61.67, 70.21, 126.62, 128.21, 128.45, 140.95.
HRMS: m/z Found M+, 217.1835. C15H23N requires M, 217.1835.
Sn(CH2CH2CH2CH3)3], 1.79–1.93 (1 H, m, CHMe2), 2.10–2.21 (1
H, m, CHCH=C), 2.21–2.30 (1 H, m, NCHPr), 2.34–2.51 (1 H, m,
CHCH=C), 2.53 (2 H, ABq, J = 12.5 Hz, NCH2Sn), 3.60 (2 H, ABq,
J = 13.5 Hz, CH2Ph), 4.96 (1 H, d, J = 10.0 Hz, CH=C), 5.03 (1 H,
d, J = 17.0 Hz, CH=C), 5.82–5.93 (1 H, m, CH=C), 7.17–7.36 (5 H,
m, C6H5).
13C NMR (CDCl3): = 9.53, 13.66, 20.59, 21.37, 27.46, 30.72,
31.09, 37.83, 58.67, 66.95, 114.95, 126.53, 128.62, 128.92, 139.24,
140.57.
HRMS: m/z Found M+, 507.2873. C27H49N120Sn requires M,
507.2887.
MS: m/z (%) = 507 (0.2, M+), 216 (100, M – SnBu3), 91 (97,
CH2Ph).
MS: m/z (%) = 218 (0.5, MH+), 174 (99, M – C3H7), 91 (100,
CH2Ph).
Stannane 14
Cyclization of the Stannanes 11; General Procedure
N,N-Diisopropylethylamine (0.8 mL, 4.7 mmol) and 109 (1.9 g, 4.7
mmol) were added to 2-allylpyrrolidine18 (473 mg, 4.3 mmol, pre-
pared from the pyrrolidine 1317 and CF3CO2H in CH2Cl2) in MeCN
(10 mL) under N2 at r.t. After 12 h, aq NaCl solution (40 mL) was
added and the mixture was extracted into CH2Cl2 (2 20 mL), dried
(MgSO4), evaporated and purified by column chromatography [ba-
sic alumina, light petroleum–EtOAc (9:1)] to give the stannane 14
as an oil.
To the appropriate stannane 11 (0.4 mmol) in anhyd hexane–Et2O
(2 mL, 10:1) at –78 °C under N2 was added BuLi (0.33 mL, 0.8
mmol, 2.5 M in hexanes). The mixture was allowed to warm to r.t.
and stirred for 5 h. The mixture was cooled to –78 °C, quenched
with MeOH (2 mL) and was allowed to warm to r.t. The mixture
was evaporated and purified by column chromatography [silica gel,
light petroleum–EtOAc (49:1 to 4:1)] to give the corresponding pyr-
rolidines 12 as a mixture of diastereomers (approx. 6:1).
IR (film): = 2925 (CH), 2870 (CH), 2855 (CH), 1640 cm–1 (C=C).
1H NMR (C6D6): = 0.89–1.00 [15 H, m, Sn(CH2CH2CH2CH3)3],
1.30–1.62 [13 H, m, NCH2CH and Sn(CH2CH2CH2CH3)3], 1.70–
1.80 (2 H, m, NCH2CHCH), 1.90–2.00 (1 H, m, NCH2CH2CH),
2.00–2.21 (2 H, m, CH2C=C), 2.15 (1 H, dt, J = 9.0, 8.5 Hz, NCH),
2.43–2.51 (1 H, m, NCH), 2.53 (1 H, d, J = 13.0 Hz, NCHSn), 2.89
(1 H, d, J = 13.0 Hz, NCHSn), 3.01 (1 H, tt, J = 7.0, 6.5 Hz, NCH),
5.02 (1 H, dd, J = 10.0, 2.5 Hz, CH=C), 5.08 (1 H, dd, J = 17.0, 2.5
Hz, CH=C), 5.77 (1 H, ddt, J = 17.0, 10.0, 7.0 Hz, CH=C).
13C NMR (C6D6): = 9.89, 12.66, 21.01, 27.11, 29.02, 29.95, 37.65,
39.58, 57.71, 67.50, 115.62, 135.43.
HRMS: m/z Found M+, 415.2275. C20H41N120Sn requires M,
cis-12a
Oil.
IR (film): = 3065 (CH), 2970 (CH), 2875 (CH), 2785 (CH), 1600
cm–1 (Ph).
1H NMR (C6D6): = 1.03 (3 H, d, J = 6.5 Hz, NCH2CHCH3), 1.08–
1.16 [1 H, m, NCH(Me)CH], 1.18 (3 H, d, J = 6.5 Hz, NCHCH3),
1.93–2.09 [2 H, m, NCH(Me)CHCH], 2.30 (1 H, dd, J = 9.5, 8.0 Hz,
NCHAHBCH), 2.39–2.47 (1 H, m, NCHMe), 2.68 (1 H, dd, J = 9.5,
3.5 Hz, NCHAHBCH), 3.57 (2 H, ABq, J = 13.0 Hz, CH2Ph), 7.17–
7.35 (5 H, m, C6H5).
13C NMR (CDCl3): = 19.20, 21.69, 29.78, 42.75, 58.00, 60.35,
61.23, 126.61, 128.08, 128.81, 139.99.
HRMS: m/z Found M+, 189.1523. C13H19N requires M, 189.1517.
MS: m/z (%) = 189 (9, M+), 91 (100, CH2Ph).
415.2261.
MS: m/z (%) = 415 (2.3, M+), 124 (100, M – SnBu3), 55 (20, C4H7).
Cyclization of the Stannane 14
The cyclization of the stannane 14 was carried out in the same way
as the stannanes 11, and after quenching with the electrophile (3
molar equiv), an excess of a solution of picric acid in EtOH was
added. The mixture was evaporated and purified by column chro-
matography [silica gel, CH2Cl2–MeOH (95:5)] to give the picrate
cis-12b
Oil.
IR (film): = 3065 (CH), 3030 (CH), 2930 (CH), 1605 cm–1 (Ph).
Synthesis 2001, No. 10, 1523–1531 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of Pyrrolidines and Pyrrolizidines
1529
salt of the pyrrolizidines 15 and 16 as a mixture of diastereomers
Picrate Salt of the Pyrrolizidine 15 + 16 (E = CH2CH=CH2)
(approx. 3:1).
Waxy solid.
IR (film): = 2965 (CH), 1640 (C=C), 1495 (NO), 1365 cm–1 (NO).
Picrate Salt of the Pyrrolizidine 15 + 16 (E = H)
1H NMR (CDCl3): (major diastereomer) = 1.25–1.32 (1 H, m,
NCHCHCHCH2CH2), 1.56–1.61 (2 H, m, CH2CH2C=C), 1.80–1.95
(1 H, m, NCH2CH2CH), 2.09–2.27 (5 H, m, NCH2CH2CH and
CH2C=C), 2.30–2.60 [3 H, m, NCHCH(CH2CH2C=C)CH], 3.07–
3.12 (1 H, m, NCHAHBCH2), 3.60–3.70 (1 H, m, NCHAHBCH2),
4.03–4.10 (1 H, m, NCHCHCH2CH2C=C), 4.42–4.46 (1 H, m,
NCHCH2CHCH2), 4.98–5.06 (2 H, m, C=CH2), 5.73–5.80 (1 H, m,
CH=C), 8.86 (2 H, s, C6H2 of picrate).
13C NMR (CDCl3): (major diastereomer) = 24.67, 30.60, 31.00,
32.06, 38.18, 40.15, 55.08, 60.76, 68.24, 115.75, 126.57, 128.17,
137.04, 141.73, 162.27.
HRMS: m/z Found MH+ – picrate, 166.1593. C11H20N requires M,
166.1596.
(Lit.27 1:1 mixture of free base)
Needles; mp 160–162 °C.
IR (film): = 2960 (CH), 2880 (CH), 1495 (NO), 1360 cm–1 (NO).
1H NMR (CDCl3): (major diastereomer) = 1.15 (3 H, d, J = 6.5
Hz, CH3),1.24–1.36 (1 H, m, NCH2CH2CH), 1.84–1.91 (1 H, m,
CHCH3), 1.92–2.00 (1 H, m, NCH2CH2CH), 2.09–2.19 (1 H, m,
NCH2CHAHB), 2.20–2.32 (2 H, m, NCH2CHAHB and NCHCH-
CHMe), 2.33–2.49 (1 H, m, NCHCHCHMe), 2.50–2.65 (1 H, m,
NCHAHBCH2), 3.09–3.10 (1 H, m, NCHCHMe), 3.63–3.66 (1 H, m,
NCHAHBCH2), 4.00–4.02 (1 H, m, NCHCHMe), 4.42–4.45 (1 H, m,
NCHCH2CHMe), 8.85 (2 H, s, C6H2 of picrate).
13C NMR (CDCl3): (major diastereomer) = 15.74, 24.71, 30.55,
35.23, 40.00, 55.05, 62.00, 68.62, 126.58, 128.08, 141.71, 162.39.
HRMS: m/z Found M+ – picric acid, 125.1205. C8H15N requires M,
MS: m/z (%) = 228 (100, picrate), 166 (100, MH+ – picrate).
125.1206.
Picrate Salt of the Pyrrolizidine 15 + 16 [E = C(OH)Ph2]
Foam.
MS: m/z (%) = 229 (71, picric acid), 125 (91, M+ – picric acid), 110
(22, C7H12N), 83 (100, C5H9N).
IR (film): = 3425 (OH), 1605 (Ph), 1495 (NO), 1365 cm–1 (NO).
1H NMR (CDCl3): (major diastereomer) = 1.26–1.38 (1 H, m,
NCHCHCHCH2COH), 1.75–1.90 (1 H, m, NCH2CH2CH), 2.15–
2.20 (2 H, m, NCH2CH2CH2), 2.25–2.53 [6 H, m, NCH2CH2CH and
NCHCH(CH2COH)CH], 3.08–3.15 (1 H, m, NCHAHBCH2), 3.50–
3.61 (1 H, m, NCHAHBCH2), 3.95–4.05 (1 H, m,
NCHCHCH2COH), 4.15–4.30 (1 H, m, NCHCH2CHCH2), 7.17–
7.42 (10 H, m, 2 C6H5), 8.84 (2 H, s, C6H2 of picrate).
13C NMR (CDCl3): (major diastereomer) = 24.41, 30.48, 36.38,
39.14, 44.14, 55.00, 61.18, 66.88, 77.72, 125.84, 126.60, 128.14,
128.42, 141.62, 145.54, 146.72, 162.24.
HRMS: m/z Found MH+ – picrate, 308.2017. C21H26NO requires M,
308.2014.
MS: m/z (%) = 308 (100, MH+ – picric acid), 228 (100, picrate), 124
(26, C8H14N).
Picrate Salt of the Pyrrolizidine (15 + 16) (E = SiMe3)
Waxy solid.
IR (film): = 2960 (CH), 1495 (NO), 1365 cm–1 (NO).
1H NMR (CDCl3): (major diastereomer) = 0.06 [9 H, s, (CH3)3Si],
0.70 (1 H, dd, J = 16, 8 Hz, CHSi), 0.76 (1 H, dd, J = 16, 5 Hz,
CHSi),1.25–1.30 (1 H, m, NCHCHCHCH2Si), 1.80–1.92 (1 H, m,
NCH2CH2CH), 2.14–2.27 (2 H, m, NCH2CH2), 2.27–2.34 (2 H, m,
NCH2CH2CH and NCHCHCH2Si), 2.36–2.49 (1 H, m,
NCHCHCHCH2Si), 2.52–2.65 (1 H, m, CHCH2Si), 3.07–3.10 (1 H,
m, NCHAHBCH2), 3.63–3.65 (1 H, m, NCHAHBCH2), 3.97–4.00 (1
H, m, NCHCHCH2Si), 4.40–4.42 (1 H, m, NCHCH2CHCH2Si),
8.94 (2 H, s, C6H2 of picrate).
13C NMR (CDCl3): (major diastereomer) = –1.11, 19.24, 24.64,
30.59, 36.98, 40.96, 55.00, 62.99, 68.30, 126.48, 130.51, 140.71,
160.21.
HRMS: m/z Found MH+ – picrate, 198.1680.C11H24NSi requires M,
198.1678.
Stannane 18
In the same way as the stannanes 11 or 14, (R)- or (S)-N- -methyl-
benzylbut-3-enylamine28 gave the stannane (R)- or (S)-18 (48–59%)
as an oil.
MS: m/z (%) = 228 (100, picrate), 198 (100, M+ – picrate).
(R)-18
Picrate Salt of the Pyrrolizidine 15 + 16 (E = SnBu3)
Oil.
IR (film): = 2965 (CH), 1495 (NO), 1365 cm–1 (NO).
[ ]D23 +36.2 (c = 1.0, CHCl3).
IR (film): = 3065 (CH), 3025 (CH), 2925 (CH), 1600 cm–1 (Ph).
1H NMR (CDCl3):
= 0.81–1.01 [18 H, m, NCHCH3 and
1.23–1.59 [12 H, m,
1H NMR (CDCl3): (major diastereomer) = 0.84–0.92 [17 H, m,
Sn(CH2CH2CH2CH3)3 and CHCH2Sn], 1.26–1.32 [7 H, m,
NCHCHCHCH2Sn and Sn(CH2CH2CH2)3], 1.43–1.57 [6 H, m,
Sn(CH2CH2CH2)3], 1.80–1.90 (1 H, m, NCH2CH2CH), 2.05–2.45
(5 H, m, NCHCHCHCH2Sn, NCH2CH2CH and NCHCHCH2Sn),
2.60–2.75 (1 H, m, CHCH2Sn), 3.07–3.10 (1 H, m, NCHAHBCH2),
3.63–3.66 (1 H, m, NCHAHBCH2), 3.90–4.00 (1 H, m,
NCHCHCH2Sn) 4.42–4.46 (1 H, m, NCHCH2CHCH2Sn), 8.90 (2
H, s, C6H2 of picrate).
Sn(CH2CH2CH2CH3)3],
Sn(CH2CH2CH2CH3)3], 2.18–2.37 (3 H, m, NCHCH2), 2.45–2.54
(1 H, m, NCH), 2.68 (2 H, ABq, J = 12.0 Hz, NCH2Sn), 3.52 (1 H,
q, J = 7.0 Hz, NCHMe), 4.98 (1 H, d, J = 10.0 Hz, CH=C), 5.02 (1
H, d, J = 17.0 Hz, CH=C), 5.76 (1 H, dddd, J = 17.0, 10.0, 7.5, 6.5
Hz, CH=C), 7.18–7.39 (5 H, m, C6H5).
13C NMR (CDCl3): = 10.19, 13.67, 18.38, 27.46, 29.26, 32.13,
39.19, 54.00, 63.37, 115.22, 126.54, 127.55, 128.04, 136.98,
145.28.
13C NMR (CDCl3): (major diastereomer) = 9.37, 10.25, 13.57,
24.71, 27.29, 29.09, 30.66, 39.42, 41.85, 55.07, 63.59, 68.44,
126.53, 128.22, 141.76, 162.30.
HRMS: m/z Found M+, 479.2588. C25H45N120Sn requires M,
479.2574.
HRMS: m/z Found MH+ – picrate, 416.2339. C20H42N120Sn requires
MS: m/z (%) = 479 (0.2, M+), 188 (92, M – SnBu3), 105 (100, Ph-
M, 416.2339.
CHMe).
MS: m/z (%) = 416 (100, MH+ – picrate), 228 (100, picrate).
Cyclization of the Stannane 18
The stannane 18 was subjected to the same cyclization conditions as
that described for the stannane 11. Alternatively, cyclization was ef-
Anal. Calcd for C26H44N4O7Sn: C, 48.54; H, 6.89; N, 8.71. Found
C, 48.98; H, 6.99; N, 8.30.
Synthesis 2001, No. 10, 1523–1531 ISSN 0039-7881 © Thieme Stuttgart · New York

1530
I. Coldham et al.
PAPER
fected using the solvent THF or THF with (–)-sparteine (2 molar
equiv) at –78 °C to give the pyrrolidines 19 and 20 as a mixture of
diastereomers (approx. 1:1 to 4:1) as an oil.
13C NMR (CDCl3): = 10.21, 13.66, 27.47, 29.25, 32.11, 39.70,
54.60, 58.82, 67.64, 74.84, 115.27, 126.97, 128.02, 128.33, 136.87,
141.07.
IR (film): = 3025 (CH), 2930 (CH), 1600 cm–1. (Ph)
HRMS: m/z Found M+, 509.2693. C26H47NO120Sn requires M,
509.2680.
1H NMR (CDCl3): = 0.98 (3 H, d, J = 7.0 Hz, NCH2CHCH3), 1.01
(3 H, d, J = 7.0 Hz, NCH2CHCH3), 1.27–1.37 (2 H, m, NCH2CHH),
1.38 (6 H, d, J = 7.0 Hz, NCHCH3), 1.90 (1 H, dd, J = 9.0, 8.0 Hz,
NCHCHMe), 1.96 (1 H, dd, J = 9.0, 7.5 Hz, NCHCHMe), 1.92–
2.09 (2 H, m, NCH2CHH), 2.15–2.30 (2 H, m, NCH2CHMe), 2.36
(1 H, dt, J = 9.0, 6.5 Hz, NCHCH2), 2.42–2.52 (2 H, m, NCH2CH2),
2.67 (1 H, dd, J = 9.0, 7.5 Hz, NCHCHMe), 2.87 (1 H, td, J = 8.5,
5.5 Hz, NCHCH2), 2.94 (1 H, m, dd, J = 9.0, 7.5 Hz, NCHCHMe),
3.18 (1 H, q, J = 7.0 Hz, NCHMe), 3.21 (1 H, q, J = 7.0 Hz,
NCHMe), 7.19–7.38 (10 H, m, C6H5).
MS: m/z (%) = 509 (6, M+), 218 (100, M – SnBu3),135 [86,
CH(Ph)CH2OMe].
Transmetallation of the Stannane 22 (R = H)
BuLi (0.25 mL, 0.63 mmol, 2.5 M in hexanes) was added to the
stannane 22 (R = H) (103 mg, 0.21 mmol) in anhyd THF (2.5 mL)
at –78 °C. After 6 h, MeOH (0.5 mL) was added and the mixture
was allowed to warm to r.t. Evaporation and purification by column
chromatography [basic alumina, light petroleum–EtOAc (99:1)]
gave the stannane 22 (R = H) (16.5 mg, 18%), the amine 21 (R = H)
(6.5 mg, 18%), the amine 23 (15 mg, 39%) and the oxazolidine 24
(8 mg, 20%).
13C NMR (CDCl3): = 20.50, 20.90, 22.99, 23.19, 31.74, 31.87,
32.52, 32.63, 52.68, 52.94, 61.01, 61.28, 66.02, 66.06, 126.75,
126.80, 127.21, 127.25, 128.23, 128.40, 145.72, 145.75.
HRMS: m/z Found M+, 189.1513. C13H19N requires M, 189.1517.
MS: m/z (%) = 189 (10, M+), 174 (100, M – Me), 105 [27,
23
Oil; [ ]D23 –50.0 (c = 0.3, CHCl3).
IR (film): = 3375 (OH), 3005 (CH), 2955 cm–1 (CH).
CH(Me)Ph].
1H NMR (CDCl3): = 2.18 (3 H, s, NCH3), 2.26 (2 H, q, J = 7.5 Hz,
CH2C=C), 2.38 (1 H, dt, J = 12.5, 7.5 Hz, NCHACHB), 2.56 (1 H,
dt, J = 12.5, 7.5 Hz, NCHACHB), 3.63 (1 H, dd, J = 9.5, 5.5 Hz,
OCHACHB), 3.79 (1 H, dd, J = 9.5, 5.5 Hz, NCHPh), 3.98(1 H, t, J
= 9.5 Hz, OCHACHB), 5.02 (1 H, d, J = 9.0 Hz, CH=C), 5.07 (1 H,
d, J = 15.0 Hz, CH=C), 5.81 (1 H, ddt, J = 15.0, 9.0, 7.5 Hz, CH=C),
7.16–7.39 (5 H, m, C6H5).
13C NMR (CDCl3): = 32.24, 36.68, 53.06, 60.37, 68.67, 116.18,
127.88, 128.22, 128.91, 135.40, 136.50.
HRMS: m/z Found M+ + H, 206.1545. C13H20NO requires M + H,
Stannane 22 (R = H)
In the same way as the stannane 14, (R)-N-but-3-
enylphenylglycinol22 gave the stannane (R)-22 (R = H) (60%) as an
oil; [ ]D23 +31.9 (c = 1.4, CHCl3).
IR (film): = 3385 (OH), 3005 (CH), 2975 (CH), 2935 (CH), 1645
cm–1 (C=C).
1H NMR (CDCl3): = 0.81–0.94 [15 H, m, Sn(CH2CH2CH2CH3)3],
1.10–1.62 [12 H, m, Sn(CH2CH2CH2CH3)3], 2.18 (1 H, d, J = 12.5
Hz, NCHSn), 2.21–2.34 (3 H, m, NCHAHBCH2), 2.51–2.64 (1 H, m,
NCHAHBCH2), 2.68 (1 H, d, J = 12.5 Hz, NCHSn), 3.11 (1 H, br d,
J = 8.5 Hz, OH), 3.57–3.66 (1 H, m, CHOH), 3.81 (1 H, dd, J = 10,
5.5 Hz, NCHPh), 3.94 (1 H, t, J = 10 Hz, CHOH), 5.04 (1 H, d, J =
8.0 Hz, CH=C), 5.09 (1 H, d, J = 16.0 Hz, CH=C), 5.76 (1 H, ddt, J
= 16.0, 8.0, 7.0 Hz, CH=C), 7.17–7.40 (5 H, m,C6H5).
206.1545.
MS: m/z (%) = 206 (8, M+ + H), 174 (74, M – CH2OH),164 (73, M
– C3H5), 131 (100, M – CH2O – C3H4), 91 (74, PhCH2).
Oxazolidine 24:
13C NMR (CDCl3): = 9.69, 13.69, 27.45, 29.20, 32.41, 36.93,
53.06, 60.77, 67.09, 116.24, 127.79, 128.13, 129.15, 135.83,
136.36.
Oil; [ ]D23 –128.2 (c = 0.4, CHCl3).
IR (film): = 2945 (CH), 2890 (CH), 1660 cm–1 (C=C).
HRMS: m/z Found M+ + H, 496.2605. C25H46NO120Sn requires M +
H, 496.2601.
MS: m/z (%) = 496 (4, M+ + H), 204 (100, M – SnBu3).
1H NMR (CDCl3): = 2.22 (2 H, q, J = 8.0 Hz, CH2C=C), 2.48 (1
H, dt, J = 13.5, 8.0 Hz, NCHACHB), 2.75 (1H, dt, J = 13.5, 8.0 Hz,
NCHACHB), 3.69 (1 H, t, J = 8.0 Hz, OCHACHB), 3.77 (1 H, t, J =
8.0 Hz, NCHPh), 4.22 (1 H, d, J = 3.0, OCHN), 4.26 (1 H, t, J = 8.0
Hz, OCHACHB), 4.80 (1 H, d, J = 3.0 Hz, OCHN), 4.99 (1 H, d, J =
9.0 Hz, CH=C), 5.03 (1 H, d, J = 16.5 Hz, CH=C), 5.81 (1 H, ddt, J
= 16.5, 9.0, 8.0 Hz, CH=C), 7.25–7.46 (5 H, m, C6H5).
13C NMR (CDCl3): = 33.68, 52.37, 67.92, 73.74, 87.40, 115.84,
127.45, 127.58, 128.56, 136.28, 139.91.
HRMS: m/z Found M+ + H, 204.1387. C13H18NO requires M + H,
Stannane 22 (R = Me)
The stannane 22 (R = H) (250 mg, 0.51 mmol) in anhyd THF (2 mL)
was added to NaH (31 mg, 0.77 mmol, 60% dispersion in oil) in an-
hyd THF (2 mL) under N2 at r.t. After 2 h, MeI (0.048 mL, 0.77
mmol) was added and the mixture was stirred for 16 h. MeOH (0.5
mL) was added, the solvent was evaporated and the residue was pu-
rified by column chromatography [silica gel, light petroleum–
EtOAc (49:1 to 4:1)] to give the stannane 22 (R = Me) (187 mg,
72%) as an oil; [ ]D23 –19.6 (c = 0.5, CHCl3).
204.1388.
MS: m/z (%) = 204 (45, M+ + H), 162 (100, M – C3H5), 103 (91, Ph-
CHCH), 91 (86, PhCH2).
IR (film): = 3065 (CH), 3030 (CH), 2925 (CH), 1595 cm–1 (Ph).
1H NMR (CDCl3): = 0.81–0.98 [15 H, m, Sn(CH2CH2CH2CH3)3],
1.23–1.56 [12 H, m, Sn(CH2CH2CH2CH3)3], 2.18–2.28 (2 H, m,
NCH2CH2), 2.32–2.42 (1 H, m, NCHAHBCH2), 2.48–2.60 (1 H, m,
NCHAHBCH2), 2.69 (2 H, ABq, J = 12.0 Hz, NCH2Sn), 3.32 (3 H,
s, OCH3), 3.60–3.76 (3 H, m, NCHCH2OMe), 5.00 (1 H, d, J = 10.0
Hz, CH=C), 5.03 (1 H, d, J = 17.0 Hz, CH=C), 5.74 (1 H, ddt, J =
17.0, 10.0, 7.0 Hz, CH=C), 7.21–7.36 (5 H, m, C6H5).
Acknowledgement
We thank the EPSRC (studentships for R.H., K.N.P., R.E.R. and
D.J.S.) and the Leverhulme Trust (G.P.V.) for funding. The EPSRC
mass spectrometry service at the University of Wales, Swansea, the
EPSRC X-ray service at the University of Southampton and the
EPSRC Chemical Database Service at Daresbury29 are thanked.
Synthesis 2001, No. 10, 1523–1531 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of Pyrrolidines and Pyrrolizidines
1531
(15) (a) Dondoni, A.; Franco, S.; Junquera, F.; Merchan, F.;
Merino, P.; Tejero, T. Synth. Commun. 1994, 24, 2537.
(b) Funk, R. L.; Daggett, J. U. Heterocycles 1987, 26, 2175.
(c) Mancini, F.; Piazza, M. G.; Trombini, C. J. Org. Chem.
1991, 56, 4246.
References
(1) Bailey, W. F.; Ovaska, T. V. Advances in Detailed Reaction
Mechanisms 1994, 3, 251.
(2) Bailey, W. F.; Khanolkar, A. D.; Gavaskar, K.; Ovaska, T.
V.; Rossi, K.; Thiel, Y.; Wiberg, K. B. J. Am. Chem. Soc.
1991, 113, 5720.
(3) (a) Broka, C. A.; Lee, W. J.; Shen, T. J. Org. Chem. 1988,
53, 1336. (b) Broka, C. A.; Shen, T. J. Am. Chem. Soc. 1989,
111, 2981.
(4) (a) Barluenga, J.; Sanz, R.; Granados, A.; Fañanás, F. J. J.
Am. Chem. Soc. 1998, 120, 4865. (b) Nishiyama, H.;
Sakata, N.; Sugimoto, H.; Motoyama, Y.; Wakita, H.;
Nagase, H. Synlett 1998, 930. (c) Comins, D. L.; Zhang, Y.
J. Am. Chem. Soc. 1996, 118, 12248. (d) Zhang, D.;
Liebeskind, L. S. J. Org. Chem. 1996, 61, 2594. (e) Bailey,
W. F.; Jiang, X.-L. J. Org. Chem. 1996, 61, 2596.
(5) (a) Woltering, M. J.; Fröhlich, R.; Wibbeling, B.; Hoppe, D.
Synlett 1998, 797. (b) Ahmed, A.; Clayden, J.; Rowley, M.
Tetrahedron Lett. 1998, 39, 6103. (c) Bragg, R. A.;
Clayden, J. Tetrahedron Lett. 1999, 40, 8327. (d) Clayden,
J.; Tchabanenko, K. Chem. Commun. 2000, 317.
(6) (a) Coldham, I.; Hufton, R. Tetrahedron 1996, 52, 12541.
(b) Coldham, I.; Fernàndez, J.-C.; Snowden, D. J.
Tetrahedron Lett. 1999, 40, 1819.
(16) Reich, H. J.; Borst, J. P.; Coplien, M. B.; Phillips, N. H. J.
Am. Chem. Soc. 1992, 114, 6577.
(17) Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109.
(18) Meyers, A. I.; Burgess, L. E. J. Org. Chem. 1991, 56, 2294.
(19) The ratio of diastereomers of the picrate salts of 15 and 16 in
the crystals was 60:40 by 1H NMR and 54:46 by X-ray, such
that confirmation of the major diastereomer by X-ray
structure analysis was not certain.
(20) (a) Karoyan, P.; Chassaing, G. Tetrahedron Lett. 1997, 38,
85. (b) Lorthiois, E.; Marek, I.; Normant, J.-F. J. Org. Chem.
1998, 63, 2442. (c) Galeazzi, R.; Geremia, S.; Mobbili, G.;
Orena, M. Tetrahedron: Asymmetry 1996, 7, 79.
(21) Andrés, C.; Duque-Soladana, J. P.; Iglesias, J. M.; Pedrosa,
R. Tetrahedron Lett. 1996, 37, 9085.
(22) Agami, C.; Couty, F.; Poursoulis, M.; Vaissermann, J.
Tetrahedron 1992, 48, 431.
(23) (a) Bailey, W. F.; Mealy, M. J. J. Am. Chem. Soc. 2000, 122,
6787. (b) Gil, G. S.; Groth, U. M. J. Am. Chem. Soc. 2000,
122, 6789. (c) Marek, I. J. Chem. Soc., Perkin Trans. 1 1999,
535.
(7) Lautens, M.; Kumanovic, S. J. Am. Chem. Soc. 1995, 117,
1954.
(8) Seyferth, D.; Andrews, S. B. J. Organomet. Chem. 1971, 30,
151.
(9) Seitz, D. E.; Carroll, J. J.; Cartata, C. P.; Lee, S.-H.; Zapata,
A. Synth. Commun. 1983, 13, 129.
(24) (a) Pirkle, W. H.; Burlingome, T. G.; Beare, S. D.
Tetrahedron Lett. 1968, 5849. (b) Benson, S. C.; Cai, P.;
Colon, M.; Haiza, M. A.; Tokles, M.; Snyder, J. K. J. Org.
Chem. 1988, 53, 5335.
(25) Coldham, I.; Collis, A. J.; Mould, R. J.; Robinson, D. E.
Synthesis 1995, 1147.
(10) (a) Quintard, J.-P.; Elissondo, B.; Jousseaume, B. Synthesis
1984, 495. (b) Pearson, W. H.; Lindbeck, A. C.; Kampf, J.
W. J. Am. Chem. Soc. 1993, 115, 2622. (c) Pearson, W. H.;
Stevens, E. P. Synthesis 1994, 904. (d) Katritzky, A. R.;
Chang, H.-I.; Wu, J. Synthesis 1994, 907.
(11) Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S. Acc. Chem.
Res. 1996, 29, 552.
(12) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. J. Am. Chem. Soc.
1994, 116, 3231.
(13) Coldham, I.; Hufton, R.; Snowden, D. J. J. Am. Chem. Soc.
1996, 118, 5322.
(14) Some of these results have been reported as a preliminary
communication: Coldham, I.; Hufton, R.; Rathmell, R. E.
Tetrahedron Lett. 1997, 38, 7617.
(26) (a) Hoffmann, R. W.; Eichler, G.; Endesfelder, A. Liebigs
Ann. Chem. 1983, 2000. (b) Wuts, P. G. M.; Jung, Y.-W. J.
Org. Chem. 1991, 56, 365. (c) Kuznetsov, V. V.; Lantsetov,
S. V.; Aliev, A. E.; Varlamov, A. V.; Prostakov, N. S. J. Org.
Chem. USSR 1992, 28, 61.
(27) Newcomb, M.; Marquardt, D. J.; Deeb, T. M. Tetrahedron
1990, 46, 2329.
(28) Karoyan, P.; Chassaing, G. Tetrahedron: Asymmetry 1997,
8, 2025.
(29) Fletcher, D. A.; McMeeking, R. F.; Parkin, D. J. Chem. Inf.
Comput. Sci. 1996, 36, 746.
Synthesis 2001, No. 10, 1523–1531 ISSN 0039-7881 © Thieme Stuttgart · New York