Intramolecular carbolithiation reactions of chiral alpha-amino-organolithium species.

Article abstract of DOI:10.1002/1521-3765(20020104)8:1<195::AID-CHEM195>3.0.CO;2-H

Enantiomerically enriched alpha-amino-organolithium species, in which the lithium atom is attached to a stereogenic carbon centre, have been found to be chemically stable at room temperature in a solvent of very low polarity and undergo intramolecular car

Full text of DOI:10.1002/1521-3765(20020104)8:1<195::AID-CHEM195>3.0.CO;2-H

FULL PAPER
Intramolecular Carbolithiation Reactions of Chiral a-Amino-organolithium
Species
Neil J. Ashweek, Iain Coldham,* David J. Snowden, and Graham P. Vennall[a]
Abstract: Enantiomerically enriched a-
amino-organolithium species, in which
the lithium atom is attached to a stereo-
genic carbon centre, have been found to
be chemically stable at room temper-
ature in a solvent of very low polarity
and undergo intramolecular carbolithia-
tion onto an unactivated alkene. The
configurational stability of the chiral
organolithium species, bearing a variety
of N-alkenyl substituents, was probed by
studying the enantiomeric purity of the
cyclization products. With N-but-3-enyl-
2-lithiopyrrolidine, cyclization to the
five-membered ring is more rapid than
racemization and a high yield of the
pyrrolizidine alkaloid (‡)-pseudohelio-
tridane was obtained with no loss of
optical purity. In contrast, with N-pent-
4-enyl-2-lithiopyrrolidine, cyclization to
the six-membered ring was found to
occur with significant loss of optical
purity. The cyclization to the six-mem-
bered ring was determined to occur with
a half-life, t1/2 ꢀ90 min at 238C. The
epimerization of this organolithium spe-
cies in hexane/Et2O 4:1 was calculated
to have a half-life, t1/2 ꢀ30 min at 238C.
Enhanced levels of enantioselectivity
for the formation of the indolizidine
ring system were obtained using an
alkene bearing a terminal phenylthio
substituent. With N-[(3-phenylthio)-
prop-2-enyl]-2-lithiopyrrolidine, cycliza-
tion to the four-membered ring occurs
with poor enantioselectivity at low tem-
perature in THF but is highly enantio-
selective at room temperature in a
solvent of very low polarity.
Keywords: alkaloids ¥ cyclization ¥
kinetics ¥ lithium ¥ tin
Our own work has made use of the ability to form an
organolithium species by tin lithium exchange from an
aminoalkylstannane.[6, 7] This led to a new route to substituted
pyrrolidines (Scheme 2).
Introduction
Inter- and intramolecular carbometallation reactions of
alkenes and alkynes are finding increasing use for regio- and
À
stereocontrolled carbon carbon bond formation in organic
chemistry.[1, 2] Considerable efforts, particularly by Bailey and
co-workers, have shown that intramolecular carbolithiation
(anionic cyclization) reactions allow ready access to substi-
tuted cyclopentanes and other carbocyclic ring systems.[3] The
core, unsubstituted substrate, 5-hexenyllithium, can be pre-
pared by iodine lithium exchange with tert-butyllithium, and
undergoes cyclization with a half-life, t1/2 ꢀ5.5 min at 238C
(Scheme 1).[4, 5]
Scheme 2. Anionic cyclizations to 3-substituted pyrrolidines.[6, 7] a) nBuLi,
hexane/Et2O 10:1, RT, 2 h, then E , 44 90%.
‡
In this work, excellent results were obtained using the very
low polarity solvent system hexane/Et2O (ꢀ10:1) at room
temperature. Under these conditions transmetallation of the
a-amino-organostannane is slow, and complete tin lithium
exchange requires approximately 30 min. Other research
groups have also studied the formation of heterocyclic
compounds using an intramolecular carbometallation reac-
tion.[2a,b, 8] Access to chiral a-hetero-organolithium species, for
example by tin lithium exchange[9] or proton abstraction,[10]
opens up the possibility to determine the extent of intra-
molecular carbolithiation by retention or inversion of config-
uration at the carbanion centre, a study that is not feasible
using iodine lithium exchange with chiral secondary iodides.
Scheme 1. Rate of anionic cyclization to cyclopentane ring in pentane/
Et2O.[5]
[a] Dr. I. Coldham, N. J. Ashweek, Dr. D. J. Snowden, Dr. G. P. Vennall
School of Chemistry, University of Exeter
Stocker Road, Exeter EX4 4QD (UK)
Fax : (‡44)1392263434
E-mail: I.Coldham@exeter.ac.uk
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I. Coldham et al.
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Chiral organolithium species are known to react intermolec-
ularly with electrophiles with retention, inversion or racemi-
zation of configuration, depending on the substrate and
electrophile.[10, 11] However, the stereoselectivity on intramo-
lecular quench (anionic cyclization) was unknown at the
outset of this work. This paper describes in full our results on
the use of enantiomerically enriched organolithium species
for the formation of cyclic amines and gives valuable
information on how the extent of racemization depends on
the N-alkenyl substituent. In addition to our own work,[7, 12]
the number of reports on the use of chiral organolithium
species for the formation of carbocyclic and heterocyclic ring
systems has been growing.[13]
after quenching with methanol (Scheme 4). The stereochem-
istry was confirmed by NOE experiments and by correlation
with the known pseudoheliotridane 5.[16] The enantiomeric
excess (ee) of the product was determined by measuring the
Results and Discussion
Scheme 4. Anionic cyclization to (‡)-pseudoheliotridane. a) nBuLi, hex-
ane/Et2O 10:1, RT, 2 h, then MeOH, 90%.
We required a route to enantiomerically enriched amino-
alkylstannanes and hence (on transmetallation) a-amino-
organolithium species, in which the nitrogen atom is tethered
to an alkenyl group to allow intramolecular carbolithiation. A
popular and convenient method to introduce a trialkyltin
group a to a heteroatom makes use of chemistry developed by
Hoppe and Beak, in which proton abstraction in the presence
of (À)-sparteine induces asymmetry.[10] With the substrate N-
tert-butoxycarbonyl (Boc) pyrrolidine, the 2-tributyltin deriv-
ative 1 (Scheme 3) was prepared with high optical purity.[14]
Removal of the N-Boc group was problematic using a protic
1
peak area of the methyl doublet in the H NMR spectrum in
the presence of the chiral solvating agent (R)-(À)-2,2,2-
trifluoro-1-(9-anthryl)ethanol.[17] Despite the ambient tem-
perature of the reaction, the product was determined to have
94% ee, which indicates a completely enantiospecific cycliza-
tion, with no loss of optical purity. This result was verified
from the specific rotation [a]2D3 ˆ ‡6.8 (c ˆ 0.5, EtOH), which
compared well with the literature value [a]2D3 ˆ ‡7.0 (c ˆ 0.5,
EtOH).[16] By the sign of rotation, we assign the product with
absolute configuration as illustrated, such that the cyclization
has occurred with complete retention of configuration at the
carbanion centre. This result suggests that the lithium atom in
the intermediate 4 (drawn as a monomer but note that the
corresponding N-methyl com-
pound has been found to be
dimeric in THF)[18] coordinates
to the alkene and that the
transition state adopts a con-
Scheme 3. Preparation of N-(but-3-enyl)-2-(tributylstannyl)pyrrolidine.
ˆ
a) B-bromocatecholborane, CH2Cl2, RT, 30 min, then CH2 CHCH2COCl,
65%; b) AlH3, Et2O, 0 8C, 2 h, 89 %.
Figure 1. Conformation of the
organolithium species 4 leading
to pyrrolizidine 5.
formation (Figure 1) with
chair-like arrangement in
which the lone pair on the
a
acid such as trifluoroacetic acid, but the use of the Lewis acid
B-bromocatechol borane[15] gave the unstable free amine,
which was treated immediately with 3-butenoyl chloride to
give the amide 2. Reduction of the amide with LiAlH4 or
alane (AlH3) gave the desired substrate 3. This amine had a
high specific rotation, [a]2D3 ˆ ‡107.0 (c ˆ 2.6, EtOH), al-
though we were not able to verify at this stage that no loss in
optical purity had occurred in the deprotection, acylation or
reduction steps.
Transmetallation of chiral a-amino-organostannanes is
often carried out at low temperature (typically À788C), in
order to avoid racemization of the chiral organolithium
species.[10a, 11a] We were somewhat disappointed to find, there-
fore, that treatment of the stannane 3 with nBuLi in THF at
À788C, followed by gradual warming to room temperature,
gave predominantly the protodestannylated product N-but-3-
enylpyrrolidine. Alternative conditions, using the much less
polar hexane/Et2O (10:1) solvent system, require temper-
atures above 08C to effect transmetallation. Gratifyingly,
these conditions resulted in a high yield of a single diaster-
eomer (as determined by NMR) of the cyclized product 5,
nitrogen atom is pseudo-axial and could interact with the
lithium atom.[18, 19] This postulate is in agreement with
calculated[3] and experimental data.[20] This chemistry allows
a very short, enantiospecific synthesis of the pyrrolizidine
alkaloid (‡)-pseudoheliotridane.
In addition, the result indicates that intramolecular carbo-
lithiation reactions onto an alkene occur with complete
retention of configuration at the carbanion centre. The
anionic cyclization contrasts sharply with the related radical
cyclization, which occurs to give predominantly the other
diastereomer, heliotridane, as a racemic mixture.[21]
We were intrigued as to the origin of the remarkable
configurational stability of the organolithium species 4.
Cyclization of the organolithium species 4 appears to proceed
at a rate that is comparable with (or faster than) 5-hexenyl-
lithium, as the cyclization of 4 is complete within the same
time scale as the tin lithium exchange (approximately 30 min
at room temperature in a solvent of very low polarity). The
organolithium species 4 is different from 5-hexenyllithium (it
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Carbolithiations
195 207
is likely to have nitrogen lithium coordination[18, 19] and is a
cyclic, secondary organolithium species), however, if it does
cyclize at the same rate as 5-hexenyllithium, then it is possible
to calculate that the half-life for epimerization of 4 must be at
least 5 h, in order that essentially no loss of optical purity
would result.
Intramolecular carbolithiation of the organolithium species
4 gives a new organolithium species which can be trapped with
a protic source to give (‡)-pseudoheliotridane 5. Trapping
with other electrophiles led to a selection of different
substituted pyrrolizidines 6a e (Scheme 5, Table 1). In each
case the products 6 were optically active, although it was no
longer possible to verify the enantiomeric excess by NMR. As
the cyclization occurs enantiospecifically, setting up both
chiral centres in the product before electrophilic quench, then
it is anticipated that there would be no loss in the optical
purity of these products.
Removal of the N-Boc protecting group from the chiral
stannane (S)-1 (94% ee), followed immediately by N-acyla-
tion of the resulting 2-(tributylstannyl)pyrrolidine with 4-pen-
tenoyl chloride gave the carboxylic amide 7 (Scheme 6).
Reduction with LiAlH4 gave the amine 8. Alternatively, the
amine 8 could be prepared directly from the stannane 1 by
deprotection and immediate reductive amination with 4-pen-
tenal.[22]
Scheme 6. Preparation of N-(pent-4-enyl)-2-(tributylstannyl)pyrrolidine.
a) B-bromocatecholborane,
CH2Cl2,
RT,
30 min,
then
ˆ
CH2 CHCH2CH2COCl, 65%; b) LiAlH4, Et2O, 0 8C, 20 min, 90%.
The amine 8 in hexane/Et2O (4:1) was treated with nBuLi
(3 molar equivalents in hexanes) at room temperature to give
the desired enantiomerically enriched organolithium species 9
(Scheme 7). Complete transmetallation required approxi-
mately 30 min and complete cyclization of this substrate
required approximately 6 h at room temperature. Quenching
Scheme 5. Anionic cyclizations to 1-substituted pyrrolizidines. a) nBuLi,
hexane/Et2O 10:1, RT, 2 h, then E , 41 63%.
‡
Table 1. Preparation of 1-substituted pyrrolizidines 6.
‡
E
E
Product
Yield [%]
CD3OD
D
6a
6b
6c
6d
6e
58
62
62
68
41[a]
ˆ
Ph2C O
C(OH)Ph2
SiMe3
SnMe3
Me3SiCl
Me3SnCl
PhCHO
Scheme 7. Anionic cyclization to 1-methylindolizidine. a) nBuLi, hexane/
Et2O 4:1, RT, 6 h, then MeOH, 80% (10:11 95:5); or nBuLi, hexane/Et2O/
TMEDA 4:1:1, RT, 6 h, then MeOH, 76% (10:11 10:90).
CH(OH)Ph
[a] 6e was a mixture (1:1) at the alcohol center.
Transmetallation of the organostannane 3 at À788C in the
solvent THF gave, after warming to room temperature, N-but-
3-enylpyrrolidine together with a small amount (ꢀ19%) of
pseudoheliotridane 5. This product was determined (1H NMR
spectrum as above) to have been formed with 94% ee and had
therefore proceeded with no loss of optical purity. The
product pseudoheliotridane was also formed in 94% ee and
in good yield using hexane/Et2O as solvent in the presence of
the additives N,N,N',N'-tetramethylethylene diamine (TME-
DA) or lithium iodide. Attempts to effect cyclization of the
racemic organolithium species 4 in the presence of (À)-
sparteine resulted in the formation of only N-but-3-enylpyr-
rolidine.
The observation that the intramolecular carbolithiation
reaction to the pyrrolizidine 5 occurs with complete retention
of configuration at the chiral carbanion centre is in agreement
with recent results on the cyclization of other chiral organo-
lithium species.[13] These cyclization reactions are restricted to
the formation of five-membered rings, and must occur at rates
that are significantly greater than the rate of racemization.
The next logical investigation is to determine the effect of ring
size on the stereochemical integrity of the chiral organo-
lithium species. We therefore selected to investigate first the
cyclization to the corresponding six-membered ring.
with MeOH resulted in the formation of the diastereomeric
indolizidines 10 and 11 in high yield (80 87%) and high
diastereoselectivity (95:5, 10:11), together with small amounts
of the protodestannylated product N-pent-4-enylpyrrolidine.
The relative stereochemistry of the major diastereomer 10
was determined by NOE experiments. Using NMR spectros-
copy in the presence of (R)-(À)-2,2,2-trifluoro-1-(9-anthry-
l)ethanol,[17] the indolizidine 10 was determined to have 13%
ee. The absolute configuration of the major enantiomer of the
indolizidine 10 is unknown but is drawn as if cyclization occurs
with retention of configuration, as determined for the
corresponding cyclization to the five-membered ring.
An experiment in which aliquots were taken at different
reaction times was carried out and the data is illustrated in
Figure 2. After approximately 30 min, to allow for complete
transmetallation, the product indolizidines 10 and 11 (95:5)
could be isolated in low yield (22%) but enhanced enantio-
meric excess (10, 62% ee). Longer reaction times gave
increasing yields of the indolizidine products, but at the
expense of enantiomeric purity. However, the enantiomeric
excess did not drop off to zero on long reaction times, which
suggests that the cyclization is irreversible. By plotting the log
of the yield of product over time or the log of the amount of
organolithium 9 (as determined by the amount of its proto-
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Figure 2. Yield [%] and enantiomeric excess [%] of 10 over time.
nated derivative) over time (Figure 3), the cyclization best fits
first order kinetics, with a rate constant, kc ꢀ1.2 Â 10À4 sÀ1,
corresponding to a half-life for cyclization, t1/2 ꢀ90 min at
238C. This is significantly slower than the rate of cyclization to
the corresponding five-membered ring.
Figure 4. Kinetics simulation and plotted experimental data for cyclization
to 10.
cyclization and indeed that the organolithium species is
racemic within 60 min. From the data, the calculated rate of
epimerization of the organolithium species 9, ke ꢀ3.4 Â
10À4 sÀ1, corresponds to a half-life for epimerization, t1/2
ꢀ30 min at 238C in hexane/Et2O (4:1). This data is approx-
imate as tin lithium exchange requires 30 min, although it
does indicate that the formation of the indolizidines 10 and 11
beyond 60 min results from racemic organolithium species
and that the enantiomeric excess (13% ee) stems from
cyclization occurring within 60 min, prior to racemization.
The picture may be complicated further, if the organolithium
species 9 exists preferentially as a heterochiral dimer
(although NMR spectroscopy indicates that N-methyl-2-
lithiopyrrolidine is a homochiral dimer[18]). The heterochiral
dimer, if it forms, would be produced during racemization and
may have different kinetics from the monomer or homochiral
dimer for epimerization and cyclization.
As far as we are aware, this is the first determination of the
rate of epimerization of a chiral, cyclic a-amino-organo-
lithium species. An acyclic benzylic a-amino-organolithium
species has been reported to epimerize rapidly (DG=ˆ
9.0 kcalmolÀ1 at 190 K).[23] With a half-life for epimerization
of the organolithium species 9 of approximately only 30 min,
racemization is (not surprizingly) slow in comparison with a
benzylic organolithium species, but still competes with
cyclization to a six-membered ring. This is in stark contrast
to the completely enantiospecific cyclization of organolithium
species 4. If the organolithium species 4 epimerizes with a
half-life that is similar to that of 9 (approximately 30 min at
room temperature), then the rate of cyclization to the five-
membered ring must be extremely rapid (the half-life for
cyclization would have to be less than 30s), in order that
essentially no loss of optical purity (within expected error
limits) in the formation of 5 occurs. Unfortunately, the slow
transmetallation and rapid cyclization of the organolithium
species 4 preclude the determination of kinetic data. If
cyclization (to the five-membered ring) occurs at a rate that is
similar to that determined by Bailey (Scheme 1), then the
organolithium species 4 must racemize considerably more
Figure 3. Determination of first order rate constant for cyclization of 9.
Once the rate of cyclization is known, then the rate of
epimerization of the organolithium species 9 can be deter-
mined (Scheme 8). The experimental data points and the
simulated kinetics for the epimerization and cyclization are
given in Figure 4. This graph illustrates the gradual formation
of the two enantiomeric indolizidine products 10 (13% ee
after 6 h) at the determined rate (1.2 Â 10À4 sÀ1) starting from
organolithium species of 94% ee [97:3 ratio of (S)-9 to (R)-9,
assuming transmetallation is rapid]. Using this data, it is clear
that epimerization of the organolithium species 9 is faster than
Scheme 8. Epimerization and cyclization of intermediate organolithium
species.
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Carbolithiations
195 207
slowly than 9 and this would have to be due to the greater ease
with which the alkene (with a shorter tether) could coordinate
to the lithium atom. We are currently investigating the
relative ease of epimerization of different N-substituted
2-lithio-pyrrolidines.
The synthesis of the stannanes E- and Z-15 was achieved by
reductive amination.[22] The best yields were obtained using
the reducing agent NaBH3CN in the solvent nitromethane,
which was not buffered with an acid (Scheme 10). Under
these conditions the products 15 were obtained in good yield
without any isomerization.
The cyclization of the organolithium species 9 was sensitive
to the solvent. When the stannane 8 was treated with nBuLi in
THF or in hexane/Et2O/(À)-sparteine, transmetallation took
place, but no cyclization occurred and only N-pent-4-enyl-
pyrrolidine could be isolated. However, the solvent system
hexane/Et2O/TMEDA (4:1:1, equating to 15 molar equiva-
lents of TMEDA) allowed transmetallation and cyclization to
give predominantly the indolizidine 11 (10:90, 10:11; 76%).
This represents a complete reversal of the diastereoselectivity
in comparison with the reaction in the absence of TMEDA.
Unfortunately, under these conditions the products 10 and 11
were both found to be racemic. The rate of transmetallation
and cyclization in the presence of TMEDA was not deter-
mined but was not significantly different from that in the
absence of TMEDA. The addition of TMEDA therefore
appears to increase the rate of racemization of the organo-
lithium species, presumably via coordination of TMEDA to
the lithium atom.[24] This coordination must also influence the
diastereoselectivity of the cyclization, to favour the product
11.
In order to improve the optical purity of the indolizidine
products, it is necessary to increase the rate of cyclization and/
or to slow the rate of racemization of the organolithium
species. Alkenes substituted with an anion stabilising group
have been shown to increase the rate of anionic cyclization
reactions.[25, 26] We chose to investigate the phenylthio-sub-
stituted alkene, as the product sulfide after cyclization would
be amenable to reductive cleavage to give the same indoli-
zidines 10 and 11. The required vinyl sulfides were prepared
from the aldehydes E- and Z-14, which were prepared
according to a modified literature procedure (Scheme 9).[26]
Scheme 10. Reductive amination to phenylthio-substituted substrates E-
and Z-15. a) B-bromocatecholborane, CH2Cl2, RT, 10 min, then wash with
aq NaOH, then MeNO2, NaBH3CN, E- or Z-14, RT, 15 min, E-15 72%,
Z-15 69%.
An alternative route to the desired stannanes 15 was
achieved from the carboxylic amide 16, which was formed
from the stannane 1 by deprotection and acylation with
4-pentynoyl chloride (Scheme 11). Reduction with LiAlH4
gave the amine 17. Subsequent sulfenylation of the alkynyl
anion provides the alkynyl sulfide 18. In this reaction the
initial deprotonation of the alkyne must be accomplished in
Et2O, in order to avoid transmetallation of the stannane, a
rapid process in THF. However, addition of diphenyl disulfide
(activated with CH3I) is best accomplished in THF. Reduction
of the alkynyl sulfide 18 with LiAlH4 gave the stannane E-15,
whereas reduction with DIBAL gave the stannane Z-15.
Scheme 11. Acylation-reduction route to substrates E- and Z-15. a) B-
ꢁ
bromocatecholborane, CH2Cl2, RT, 10 min, then CH CCH2CH2COCl,
59%; b) LiAlH4, Et2O, 0 8C, 20 min, 84%; c) nBuLi, Et2O, 0 8C, then
PhSSPh, MeI, THF, RT, 16 h, 66%; d) LiAlH4, THF, 408C, 3 h, E-15 80%;
e) DIBAL, hexane, À188C to RT, 7 h, Z-15 59%.
Treatment of the stannanes 15 with nBuLi in hexane/Et2O
(4:1) gave the diastereomeric cyclized products 19 and 20
(Scheme 12). From the stannane E-15, the major product was
the indolizidine 19 (77%, 70:30, 19:20), formed in good
enantiomeric excess (19, 75% ee; 20, 72% ee). The enantio-
meric excess values were determined by reduction to the
Scheme 9. Preparation of E- and Z-5-(phenylthio)pent-4-enal. a) LiAlH4,
THF, 408C, 3 h, 93% (E-:Z-13 100:0); b) DIBAL, hexane, À188C to RT,
7 h, 99% (E-:Z-13 0:100); c) TsOH, MeOH, H2O, RT, 16 h, 100%;
d) (COCl)2, DMSO, CH2Cl2, À608C then Et3N, E-14 69%, Z-14 64%.
Reduction of the alkyne 12 with LiAlH4 gave exclusively the
vinyl sulfide E-13, whereas reduction with diisobutylalumi-
nium hydride (DIBAL) gave exclusively the vinyl sulfide Z-
13. Acid-catalyzed deprotection and Swern oxidation of the
resulting alcohol gave the desired aldehydes E- and Z-14.
Scheme 12. Anionic cyclization to 1-(phenylthiomethyl)indolizidines.
a) nBuLi, hexane/Et2O 4:1, RT, 2 h, then MeOH, from E-15 77% (19:20
70:30), from Z-15 79% (19:20 50:50); or nBuLi, hexane/Et2O/TMEDA
4:1:1, RT, 6 h, then MeOH, from E-15 71% (19:20 0:100), from Z-15 73%
(19:20 0:100).
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I. Coldham et al.
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indolizidines 10 and 11 with Raney nickel. The organolithium
species derived from the stannane Z-15 cyclized to give a
mixture of indolizidines 19 and 20 (79%, 50:50, 19:20) in
slightly lower enantiomeric excess (19, 55% ee; 20, 53% ee).
The transmetallation and cyclization of the stannanes 15 was
complete within 1 h at room temperature and the much
improved optical activity of the product indolizidines results
from the faster rate of cyclization in comparison with the
stannane 8. It is possible that, in addition to the faster rate of
cyclization, the organolithium species derived from E- or Z-15
epimerize at a rate that is slower than the epimerization of the
organolithium species 9. Assuming, however, that the rate of
epimerization of the organolithium species E-15 is the same as
that of the organolithium species 9 (in which ke ꢀ3.4 Â
10À4 sÀ1 at 238C in hexane/Et2O), then it is possible to
calculate that the cyclization onto the vinylsulfide to produce
the indolizidines with 75% ee would occur with a rate
constant k ꢀ3 Â 10À3 sÀ1, corresponding to a half-life for
cyclization, t1/2 ꢀ4 min at 238C. Whilst this determination is
based on the rate of epimerization of a different, although
related substrate, it does indicate that the presence of a
phenylthio substituent at the terminus of the alkene enhances
the rate of cyclization to give a six-membered ring to a level
that is similar to the cyclization onto an unactivated alkene to
give a five-membered ring.
Using the solvent system hexane/Et2O/TMEDA (4:1:1), the
organolithium species derived from the stannanes E- or Z-15
cyclized to give exclusively the indolizidine 20 in good yield
(71 73%). The indolizidine 20 was formed as a racemic
mixture in both cases. These results are similar to those
obtained with the substrate 8 and we speculate that coordi-
nation of TMEDA to the lithium atom increases the rate of
racemization of the organolithium species, in addition to
altering the preferred conformation of the transition state for
cyclization, such that only the product 20 is formed. Attempt-
ed cyclization of the alkynyl stannanes 17 or 18 was
unsuccessful.
(48% ee). It is interesting to note that the organolithium
species 22 had significant configurational stability (on quench-
ing after 2 h at 138C with tributyltin chloride, the stannane 21
was recovered in 65% ee). It is possible to calculate from this
data that the half-life for epimerization of the organolithium
species 22 must be approximately 7.5 h. This slow rate of
epimerization supports our results with the lack of racemiza-
tion of the organolithium species 4, but contrasts with the
much faster rate of epimerization of the organolithium spe-
cies 9.
We postulated that the presence of a phenylthio substituent
at the terminus of the allyl unit would promote cyclization in
preference to rearrangement. We were intrigued by the
possibility of influencing the reaction pathway and the
enantioselectivity by a pendent phenylthio group and describe
the results of this study below.
The desired substrate 26 bearing an N-(3-phenylthio)allyl
substituent was prepared from the stannane 1 by N-depro-
tection and immediate alkylation with propargyl bromide
(Scheme 14). Deprotonation of the resulting N-propargyl
compound 24 in Et2O (to avoid tin lithium exchange) and
addition of diphenyl disulfide (activated with CH3I) in THF
gave the alkynyl sulfide 25. Reduction of the alkyne with
LiAlH4 led to the vinyl sulfide E-26. In this case, use of
DIBAL for the reduction also led to the same E-stereoisomer,
rather than the isomer Z-26.
Scheme 14. Preparation of phenylthio-substituted substrate E-26. a) B-
ꢁ
bromocatecholborane, CH2Cl2, RT, 10 min, then CH CCH2Br, 65%;
b) nBuLi, Et2O, 0 8C, 1 h, then PhSSPh, MeI, THF, RT, 1 h, 65%;
c) LiAlH4, THF, 408C, 1.5 h, E-26 80%.
The successful intramolecular carbolithiation to give the
indolizidine ring system and the more favourable cyclization
with a pendent phenylthio substituent prompted us to
investigate the possibility of forming a four-membered ring
by this process. Gawley has described the addition of nBuLi to
the stannane 21 (94% ee) to give the corresponding organo-
lithium species 22 (Scheme 13).[27] This organolithium species
does not undergo cyclization, but does rearrange by a
combination of [2,3]- and [1,2]-sigmatropic rearrangement
pathways. The [2,3]-sigmatropic rearrangement occurs with
inversion of configuration at the carbanion centre, whereas
the [1,2]-process occurs with racemization. The product was
quenched with a-naphthoyl chloride to give the amide 23
Treatment of the stannane 26 with excess nBuLi in the low
polarity solvent system hexane/Et2O (4:1) at room temper-
ature resulted in partial transmetallation. The desired cycli-
zation products 27 and 28 were isolated (52%) with a high
diastereoselectivity (10:1) in favour of the isomer 27 as
determined by NMR spectroscopy (NOE experiments) on the
inseparable mixture (Scheme 15). No products from [2,3]- or
[1,2]-sigmatropic rearrangement were isolated. The remaining
material was recovered stannane 26 (35%). Attempts to
achieve complete transmetallation with further nBuLi or
longer reaction times were unsuccessful and it was deter-
Scheme 13. Sigmatropic rearrangement of N-allyl-2-(tributylstannyl)pyr-
rolidine.[27] a) nBuLi, THF-TMEDA, 138C, 4 h, then a-naphthoyl chloride,
64%.
Scheme 15. Anionic cyclization to azabicyclo[3.2.0]heptanes. a) nBuLi,
hexane/Et2O 4:1, RT, 30 min, then MeOH, 52% (27:28 10:1), or a) nBuLi,
THF, À788C, 2 min, then MeOH, 86% (27:28 1:1).
200
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Chem. Eur. J. 2002, 8, No. 1

Carbolithiations
195 207
mined, by quenching the reaction with MeOD, that the
recovered starting material was deuterated in the vinylic
position to give 29. Therefore tin lithium exchange competes
with deprotonation of this substrate in solvent of very low
polarity at room temperature.
In order to determine the enantiomeric excess of the
products 27 and 28, the phenylthio group was removed by
treatment with Raney nickel to give the amines 30 and 31
(Scheme 16). In a similar way to that used for the bicyclic
amines 5, 10 and 11, addition of the chiral solvating agent (R)-
(À)-2,2,2-trifluoro-1-(9-anthryl)ethanol[17] to the amines 30 or
cyclization of the alkyne 25 was rapid in THF and a good
yield (78%) of the bicyclic ring system 32 was obtained
(Scheme 17). The product was found to be a 1:1 mixture of
alkene geometrical isomers. Attempts to determine the
optical purity of these isomeric sulfides or to reduce the
alkene or to cleave the phenylthio group (e.g. with Raney
nickel or NaBH4/NiCl2) were unsuccessful.
Scheme 17. Anionic cyclization of phenylthio-substituted alkyne 25.
a) nBuLi, THF, À788C, 1.5 h, then MeOH, 78%.
In conclusion, chiral organolithium species a- to a nitrogen
atom of a tertiary amine can be used for the synthesis of
bicyclic amines with high enantiomeric excess. 1-Azabicyclo-
[3.2.0]heptane, 1-azabicyclo[3.3.0]octane and 1-azabicyclo-
[4.3.0]nonane ring systems have been prepared and the
stereoselectivity of the cyclization has been determined.
Cyclization competes with epimerization of the organolithium
species and a comparison of the rates of these processes has
been achieved. High yields and high optical purities of the
products can be obtained using, if necessary, a phenylthio-
substituted alkene as the electrophilic tether.
Scheme 16. Reduction of azabicyclo[3.2.0]heptanes 27 and 28. a) Raney
nickel, EtOH, 608C, 1 h, 54 71%.
31 promoted splitting of the methyl doublet peaks in the
1H NMR spectrum that allowed determination of the optical
purity. We were pleased to find that the product 30, and hence
27, had been formed in 88 90% ee. The enantiomeric excess
of the minor diastereomer 28/31 could not be determined. The
high enantiomeric excess of 27 must reflect a cyclization that
is much more rapid than epimerization of the intermediate
organolithium species in hexane/Et2O. Cyclization to give an
azetidine ring with a phenylthio-stabilized organolithium
species therefore takes place with almost complete retention
(or inversion) of configuration at the carbanion centre (we
have not been able to determine the absolute configuration of
the products 27 and 28 and these are drawn as if cyclization
had occurred with retention of configuration).
The cyclization of the stannane 26 was sensitive to the
solvent. The solvent system hexane/Et2O/TMEDA (4:1:1)
gave similar results (yield 27 ‡ 28 43%, ratio 10:1, but with
reduced enantioselectivity: 27 54% ee) in comparison with
experiments in the absence of TMEDA (in contrast to the
influence of TMEDA on the cyclization of the stannanes 8 and
15). However, the use of THF caused a completely different
outcome. In THF, transmetallation and cyclization were
extremely rapid, being complete in less than 2 min at
À788C. The yield (86%) of the bicyclic amine products 27
and 28 was high using THF as the solvent, however, there was
no diastereomeric excess and both 27 and 28 were formed in
low enantiomeric excess (14 24%). This result is surprising
considering the known configurational stability of N-methyl-
2-lithiopyrrolidine in THF at low temperature.[11a] Although
the cyclization in THF gives only a low enantiomeric excess,
the major enantiomer of 27 is the same as that formed in
hexane/Et2O.[28] It is not clear whether the low enantiomeric
excess in THF is a result of rapid epimerization of this
substrate in this solvent (at a rate that is competitive with
cyclization) or whether there is a mixture of cyclization with
retention and cyclization with inversion of configuration at
the carbanion centre.
Experimental Section
General: Optical rotations were measured on an Optical Activity Ltd. AA-
1000 polarimeter, using a cell with a path length of 0.5 dm. IR spectra were
recorded as liquid films on NaCl plates unless otherwise stated, using a
Perkin Elmer 881 or Nicolet FT-IR Magna 550 spectrometer. 1H NMR
spectra were recorded on a Bruker AC 300 MHz or Bruker DRX 400 MHz
spectrometer using the residual solvent peak as an internal reference.
Chemical shifts are given in parts per million. Coupling constants J are
given in Hz. 13C NMR spectra are recorded on the above spectrometers
operating at 75 or 100 MHz, respectively, and are proton decoupled.
Additional analysis by DEPT, HMQC and NOE experiments was
performed when necessary. Mass spectra were measured on a Kratos
Profile HV3 spectrometer or by the EPSRC mass spectrometry service,
University of Wales Swansea. Elemental analyses were recorded on a Carlo
Erba EA1110 elemental analyser.
THF was freshly distilled from sodium/benzophenone. Petrol refers to light
petroleum ether (b.p. 40 608C). For the transmetallation reactions, hexane
was distilled from calcium hydride and Et2O from sodium/benzophenone.
Flash column chromatography was performed on silica gel 60H (230
400 mesh) (Merck 9385) or on basic alumina (150 mesh) (Brockmann 1).
Thin-layer chromatography was performed on silica-coated Merck Kiesel-
gel 60F254 0.25 mm plates, and visualised by UV irradiation at 254 nm or
potassium permanganate dip.
(2S)-1-[2-(Tributylstannyl)pyrrolidin-1-yl]-but-3-en-1-one (2): B-Bromo-
catecholborane[15] (3.3 g, 16.5 mmol) in CH2Cl2 (80 mL) was added to
carbamate (S)-1[14] (3.8 g, 8.2 mmol, 97:3 er) in CH2Cl2 (30 mL) at room
temperature. After 30 min, 3-butenoyl chloride (1.0 g, 9.6 mmol) in CH2Cl2
(40 mL) was added. After 2 h, sat. aqueous NaHCO3 (100 mL) was added
and the mixture was extracted with CH2Cl2 (2 Â 100 mL). The combined
organic extracts were dried (MgSO4), evaporated and purified by column
chromatography on silica gel, eluting with petrol/EtOAc 9:1 to give the
stannane 2 (2.2 g, 65%) as an oil; Rf ˆ 0.29 (petrol/EtOAc 9:1); [a]D23
ˆ
À1
1
ˆ
ˆ
‡189 (c ˆ 2.8 in EtOH); IR: nÄ ˆ 1640 (C C), 1610 cm (C O); H NMR
(300 MHz, C6D6, 258C): d ˆ 0.94 1.07 [m, 15H; Sn(CH2CH2CH2CH3)3],
1.34 1.48 [m, 6H; Sn(CH2CH2CH2)3], 1.50 1.73 [m, 6H; Sn(CH2CH2)3],
Attempted transmetallation and cyclization of the alkyne
24 led only to N-propargyl-pyrrolidine (80%), although
Chem. Eur. J. 2002, 8, No. 1
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201

I. Coldham et al.
FULL PAPER
1.73 1.92 (m, 4H; NCH2CH2CH2), 2.77 (d, 3J(H,H) ˆ 7 Hz, 2H; OCCH2),
1.82 1.98 (m, 2H; 2 Â CH), 1.98 2.16 (m, 2H; 2 Â CH), 2.17 2.33 (m,
3H; 3 Â CH), 2.84 2.93 (m, 1H; NCH), 3.03 3.13 (m, 1H; NCH), 3.64
3.74 (m, 1H; NCH), 3.85 3.95 (m, 1H; NCH), 3.99 4.05 (m, 1H; NCH),
8.82 (s, 2H; Ar); 13C NMR (100 MHz, CDCl3, picrate salt, 258C): d ˆ 16.2,
16.4/16.6 (CH2D), 24.8 (CH2), 29.3 (CH2), 33.9 (CH2), 39.9 (CH), 55.4
(CH2), 55.6 (CH2), 74.1 (CH), 126.6 (CH), 128.1 (C), 141.7 (C), 162.4 (C);
2.80 2.94 (m, 2H; 2  NCH), 3.12 (dd, 3,3J(H,H) ˆ 9, 7 Hz, 1H; NCH),
3,3
A
B
4.98 (dd, J(H,H) ˆ 12.5, 2 Hz, 1H; CH H ), 5.03 (dd, 3,3J(H,H) ˆ 6,
ˆ
2 Hz, 1H; CH H ), 5.97 6.12 (m, 1H; CH ); 13C NMR (75 MHz, C6D6,
A
B
ˆ
ˆ
258C): d ˆ 11.2 (CH2), 14.1 (CH3), 27.9 (CH2), 28.1 (CH2), 29.8 (CH2), 30.0
ˆ
ˆ
(CH2), 40.0 (CH2), 46.8 (CH, CH2), 117.0 ( CH2), 132.8 ( CH), 167.3
(C O); MS (EI): calcd for C20H39NO120Sn: 429.2054; found: 429.2060 [M] ;
MS (EI): calcd for C8H14DN: 126.1267; found: 126.1270 [M] ; m/z (%): 229
‡
‡
ˆ
‡
‡
‡
‡
‡
‡
m/z (%): 429 (0.5) [M] , 372 (62) [M À Bu] , 70 (100) [C4H6O] .
(23) [picric acid] , 126 (25) [M] , 83 (100) [C5H9N] ; elemental analysis
calcd (%) for C14H17DN4O7 (355.3): C 47.33, H 4.82, N 15.77; found: C 47.80,
H 5.18, N 15.62.
(2S)-N-(But-3-enyl)-2-(tributylstannyl)pyrrolidine (3): Aluminium chlor-
ide (133 mg, 0.97 mmol) and lithium aluminium hydride (96 mg, 2.9 mmol)
in Et2O (5 mL) were stirred at 08C for 15 min. The amide (S)-2 (831 mg,
1.9 mmol) in Et2O (5 mL) was added dropwise through cannula. After 2 h,
aqueous NaOH (25 mL, 0.1m) and sodium potassium tartrate were added.
The mixture was filtered and extracted with Et2O (2 Â 25 mL). The
combined organic extracts were dried (Na2SO4), evaporated and purified
by column chromatography on alumina, eluting with petrol/EtOAc 9:1 to
give the amine 3 (718 mg, 89%) as an oil. Rf ˆ 0.15 (petrol/EtOAc 4:1);
(1R,8R)-1-[2,2-Diphenyl-2-hydroxyethyl)hexahydro-1H-pyrrolizine (6b,
E ˆ C(OH)Ph2): In the same way as the amine 5, nBuLi (1.1m in hexanes,
0.92 mL, 0.97 mmol), the amine 3 (200 mg, 0.48 mmol) in hexane/Et2O 9:1
(10 mL) and benzophenone (175 mg, 0.96 mmol) in Et2O (1 mL), gave,
after purification by column chromatography on alumina, eluting with
petrol/EtOAc 1:0 to 0:1, the amine 6b, E ˆ C(OH)Ph2 (92 mg, 62%) as
needles. M.p. 164 1668C; Rf ˆ 0.11 (CH2Cl2/MeOH 9:1); [a]2D3 ˆ ‡19.6
(c ˆ 0.5 in EtOH); IR (KBr disc): nÄ ˆ 3425 (OH), 1595, 1490 cmÀ1 (Ph);
[a]2D3 ˆ ‡107 (c ˆ 2.6 in EtOH); IR: nÄ ˆ 1640 cmÀ1 (C C); 1H NMR
ˆ
1H NMR (400 MHz, CD3OD, 258C): d ˆ 1.34 1.45 (m, 2H; CH2CO),
(400 MHz, C6D6, 258C): d ˆ 1.04 1.12 [m, 15H; Sn(CH2CH2CH2CH3)3],
2,3,3
1.58 1.82 (m, 5H; 5 Â CH), 2.30 (ddd,
ˆ 11, 10, 6 Hz, 1H; CH), 2.38
1.43 1.53 [m, 6H; Sn(CH2CH2CH2)3], 1.62 1.84 [m, 6H; Sn(CH2CH2)3],
ˆ
(dd, 2,3J(H,H) ˆ 13.5, 7.5 Hz, 1H; CH), 2.47 2.53 (m, 2H; 2  NCH), 2.81
(dt, 2,3J(H,H) ˆ 11, 6.5 Hz, 1H; NCH), 2.95 3.01 (m, 1H; NCH), 3.08 (td,
3,3J(H,H) ˆ 8, 5 Hz, 1H; NCH), 7.10 7.18 (m, 2H; Ph), 7.22 7.30 (m, 4H;
Ph), 7.41 7.48 (m, 4H; Ph); 13C NMR (100 MHz, CD3OD, 258C): d ˆ 24.7
(CH2), 30.4 (CH2), 34.9 (CH2), 41.5 (CH), 45.3 (CH2), 54.4 (CH2), 54.5
(CH2), 71.1 (CH), 77.1 (C), 125.9 (CH), 126.0 (CH), 126.1 (CH), 127.5 (2 Â
CH), 148.0 (C), 148.1 (C); MS (EI): calcd for C21H25NO: 307.1936; found:
1.84 2.10 (m, 5H; NCH2CH2CH , NCH2CH2CH), 2.23 2.33 (m, 1H;
CH), 2.33 2.45 (m, 2H; 2  NCH), 2.52 (dd, 3,3J(H,H) ˆ 9.5, 7.5 Hz, 1H;
NCH), 2.97 3.10 (m, 2H; 2  NCH), 5.11 (dd, 3,4J(H,H) ˆ 10, 2 Hz, 1H;
A
B
A
B
CH H ), 5.17 (dd, 3J(H,H) ˆ 17, 2 Hz, 1H; CH H ), 6.00 (ddt,
ˆ
ˆ
J(H,H) ˆ 17, 10, 7 Hz, 1H; CH ); 13C NMR (100 MHz, C6D6, 258C):
3
ˆ
d ˆ 9.2 (CH2), 13.7 (CH3), 25.0 (CH2), 27.7 (CH2), 29.5 (CH2), 29.7 (CH2),
33.9 (CH2), 53.7 (CH2), 56.5 (CH2), 57.5 (CH), 115.0 (CH2), 137.2 (CH); MS
‡
‡
‡
(EI): calcd for C20H41N120Sn: 415.2261; found: 415.2257 [M] ; m/z (%): 415
‡
307.1941 [M] ; m/z (%): 307 (1.0) [M] , 183 (4.5) [Ph2COH] , 124 (100)
‡
‡
‡
‡
[C8H14N] .
(0.1) [M] , 124 (100) [M À SnBu3] , 55 (72) [C4H7] ; elemental analysis
calcd (%) for C20H41NSn (414.3): C 57.99, H 9.98, N 3.38; found: C 58.06, H
10.07, N 3.23.
(1R,8R)-1-(Trimethylsilylmethyl)hexahydro-1H-pyrrolizine
(6c,
E ˆ
SiMe3): In the same way as the amine 5, nBuLi (1.8m in hexane, 0.48 mL,
0.86 mmol), the amine 3 (180 mg, 0.43 mmol) in hexane/Et2O 9:1 (10 mL)
and Me3SiCl (0.11 mL, 0.86 mmol), gave, after adding an excess picric acid
in EtOH and purifying by column chromatography on silica gel, eluting
with CH2Cl2/MeOH 1:0 to 98:2, the picrate salt of the amine 6c, E ˆ SiMe3
(113 mg, 62%) as needles. M.p. 145 1468C (picrate salt); Rf ˆ 0.64
(CH2Cl2/MeOH 9:1); [a]2D3 ˆ ‡5.3 (c ˆ 0.7 in CHCl3, picrate salt); IR
(picrate salt, CDCl3): nÄ ˆ 1565, 1360 cmÀ1 (NO2); 1H NMR (400 MHz,
CDCl3, picrate salt, 258C): d ˆ 0.06 [s, 9H; (CH3)3Si], 0.70 (dd, 2,3J(H,H) ˆ
14, 9.5 Hz, 1H; CHSi), 0.88 (dd, 2,3J(H,H) ˆ 14, 4 Hz, 1H; CHSi), 1.59 (brs,
1H; NH), 1.80 2.34 (m, 7H; NCH2CH2CH2CHCHCH2), 2.79 2.92 (m,
1H; NCH), 3.03 3.11 (m, 1H; NCH), 3.63 3.74 (m, 1H; NCH), 3.84
3.95 (m, 1H; NCH), 3.97 4.08 (m, 1H; NCH), 8.87 (s, 2H; Ar); 13C NMR
(100 MHz, CDCl3, picrate salt, 258C): d ˆ À1.1 (CH3), 19.8 (CH2), 24.7
(CH2), 29.3 (CH2), 34.2 (CH2), 41.9 (CH), 55.4 (CH2), 55.6 (CH2), 75.5
(CH), 126.5 (CH), 128.0 (C), 141.7 (C), 162.4 (C); MS (EI): calcd for
(1S,8R)-1-Methylhexahydro-1H-pyrrolizine (pseudoheliotridane) (5): n-
Butyllithium (1.5m in hexanes, 1.2 mL, 1.3 mmol) was added to the amine
(S)-3 (261 mg, 0.63 mmol) in dry hexane/Et2O 9:1 (10 mL) under argon at
À788C. The mixture was warmed to 258C for 4 h and was quenched with
MeOH (0.5 mL) at À788C. The mixture was warmed to 258C and sat.
aqueous NaCl (30 mL) was added. The mixture was extracted with Et2O
(2 Â 25 mL). The combined organic extracts were dried (NaSO4), evapo-
rated and purified by column chromatography on alumina, eluting with
petrol (b.p. 30 408C), then Et2O to give pyrrolizidine 5[16] (69 mg, 87%) as
an oil. An excess of picric acid in EtOH was added and the mixture was
purified by column chromatography on silica gel, eluting with MeOH/
CH2Cl2 0:1 to 1:49 to give the picrate salt of the pyrrolizidine 5. M.p.
(picrate salt) 230 2348C, lit.[16a] 234 2368C; Rf (picrate salt) ˆ 0.10
(CH2Cl2/MeOH/NH3 9:1:0.1); [a]2D3 ˆ ‡6.8 (c ˆ 0.5 in EtOH, free base);
IR (picrate salt, KBr disk): nÄ ˆ 1560, 1365 cmÀ1 (NO2); 1H NMR (400 MHz,
CDCl3, picrate salt, 258C): d ˆ 1.21 (d, 3J(H,H) ˆ 6.5 Hz, 3H; CH3), 1.80
2.33 (m, 7H; 3 Â CH2, CH), 2.82 2.92 (m, 1H; NCHAHBCH2CH), 3.02
3.12 (m, 1H; NCHAHBCH2CH2), 3.65 3.75 (m, 1H; NCHAHBCH2CH2),
3.86 3.95 (m, 1H; NCH), 3.98 4.07 (m, 1H; NCHAHBCH2CH), 8.85 (s,
2H; Ar); 13C NMR (100 MHz, CDCl3, picrate salt, 258C): d ˆ 16.7 (CH3),
24.8 (CH2), 29.3 (CH2), 33.9 (CH2), 40.0 (CH), 55.4 (CH2), 55.6 (CH2), 74.1
(CH), 126.6 (CH), 128.6 (C), 141.6 (C), 162.1 (C); MS (EI): calcd for
‡
‡
C11H23NSi: 197.1601; found: 197.1600 [M] ; m/z (%): 229 (12) [picric acid] ,
‡
‡
‡
197 (9) [M] , 124 (28) [C8H14N] , 83 (100) [C5H9N] .
(1R,8R)-1-(Trimethylstannylmethyl)hexahydro-1H-pyrrolizine (6d, E ˆ
SnMe3): In the same way as the amine 5, nBuLi (2.5m in hexane, 0.3 mL,
0.75 mmol), the amine 3 (150 mg, 0.36 mmol) in hexane/Et2O 9:1 (7.5 mL)
and Me3SnCl (0.8 mL, 1m in THF), gave, after adding an excess picric acid
in EtOH and purifying by column chromatography on silica gel, eluting
with CH2Cl2/MeOH 1:0 to 98:2, the picrate salt of the amine 6d, E ˆ SnMe3
(126 mg, 68%) as needles. M.p. 146 1488C (picrate salt); Rf ˆ 0.53
(CH2Cl2/MeOH 9:1); [a]2D3 ˆ ‡29.5 (c ˆ 0.9 in CHCl3, picrate salt); IR
(picrate salt, CDCl3): nÄ ˆ 1565, 1360 cmÀ1 (NO2); 1H NMR (400 MHz,
CDCl3, picrate salt, 258C): d ˆ 0.12 [s, 9H; (CH3)3Sn], 0.87 (dd, 2,3J(H,H) ˆ
13, 9.5 Hz, 1H; CHSn), 1.11 (dd, 2,3J(H,H) ˆ 13, 5 Hz, 1H; CHSn), 1.82
1.95 (m, 3H; 3 Â CH), 2.04 2.31 (m, 5H; 4 Â CH, NH), 2.83 2.92 (m, 1H;
NCH), 3.04 3.11 (m, 1H; NCH), 3.62 3.70 (m, 1H; NCH), 3.82 3.89 (m,
1H; NCH), 3.97 4.03 (m, 1H; NCH), 8.85 (s, 2H; Ar); 13C NMR
(100 MHz, CDCl3, picrate salt, 258C): d ˆ À9.6 (CH3), 13.5 (CH2), 24.8
(CH2), 29.3 (CH2), 35.0 (CH2), 44.0 (CH), 55.4 (CH2), 55.5 (CH2), 75.7
(CH), 126.6 (CH), 128.0 (C), 141.7 (C), 162.4 (C); MS (EI): calcd for
‡
‡
C8H15N: 125.1204; found: 125.1201 [M] ; m/z (%): 229 (4) [picric acid] ,
‡
‡
125 (51) [M] , 83 (100) [C5H9N] ; elemental analysis calcd (%) for
C14H18N4O7 (354.3): C 47.46, H 5.12, N 15.81; found: C 47.47, H 5.04, N
15.51. The chiral solvating agent (R)-(À)-2,2,2-trifluoro-1-(9-anthryl)etha-
nol[17] (0.03 mmol) split and shifted the CH3 doublet of the free base,
pseudoheliotridane (5 mg, 0.04 mmol) in CDCl3 (0.7 mL) from d ˆ 1.02 (d,
J ˆ 6.5 Hz, 3H) to d ˆ 0.69 (d, J ˆ 6.5 Hz, 3H) and d ˆ 0.67 (d, J ˆ 6.5 Hz,
3H), thereby allowing the measurement of the ee of 94%.
(1R,8R)-1-(Monodeutereomethyl)hexahydro-1H-pyrrolizine (6a, E ˆ D):
In the same way as the amine 5, nBuLi (2.5m in hexanes, 0.30 mL,
0.75 mmol), the amine 3 (150 mg, 0.36 mmol) in hexane/Et2O 9:1 (7.5 mL)
and MeOD (0.04 mL, 1.0 mmol), gave, after adding an excess picric acid in
EtOH and purifying by column chromatography on silica gel, eluting with
CH2Cl2/MeOH 1:0 to 98:2, the picrate salt of the amine 6a, E ˆ D (74 mg,
58%) as needles. M.p. 235 2368C (picrate salt); Rf ˆ 0.10 (CH2Cl2/MeOH/
NH3 9:1:0.1); [a]2D4 ˆ ‡0.95 (c ˆ 0.6 in CHCl3, picrate salt); IR (picrate salt,
CDCl3): nÄ ˆ 1570, 1365 cmÀ1 (NO2); 1H NMR (400 MHz, CDCl3, picrate
salt, 258C): d ˆ 1.18 (dt, 3J(H,H) ˆ 6.5 Hz, 2J(H,D) ˆ 2 Hz, 2H; CH2D),
‡
‡
C11H23N120Sn: 289.0863; found: 289.0863 [M] ; m/z (%): 289 (0.4) [M] , 126
(20) [C8H16N] , 124 (100) [C8H14N] .
‡
‡
(1R,8R,2'RS)-1-(2'-Hydroxy-2'-phenyl)ethylhexahydro-1H-pyrrolizine
(6e, E ˆ CH(OH)Ph): In the same way as the amine 5, nBuLi (1.9m in
hexanes, 0.56 mL, 1.06 mmol), the amine 3 (220 mg, 0.53 mmol) in hexane/
Et2O 9:1 (10 mL) and PhCHO (0.11 mL, 1.06 mmol), gave, after adding an
202
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Chem. Eur. J. 2002, 8, No. 1

Carbolithiations
195 207
excess of picric acid in EtOH and purifying by column chromatography on
silica gel, eluting with CH2Cl2/MeOH 1:0 to 98:2, the picrate salt of the
amine 6e, E ˆ CH(OH)Ph (102 mg, 41%) as a 1:1 mixture of diaster-
eomers as needles. M.p. 140 1438C (picrate salt); Rf ˆ 0.55 (CH2Cl2/
MeOH 9:1); IR (picrate salt, CHCl3): nÄ ˆ 3610 (OH), 1610, 1495 (Ar), 1565,
1365 cmÀ1 (NO2); 1H NMR (400 MHz, CDCl3, picrate salt, 258C): d ˆ
1.20 1.26 (m, 0.5H; 0.5 Â CH), 1.75 1.84 (m, 0.5H; 0.5 Â CH), 1.87
2.34 (m, 10H; 8 Â CH, NH, OH), 2.79 2.83 (m, 1H; NCH), 3.00 3.13
(m, 1H; NCH), 3.63 3.74 (m, 1H; NCH), 3.98 4.18 (m, 2H; 2 Â NCH),
4.71 4.79 (m, 1H; CHOH), 7.26 7.39 (m, 5H; Ph), 8.84 (s, 2H; Ar);
13C NMR (100 MHz, CDCl3, picrate salt, 258C): d ˆ 24.8 (CH2), 25.0 (CH2),
29.9 (CH2), 30.1 (CH2), 32.1 (CH2), 32.7 (CH2), 41.2 (CH2), 41.4 (CH2), 41.9
(CH), 42.4 (CH), 55.2 (CH2), 55.3 (CH2), 55.4 (CH2), 72.6 (CH), 72.7 (CH),
72.8 (CH), 73.0 (CH), 125.6 (CH), 126.6 (CH), 128.1 (C, CH), 128.2 (CH),
128.8 (CH), 141.6 (C), 143.8 (C) 144.0 (C), 162.3 (C); MS (EI): calcd for
chromatography on silica gel, eluting with MeOH/CH2Cl2 0:1 to 1:49 to
give an inseparable mixture of the picrate salts of 10, 11 and N-pent-4-
enylpyrrolidine (68 mg, 93%), consisting of amine 10[29] (76%, 13% ee),
amine 11 (4%) and N-pent-4-enylpyrrolidine (13%) as a powder. Rf ˆ 0.34
(CH2Cl2/MeOH 9:1); IR (picrate salt, CHCl3): nÄ ˆ 1630, 1610 (Ar), 1565,
1310 cmÀ1 (NO2); 1H NMR (400 MHz, CDCl3, picrate salt, major product,
258C): d ˆ 1.02 (d, 3J(H,H) ˆ 7 Hz, 3H; CH3), 1.21 1.33 (m, 1H;
CHAHBCHMe), 1.66 74 (m, 1H; CHAHBCHMe), 1.84 2.23 (m, 6H;
CH2CH2CH, CH2CH2CHMe), 2.37 2.47 (m, 1H; CHMe), 2.64 2.74 (m,
1H; NCHCHD), 3.22 (ddd, 2,3,3J(H,H) ˆ 13, 8, 3.5 Hz, 1H; NCHEHF), 3.42
(brd, 2J(H,H) ˆ 12 Hz, 1H; NCHCHD), 3.55 3.65 (m, 1H; NCHEHF),
3.79 3.87 (m, 1H; NCH), 8.88 (s, 2H; Ar); 13C NMR (100 MHz, CDCl3,
picrate salt, 258C): d ˆ 18.3 (CH3), 19.0 (CH2), 19.9 (CH2), 22.8 (CH2), 24.4
(CH2), 29.5 (CH), 47.7 (CH2), 54.2 (CH2), 65.9 (CH), 126.6 (CH), 128.2 (C),
141.7 (C), 162.2 (C); MS (CI): calcd for C9H18N: 140.1439; found: 140.1438
‡
‡
‡
‡
‡
C15H21NO: 231.1623; found: 231.1622 [M] ; m/z (%): 231 (20) [M] , 229
[M‡H] ; m/z (%): 140 (52) [M‡H] , 138 (42) [M À H] 96 (55), 84 (100);
elemental analysis calcd (%) for C15H20N4O7 (368.3): C 48.91, H 5.47, N
15.21; found: C 49.09, H 5.48, N 14.98.
‡
‡
(16) [picric acid] , 124 (100) [C8H14N] , 109 (86).
(2S)-1-[2-(Tributylstannyl)pyrrolidin-1-yl]-pent-4-en-1-one (7): B-Bromo-
catechol borane[15] (4.4 mL, 1.3 mmol, 0.3m in CH2Cl2) was added at room
temperature to a solution of the carbamate 1 (0.5 g, 1.1 mmol) in CH2Cl2
(10 mL). After 5 min, aq NaOH (5 mL, 2m) and 4-pentenoyl chloride
(0.59 g, 5.0 mmol) were added. The mixture was stirred for 16 h, extracted
into CH2Cl2 (3 Â 5 mL), dried (MgSO4) and evaporated. Purification by
chromatography on silica gel eluting with petrol/EtOAc 9:1 gave the
stannane (S)-7 (318 mg, 65%) as an oil. Rf ˆ 0.35 (petrol/EtOAc 9:1);
The enantioselectivity of the cyclization reaction was determined by
measuring (1H NMR) the relative peak areas of the methyl doublets of the
picrate salt of the amine 10 in the presence of the chiral solvating agent (R)-
(À)-2,2,2-trifluoro-1-(9-anthryl)ethanol.[17]
(1S,9R)-1-Methyloctahydroindolizine (11): The stannane
8 (40 mg,
0.09 mmol) in hexane/Et2O/TMEDA (2 mL, 4:1:1) was treated with n-
butyllithium (0.17 mL, 0.37 mmol, 2.2m in hexanes) at room temperature.
After 6 h, MeOH (0.5 mL) and picric acid (0.45 mL, 0.09 mmol, 0.2m in
EtOH) were added. The mixture was absorbed on silica gel and purified by
column chromatography on silica gel, eluting with MeOH/CH2Cl2 0:1 to
1:49 to give an inseparable mixture of the picrate salts of 10, 11 and N-pent-
4-enylpyrrolidine (33 mg, 97%), consisting of amine 10 (7.5%, 0% ee),
amine 11[29] (68.5%, 0% ee) and N-pent-4-enylpyrrolidine (21%) as a
powder. Rf ˆ 0.34 (CH2Cl2/MeOH 9:1); IR (picrate salt, CHCl3): nÄ ˆ 1630,
1610 (Ar), 1565, 1320 cmÀ1 (NO2); 1H NMR (400 MHz, CDCl3, picrate salt,
major product, 258C): d ˆ 1.05 (d, 3J(H,H) ˆ 7 Hz, 3H; CH3), 1.88 2.30
(m, 9H; CH2CH2CHMeCHCH2CH2), 2.43 2.54 (m, 1H; NCH), 2.60 2.72
(m, 1H; NCHAHB), 2.76 2.88 (m, 1H; NCHCHD), 3.82 3.95 (m, 2H;
NCHAHB, NCHCHD), 8.87 (s, 2H; Ar); 13C NMR (100 MHz, CDCl3, picrate
salt, 258C): d ˆ 18.4 (CH3), 19.4 (CH2), 22.9 (CH2), 26.6 (CH2), 31.6 (CH2),
33.5 (CH), 52.9 (CH2), 53.9 (CH2), 73.5 (CH), 126.7 (CH), 128.2 (C), 141.7
[a]2D2 ˆ ‡188 (c ˆ 1.48 in CHCl3); IR: nÄ ˆ 1615 cmÀ1 (C O); 1H NMR
ˆ
(300 MHz, CDCl3, 258C): d ˆ 0.82 0.95 [m, 15H; Sn(CH2CH2CH2CH3)3],
1.22 1.38 [m, 6H; Sn(CH2CH2CH2)3], 1.43 1.58 [m, 6H; Sn(CH2CH2)3],
1.86 2.02 (m, 3H; CH2CHAHB), 2.11 2.20 (m, 1H; CH2CHAHB), 2.31
ˆ
2.46 (m, 4H; CH2CO, CH2C ), 3.32 3.41 (m, 2H; 2 Â NCH), 3.47 3.55
A
B
(m, 1H; NCH), 5.00 (d, 3J(H,H) ˆ 9.5 Hz, 1H; CH H ), 5.08 (d,
ˆ
3
A
B
J(H,H) ˆ 16.5 Hz, 1H; CH H ), 5.82 5.95 (m, 1H; CH ); 13C NMR
ˆ
ˆ
(75 MHz, CDCl3, 258C): d ˆ 10.3 (CH2), 13.7 (CH3), 27.5 (CH2), 27.6 (CH2),
29.1 (CH2), 29.2 (CH2), 29.6 (CH2), 34.0 (CH2), 46.9 (CH), 47.2 (CH2), 114.9
(CH2), 137.8 (CH), 169.1 (C O); MS (CI): calcd for C21H41NO120Sn:
ˆ
‡
‡
443.2210; found: 443.2217 [M] ; m/z (%): 443 (0.5) [M] , 386 (56) [M À
‡
C4H9] , 70 (100).
(2S)-N-(Pent-4-enyl)-2-(tributylstannyl)pyrrolidine (8): LiAlH4 (0.70 mL,
0.70 mmol, 1m in Et2O) was added to a solution of the amide 7 (222 mg,
0.50 mmol) at 08C in Et2O (5 mL). After 20 min at 08C, MeOH (0.5 mL)
was added and the mixture was absorbed on alumina. Column chromatog-
raphy on alumina, eluting with petrol/EtOAc 9:1 gave the stannane (S)-8
(191 mg, 90%) as an oil. Rf ˆ 0.17 (petrol/EtOAc 4:1); [a]2D0 ˆ ‡67.5 (c ˆ
‡
(C), 161.9 (C); MS (EI): calcd for C9H18N: 139.1361; found: 139.1362 [M] ;
‡
‡
m/z (%): 139 (5) [M] , 138 (7) [M À H] 96 (7), 84 (100); elemental analysis
calcd (%) for C15H20N4O7 (368.3): C 48.91, H 5.47, N 15.21; found: C 48.87,
H 5.46, N 14.80.
1.20 in CHCl3); IR: nÄ ˆ 1630 cmÀ1 (C C); 1H NMR (400 MHz, C6D6,
ˆ
The enantioselectivity of the cyclization reaction was determined by
measuring (1H NMR) the relative peak areas of the methyl doublets of the
free base of the amine 11 in the presence of the chiral solvating agent (R)-
(À)-2,2,2-trifluoro-1-(9-anthryl)ethanol.[17]
258C): d ˆ 0.92 1.20 [m, 15H; Sn(CH2CH2CH2CH3)3], 1.43 1.60 [m, 6H;
Sn(CH2CH2CH2)], 1.67 1.80 [m, 6H; Sn(CH2CH2], 1.80 2.33 (m, 10H;
5  CH2), 2.53 (dd, 2,3J(H,H) ˆ 11, 7.5 Hz, 1H; CHAHBN), 2.95 (ddd,
2,3,3J(H,H) ˆ 11, 8, 7.5 Hz, 1H; CHAHBN), 3.03 (dd, 3,3J(H,H) ˆ 8, 7.5 Hz,
3,2
A
B
ˆ
1H; NCHSn), 5.10 (dd, J(H,H) ˆ 10, 2 Hz, 1H; CH H ), 5.17 (dd,
O-(2'-Tetrahydropyranyl)-5-phenylthiopent-4-ynol (12): nBuLi (7.5 mL,
18.80 mmol, 2.5m in hexanes) was added at 08C to a solution of alkyne
O-(2'-tetrahydropyranyl)-pent-4-ynol[26] (3.0 g, 17.9 mmol) in THF
(90 mL). After 1 h, a pre-mixed solution of PhSSPh (4.65 g, 21.5 mmol)
and MeI (3.0 g, 21.3 mmol) in THF (75 mL) was added over 45 min. After
30 min, the mixture was warmed to room temp and stirred for 18 h. Water
(75 mL) was added and the mixture was extracted into CH2Cl2 (3 Â 40 mL),
dried (MgSO4), evaporated and purified by column chromatography on
silica gel, eluting with petrol/EtOAc 19:1 to give the alkyne 12 (4.55 g,
92%) as an oil. Rf ˆ 0.38 (petrol/EtOAc 10:1); IR: nÄ ˆ 1580, 1475 cmÀ1
(Ar); 1H NMR (400 MHz, CDCl3, 258C): d ˆ 1.48 1.86 (m, 6H; 3  CH2),
J(H,H) ˆ 17, 2 Hz, 1H; CH H ), 5.94 (ddt, 3,3,3J(H,H) ˆ 17, 10, 6.5 Hz,
3,2
A
B
ˆ
1H; CH ); 13C NMR (100 MHz, C6D6, 258C): d ˆ 9.2 (CH2), 13.7 (CH3),
24.9 (CH2), 27.7 (CH2), 28.7 (CH2), 29.6 (CH2), 29.7 (CH2), 32.0 (CH2), 53.8
(CH2), 56.5 (CH2), 57.7 (CH), 114.4 (CH2), 138.8 (CH); MS (EI): calcd for
ˆ
C21H43N120Sn: 429.2417; found: 429.2418 [M] ; m/z (%): 429 (0.5) [M] , 176
‡
‡
(35), 138 (100).
Alternatively, the amine 8 could be prepared from 1 by deprotection and
reductive amination: B-Bromocatecholborane[15] (2.2 mL, 0.66 mmol, 0.3m
in CH2Cl2) was added to carbamate (S)-1[14] (250 mg, 0.54 mmol) in CH2Cl2
(5 mL) at room temperature. After 10 min the mixture was washed rapidly
with aq 2m NaOH (3 Â 5 mL), dried (MgSO4) and evaporated. The residue
was dissolved in MeNO2 (2.5 mL) and NaBH3CN (126 mg, 2.0 mmol),
4-pentenal (92 mg, 1.1 mmol) and 4 ä molecular sieves were added at room
temperature. After 15 min the mixture was absorbed on alumina and
purified by column chromatography on alumina, eluting with petrol/EtOAc
9:1 to give the stannane (S)-8 (143 mg, 62%) as an oil, data identical to
above.
1.90 (quintet, 3J(H,H) ˆ 6.5 Hz, 2H; CH2CH2C ), 2.59 (t, 3J(H,H) ˆ
ꢁ
6.5 Hz, 2H; CH2), 3.47 3.55 (m, 2H; CHAHBO, CHCHDO), 3.84 3.91
(m, 2H; CHAHBO, CHCHDO), 4.62 (t, 3J(H,H) ˆ 3.5 Hz, 1H; CHO), 7.19 (t,
3J(H,H) ˆ 7.5 Hz, 1H; Ar), 7.32 (t, 3J(H,H) ˆ 7.5 Hz, 2H; Ar), 7.41 (d,
3J(H,H) ˆ 7.5 Hz, 2H; Ar); 13C NMR (100 MHz, CDCl3, 258C): d ˆ 17.3
(CH2), 19.5 (CH2), 25.5 (CH2), 28.9 (CH2), 30.7 (CH2), 62.2 (CH2), 65.0 (CS),
65.8 (CH2), 98.8 (CH), 99.3 (C), 125.8 (CH), 126.1 (CH), 129.1 (CH), 133.6
‡
(C); MS (CI): calcd for C16H21O2S: 277.1262; found: 277.1264 [M‡H] ; m/z
(1R,9R)-1-Methyloctahydroindolizine (10): The stannane
8 (84 mg,
‡
(%): 277 (18%) [M‡H] , 193 (13), 102 (100); elemental analysis calcd (%)
0.20 mmol) in hexane/Et2O (3 mL, 4:1) was treated with n-butyllithium
(0.24 mL, 0.63 mmol, 2.5m in hexanes) at room temperature. After 6 h,
MeOH (0.5 mL) and picric acid (1.0 mL, 0.2 mmol, 0.2m in EtOH) were
added. The mixture was absorbed on silica gel and purified by column
for C16H20O2S (276.4): C 69.53, H 7.29; found: C 69.97, H 7.57.
E-O-(2'-Tetrahydropyranyl)-5-phenylthiopent-4-enol (13): Alkyne 12
(3.00 g, 10.9 mmol) in THF (30 mL) was added to a suspension of LiAlH4
Chem. Eur. J. 2002, 8, No. 1
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
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203

I. Coldham et al.
FULL PAPER
(800 mg, 21.0 mmol) in THF (20 mL). After heating at 40 458C for 3 h, the
mixture was cooled to room temperature and stirred for 16 h. MeOH
(5 mL) and water (50 mL) were added and the mixture was extracted into
CH2Cl2 (3 Â 50 mL), dried (MgSO4) and evaporated. Purification by
column chromatography on silica gel, eluting with petrol/EtOAc 9:1 gave
the alkene E-13 (2.81 g, 93%) as an oil. Rf ˆ 0.38 (petrol/EtOAc 10:1); IR:
13C NMR (100 MHz, CDCl3, 258C): d ˆ 25.5 (CH2), 42.9 (CH2), 123.3
(CHS), 126.5 (CH), 128.9 (CH), 129.0 (CH), 133.2 (CH), 135.7 (C), 201.3
‡
(CO); MS (EI): calcd for C11H12OS: 192.0609; found: 192.0608 [M] ; m/z
‡
(%): 192 (25) [M] , 110 (80), 86 (100).
Z-5-(Phenylthio)pent-4-enal (14): In the same way as the aldehyde E-14,
the sulfide Z-13 (4.17 g, 15.0 mmol) in MeOH (200 mL) and water (4 mL)
and TsOH ¥ H2O (100 mg, 0.53 mmol) gave, after purification by column
chromatography on silica gel, eluting with petrol/EtOAc 4:1, the alcohol
(2.91 g, 100%) as an oil. Rf ˆ 0.48 (petrol/EtOAc 1:1); IR: nÄ ˆ 3350 (O-H),
nÄ ˆ 1730 (C C), 1575, 1480 cmÀ1 (Ar); 1H NMR (400 MHz, CDCl3, 258C):
ˆ
d ˆ 1.49 1.87 (m, 8H; 4  CH2), 2.28 (dtd, 3,3,4J(H,H) ˆ 7, 6.5, 1 Hz, 2H;
CH2C ), 3.43 (dt, 3,3J(H,H) ˆ 9.5, 6.5 Hz, 1H; CHAHBO), 3.48 3.54 (m,
ˆ
1H; CHCHDO), 3.78 (dt, 3,3J(H,H) ˆ 9.5, 6.5 Hz, 1H; CHAHBO), 3.87 (ddd,
1745 (C C), 1575, 1475 cmÀ1 (Ar); 1H NMR (400 MHz, CDCl3, 258C): d ˆ
ˆ
2,3J(H,H) ˆ 11, 7.5, 3.5 Hz, 1H; CHCHDO), 4.59 (t, 3J(H,H) ˆ 3.5 Hz, 1H;
3,3
ˆ
1.63 (s, 1H; OH), 1.73 (tt, J(H,H) ˆ 7, 6.5 Hz, 2H; CH2CH2C ), 2.35 (q,
3,3
CHO), 6.00 (dt, J(H,H) ˆ 14.5, 7 Hz, 1H; CH ), 6.18 (dt, 3,4J(H,H) ˆ
ˆ
3
3
ˆ
J(H,H) ˆ 7 Hz, 2H; CH2C ), 3.70 (t, J(H,H) ˆ 6.5 Hz, 2H; CH2O), 5.84
14.5, 1 Hz, 1H; CHS), 7.17 7.21 (m, 1H; Ar), 7.27 7.33 (m, 4H; Ar);
13C NMR (100 MHz, CDCl3, 258C): d ˆ 19.7 (CH2), 25.5 (CH2), 29.1 (CH2),
29.8 (CH2), 30.7 (CH2), 62.4 (CH2), 66.7 (CH2), 98.9 (CHO), 121.4 (CHS),
126.1 (CH), 128.5 (CH), 128.9 (CH), 136.4 (C), 136.5 (CH); MS (CI): calcd
3
(dt, 3,3J(H,H) ˆ 9.5, 7 Hz, 1H; CH ), 6.24 (d, J(H,H) ˆ 9.5 Hz, 1H; CHS),
7.18 7.24 (m, 1H; Ar), 7.26 7.37 (m, 4H; Ar); 13C NMR (100 MHz,
CDCl3, 258C): d ˆ 25.4 (CH2), 31.8 (CH2), 62.2 (CH2), 123.7 (CHS), 126.3
(CH), 128.9 (CH), 129.0 (CH), 132.2 (CH), 136.1 (C); MS (CI): calcd for
ˆ
‡
for C16H26NO2S: 296.1684; found: 296.1684 [M‡NH4] ; m/z (%): 296 (10)
‡
C11H18NOS: 212.1109; found: 212.1104 [M‡NH4] ; m/z (%): 212 (55)
‡
‡
[M‡NH4] , 278 (3) [M] ,102 (100); elemental analysis calcd (%) for
‡
‡
[M‡NH4] , 195 (100) [M‡H] , 102 (41); elemental analysis calcd (%) for
C16H22O2S (278.4): C 69.02, H 7.96; found: C 68.62, H 8.20.
C11H14OS (194.3): C 68.00, H 7.26; found: C 68.48, H 7.54.
Z-O-(2'-Tetrahydropyranyl)-5-phenylthiopent-4-enol
(13):
DIBAL
In the same way as the aldehyde E-14, oxalyl chloride (0.60 mL, 6.7 mmol)
in CH2Cl2 (15 mL), DMSO (1.1 mL, 13.4 mmol) and the alcohol (1.3 g,
6.70 mmol) in CH2Cl2 (2 mL) then Et3N (4.1 mL, 30.0 mmol) gave, after
purification by column chromatography on silica gel, eluting with petrol/
(30 mL, 1m in hexane) over 45 min was added at À188C to a solution of
the alkyne 12 (4.85 g, 17.6 mmol) in hexane (150 mL). The mixture was
warmed to 08C for 1 h, and then to room temperature for 16 h. MeOH
(2 mL) then aq NaOH (60 mL, 1m) were added and the mixture was
extracted into hexane (3 Â 50 mL), dried (MgSO4) and evaporated.
Purification by column chromatography on silica gel, eluting with petrol/
EtOAc 9:1, the aldehyde Z-14 (821 mg, 64%) as an oil. Rf ˆ 0.37 (petrol/
À1
EtOAc 10:1); IR: nÄ ˆ 1730 (C O, C C), 1590, 1480 cm (Ar); 1H NMR
ˆ
ˆ
(400 MHz, CDCl3, 258C): d ˆ 2.56 2.62 (m, 4H; CH2CH2), 5.76 5.84 (m,
EtOAc 9:1 gave the alkene Z-13 (4.83 g, 99%) as an oil. Rf ˆ 0.38 (petrol/
3
ˆ
1H; CH ), 6.28 (d, J(H,H) ˆ 10.5 Hz, 1H; CHS), 7.21 7.26 (m, 1H; Ar),
EtOAc 10:1); IR: nÄ ˆ 1730 (C C), 1580, 1480 cm (Ar); 1H NMR
À1
ˆ
7.29 7.38 (m, 4H; Ar), 9.81 (s, 1H; CHO); 13C NMR (100 MHz, CDCl3,
258C): d ˆ 21.9 (CH2), 43.0 (CH2), 125.0 (CHS), 126.5 (CH), 129.0 (CH),
129.1 (CH), 130.1 (CH), 135.7 (C), 201.6 (CO); MS (ES): calcd for
(400 MHz, CDCl3, 258C): d ˆ 1.48 1.94 (m, 8H; 4  CH2), 2.36 (dt,
3,3
J(H,H) ˆ 7.5, 6.5 Hz, 2H; CH2C ), 3.45 (dt, 3,3J(H,H) ˆ 10, 6.5 Hz, 1H;
ˆ
CHAHBO), 3.47 3.54 (m, 1H; CHCHDO), 3.79 (dt, 3,3J(H,H) ˆ 10, 6.5 Hz,
‡
C11H13OS: 193.0687; found: 193.0684 [M‡H] ; m/z (%): 193 (100)
1H; CHAHBO), 3.84 3.91 (m, 1H; CHCHDO), 4.60 (t, 3J(H,H) ˆ 3.5 Hz,
‡
[M‡H] , 118 (87).
1H; CHO), 5.84 (dt, J(H,H) ˆ 9, 7.5 Hz, 1H; CH ), 6.22 (d, 3J(H,H) ˆ
3,3
ˆ
9 Hz, 1H; CHS), 7.19 (t, 3J(H,H) ˆ 7 Hz, 1H; Ar), 7.26 7.35 (m, 4H; Ar);
13C NMR (100 MHz, CDCl3, 258C): d ˆ 19.6 (CH2), 25.5 (CH2), 25.9 (CH2),
29.1 (CH2), 30.7 (CH2), 62.2 (CH2), 66.8 (CH2), 98.9 (CHO), 123.2 (CHS),
126.1 (CH), 128.7 (CH), 129.0 (CH), 132.7 (CH), 136.4 (C); MS (CI): calcd
E-(2S)-N-(5-Phenylthiopent-4-enyl)-2-(tributylstannyl)pyrrolidine (E-15):
In the same way as the alkene E-13, LiAlH4 (90 mg, 2.4 mmol) and the
alkyne 18 (388 mg, 0.73 mmol) gave, after purification by column
chromatography on alumina, eluting with petrol/EtOAc 10:1, the stannane
E-15 (314 mg, 80%) as an oil. Rf ˆ 0.11 (petrol/EtOAc 4:1); [a]2D0 ˆ ‡55.3
‡
for C16H26NO2S: 296.1684; found: 296.1685 [M‡NH4] ; m/z (%): 296 (7)
À1
(c ˆ 1.14 in CHCl3); IR: nÄ ˆ 1740 (C C), 1585, 1480 cm (Ar); 1H NMR
‡
‡
ˆ
[M‡NH4] , 278 (2) [M] , 102 (100); elemental analysis calcd (%) for
(400 MHz, CDCl3, 258C): d ˆ 0.86 0.93 [m, 15H; Sn(CH2CH2CH2CH3)3],
C16H22O2S (278.4): C 69.02, H 7.96; found: C 69.10, H 8.27.
1.26 1.37 [m, 6H; Sn(CH2CH2CH2)3], 1.45 1.52 [m, 6H; Sn(CH2CH2)3],
E-5-(Phenylthio)pent-4-enal (14): Water (2.6 mL) and TsOH ¥ H2O
(100 mg, 0.53 mmol) were added at room temperature to a solution of
the sulfide E-13 (2.60 g, 9.60 mmol) in MeOH (100 mL). After 16 h, K2CO3
(150 mg) and water (100 mL) were added. The mixture was extracted into
CH2Cl2 (3 Â 50 mL), dried (MgSO4) and evaporated. Purification by
column chromatography on silica gel, eluting with petrol/EtOAc 4:1 gave
1.59 2.90 (m, 13H; 6  CH2, CH), 5.95 (dt, 3,3J(H,H) ˆ 15, 6.5 Hz, 1H;
3
ˆ
CH ), 6.16 (d, J(H,H) ˆ 15 Hz, 1H; CHS), 7.16 7.24 (m, 1H; Ar), 7.27
7.34 (m, 4H; Ar); 13C NMR (100 MHz, CDCl3, 258C): d ˆ 9.3 (CH2), 13.7
(CH3), 24.5 (CH2), 26.8 (CH2), 27.5 (CH2), 27.8 (CH2), 29.3 (CH2), 31.1
(CH2), 54.0 (CH2), 56.3 (CH2), 57.7 (CH), 121.6 (CH), 126.1 (CH), 128.6
(CH), 128.9 (CH), 134.7 (CH), 136.4 (C); MS (CI): calcd for C27H47NS120Sn:
the alcohol (1.86 g, 100%) as an oil. Rf ˆ 0.48 (petrol/EtOAc 1:1); IR: nÄ ˆ
‡
‡
538.2529; found: 538.2530 [M‡H] ; m/z (%): 538 (18) [M‡H] , 308 (33),
À1
3350 (O-H), 1740 (C C), 1540, 1480 cm (Ar); 1H NMR (400 MHz,
ˆ
246 (100).
3
CDCl3, 258C): d ˆ 1.44 (s, 1H; OH), 1.72 (quintet, J(H,H) ˆ 6.5 Hz, 2H;
CH2CH2C ), 2.28 (qd, 3,4J(H,H) ˆ 6.5, 1.5 Hz, 2H; CH2C ), 3.69 (t,
ˆ
ˆ
Z-(2S)-N-(5-Phenylthiopent-4-enyl)-2-(tributylstannyl)pyrrolidine (15): In
the same way as the alkene Z-13, DIBAL (0.65 mL, 1m in hexane) and the
alkyne 18 (169 mg, 0.32 mmol) gave, after purification by column
chromatography on alumina, eluting with petrol/EtOAc 10:1, the alkene
3J(H,H) ˆ 6.5 Hz, 2H; CH2O), 5.98 (dt, 3,3J(H,H) ˆ 14.5, 6.5 Hz, 1H;
CH ), 6.20 (dt, 3,4J(H,H) ˆ 14.5, 1.5 Hz, 1H; CHS), 7.17 7.22 (m, 1H; Ar),
ˆ
7.27 7.36 (m, 4H; Ar); 13C NMR (100 MHz, CDCl3, 258C): d ˆ 29.4 (CH2),
31.9 (CH2), 62.2 (CH2), 121.8 (CHS), 126.2 (CH), 128.6 (CH), 129.0 (CH),
135.9 (CH), 136.2 (C); MS (CI): calcd for C11H18NOS: 212.1109; found:
Z-15 (101 mg, 59%) as an oil. Rf ˆ 0.13 (petrol/EtOAc 4:1); [a]2D0 ˆ ‡46
À1
(c ˆ 0.98, CHCl3); IR: nÄ ˆ 1760 (C C), 1605, 1480 cm (Ar); 1H NMR
ˆ
‡
‡
‡
(400 MHz, CDCl3, 258C): d ˆ 0.87 0.94 [m, 15H; Sn(CH2CH2CH2CH3)3],
1.26 1.38 [m, 6H; Sn(CH2CH2CH2)3], 1.46 1.54 [m, 6H; Sn(CH2CH2)3],
1.59 3.00 (m, 13H; 6  CH2, CH), 5.80 (dt, 3,3J(H,H) ˆ 8.5, 7 Hz, 1H;
212.1106 [M‡NH4] ; m/z (%): 212 (52) [M‡NH4] , 195 (100) [M ‡ H] ,
102 (41); elemental analysis calcd (%) for C11H14OS (194.3): C 68.00, H
7.26; found: C 68.00, H 7.46.
CH ), 6.24 (d, 3J(H,H) ˆ 8.5 Hz, 1H; CHS), 7.20 (t, 3J(H,H) ˆ 7 Hz, 1H;
ˆ
DMSO (1.6 mL, 20.0 mmol), followed by the above alcohol (1.92 g,
9.90 mmol) in CH2Cl2 (2 mL), was added to a solution of oxalyl chloride
(0.90 mL, 10.0 mmol) in CH2Cl2 (25 mL) at À608C. After 15 min at
À608C, Et3N (6.2 mL, 45.0 mmol) was added and the mixture was stirred
for a further 5 min then warmed to room temperature. Water (50 mL) was
added and the mixture was extracted into CH2Cl2 (3 Â 40 mL), dried
(MgSO4) and evaporated. Purification by column chromatography on silica
gel, eluting with petrol/EtOAc 9:1 gave the aldehyde E-14 (1.31 g, 69%) as
Ar), 7.27 7.34 (m, 4H; Ar); 13C NMR (100 MHz, CDCl3, 258C): d ˆ 9.7
(CH2), 13.7 (CH3), 24.4 (CH2), 27.0 (CH2), 27.5 (CH2), 27.6 (CH2), 29.2
(CH2), 31.1 (CH2), 47.2 (CH2), 53.8 (CH2), 57.7 (CH), 123.9 (CH), 126.1
(CH), 128.7 (CH), 128.8 (CH), 131.7 (CH), 136.1 (C); MS (CI): calcd for
C27H47NS120Sn: 538.2529; found: 538.2533 [M‡H] ; m/z (%): 538 (4)
‡
‡
[M‡H] , 248 (100), 140 (95); elemental analysis calcd (%) for C27H47NSSn
(536.4): C 60.45, H 8.83, N 2.61; found: C 60.63, H 9.21, N 2.51.
ˆ
ˆ
an oil. Rf ˆ 0.35 (petrol/EtOAc 10:1); IR: nÄ ˆ 1740 (C O, C C), 1540,
Alternatively, the amines E- and Z-15 could be prepared from 1 by
deprotection and reductive amination with 14: In the same way as the
amine 8, the stannane 1 (250 mg, 0.54 mmol), B-bromocatecholborane
(2.2 mL, 0.66 mmol, 0.3m in CH2Cl2) then NaBH3CN (126 mg, 2.0 mmol) in
MeNO2 (2.5 mL) and the aldehyde E- or Z-14 (211 mg, 1.1 mmol) gave,
1480 cmÀ1 (Ar); 1H NMR (400 MHz, CDCl3, 258C): d ˆ 2.48 (q, 3J(H,H) ˆ
3
ˆ
ˆ
6.5 Hz, 2H; CH2C ), 2.59 (t, J(H,H) ˆ 6.5 Hz, 2H; CH2CH2C ), 5.92 (dt,
J(H,H) ˆ 14, 6.5 Hz, 1H; CH ), 6.22 (d, 3J(H,H) ˆ 14 Hz, 1H; CHS),
3,3
ˆ
7.18 7.24 (m, 1H; Ar), 7.27 7.36 (m, 4H; Ar) and 9.82 (s, 1H; CHO);
204
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0801-0204 $ 17.50+.50/0
Chem. Eur. J. 2002, 8, No. 1

Carbolithiations
195 207
after purification by column chromatography on alumina, eluting with
petrol/EtOAc 10:1, the stannane E-15 (209 mg, 72%) or Z-15 (198 mg,
0.37 mmol, 69%), data identical to above.
(CH2), 28.5 (CH2), 29.3 (CH2), 31.4 (CH2), 35.4 (CH), 37.7 (CH2), 41.9
(CH), 52.5 (CH2), 53.8 (CH2), 54.4 (CH2), 54.7 (CH2), 66.6 (CH), 68.3 (CH),
125.3 (CH), 125.5 (CH), 127.7 (CH), 127.8 (CH), 128.8 (CH), 138.2 (C),
138.3 (C); MS (CI): calcd for C15H22NS: 248.1473; found: 248.1468
(2S)-1-[2-(Tributylstannyl)pyrrolidin-1-yl]-pent-4-yn-1-one (16): In the
same way as the amide 7, B-bromocatechol borane[15] (4.4 mL, 1.2 mmol,
0.3m in CH2Cl2), the carbamate (S)-1[14] (0.5 g, 1.1 mmol) in CH2Cl2
(10 mL) and 4-pentynoyl chloride (392 mg, 4.0 mmol) gave, after purifica-
tion by column chromatography on silica gel eluting with petrol/EtOAc 9:1,
‡
‡
‡
[M‡H] ; m/z (%): 248 (100) [M‡H] , 140 (62) [C9H18N] , 138 (60)
‡
[M À C6H5S] . The enantioselectivity of the cyclization was determined by
treating the mixture of amines 19 and 20 with Raney nickel in EtOH (608C,
30 min, 90%) to give the amines 10 and 11.
the stannane 16 (279 mg, 59%) as an oil. Rf ˆ 0.36 (petrol/EtOAc 4:1);
Cyclization of the stannanes E- or Z-15 in the presence of TMEDA: The
stannane E- or Z-15 (1 mol equiv, 0.1m) in hexane/Et2O/TMEDA 4:1:1 was
treated with n-butyllithium (3 mol equiv) at room temperature. After 2 h,
MeOH (excess) was added, the solvent was removed under reduced
pressure and the residue was passed through a plug of alumina, eluting with
petrol/EtOAc 4:1 to give the amine 20 as an oil. Treatment with Raney
nickel in EtOH (608C, 30 min), filtration and treatment with picric acid
(1 mol equiv) gave, after chromatography on silica gel, eluting with MeOH/
CH2Cl2 0:1 to 1:49, the amine 11 (71 73%), data identical to above.
À1
[a]2D2 ˆ ‡248 (c ˆ 1.2 in CHCl3); IR: nÄ ˆ 3305 ( C-H), 1615 cm (C O);
1H NMR (400 MHz, CDCl3, 258C): d ˆ 0.80 0.90 [m, 15H;
Sn(CH2CH2CH2CH3)3], 1.23 1.33 [m, 6H; Sn(CH2CH2CH2)3], 1.41 1.52
ꢁ
ˆ
A
B
ꢁ
[m, 6H; Sn(CH2CH2)3], 1.84 2.00 (m, 4H; CH, CH2CH H ), 2.12 2.19
(m, 1H; CHAHB), 2.46 2.57 (m, 4H; CH2CH2C ), 3.31 3.39 (m, 2H; 2 Â
ꢁ
NCH), 3.47 3.54 (m, 1H; NCH); 13C NMR (100 MHz, CDCl3, 258C): d ˆ
10.2 (CH2), 13.8 (CH3), 14.6 (CH2), 27.5 (CH2), 27.6 (CH2), 29.2 (CH2), 29.6
(CH2), 33.6 (CH2), 47.0 (CH), 47.2 (CH2), 68.6 (CH), 83.8 (C), 167.5 (CO);
MS (EI): calcd for C21H39NO120Sn: 441.2054; found: 441.2054 [M] ; m/z
‡
(2S)-N-(Prop-2-ynyl)-2-(tributylstannyl)pyrrolidine (24): B-Bromocate-
chol borane[15] (4.4 mL, 0.3m in CH2Cl2, 1.32 mmol) was added to the
carbamate (S)-1[14] (0.5 g, 1.1 mmol) in CH2Cl2 (10 mL) at room temper-
ature. After 10 min, aqueous NaOH (10 mL, 2m) was added, followed by
propargyl bromide (0.12 mL, 1.1 mmol, 80% w/w in PhMe). After 75 min,
the organic layer was separated and the aqueous layer was extracted with
CH2Cl2 (3 Â 10 mL). The combined organic extracts were dried (MgSO4),
absorbed on alumina and purified by column chromatography on alumina,
eluting with petrol/EtOAc 1:0 to 9:1 to give the alkyne 24 (280 mg, 65%) as
an oil. Rf ˆ 0.65 (petrol/EtOAc 4:1); [a]2D2 ˆ ‡93.4 (c ˆ 3.5 in CHCl3); IR:
‡
(%): 441 (5) [M] , 384 (100), 382 (78); elemental analysis calcd (%) for
C21H39NOSn (440.3): C 57.29, H 8.93, N 3.18; found: C 57.40, H 9.27, N 3.14.
(2S)-N-(Pent-4-ynyl)-2-(tributylstannyl)pyrrolidine (17): In the same way
as the amine 8, the amide 16 (183 mg, 0.42 mmol) and LiAlH4 (0.60 mL,
0.60 mmol, 1m in Et2O) gave, after purification by column chromatography
on alumina, eluting with petrol/EtOAc 19:1, the stannane 17 (151 mg,
84%) as an oil. Rf ˆ 0.18 (petrol/EtOAc 4:1); [a]2D2 ˆ ‡73.1 (c ˆ 0.73 in
CHCl3); IR: nÄ ˆ 3310 cmÀ1 ( C-H); 1H NMR (400 MHz, CDCl3, 258C):
ꢁ
d ˆ 0.81 0.98 [m, 15H; Sn(CH2CH2CH2CH3)3], 1.24 1.35 [m, 6H;
nÄ ˆ 3320 cmÀ1 ( C-H); 1H NMR (300 MHz, CDCl3, 258C): d ˆ 0.82 0.95
ꢁ
Sn(CH2CH2CH2)3], 1.41 1.56 [m, 6H; Sn(CH2CH2)3], 1.68 1.90 (m, 5H;
4
5  CH), 1.93 (t, J(H,H) ˆ 2 Hz, 1H; CH), 1.94 2.07 (m, 2H; 2  CH),
[m, 15H; Sn(CH2CH2CH2CH3)3], 1.30 [sextet, 3J(H,H) ˆ 7Hz, 6H;
ꢁ
2.09 2.33 (m, 3H; 3 Â CH), 2.35 2.46 (m, 1H; CH), 2.79 3.03 (m, 2H;
2  CH); 13C NMR (100 MHz, CDCl3, 258C): d ˆ 9.2 (CH2), 13.7 (CH3),
16.5 (CH2), 24.5 (CH2), 27.5 (CH2), 27.7 (CH2), 29.3 (CH2), 29.4 (CH2), 53.9
(CH2), 55.7 (CH2), 57.6 (CH), 68.5 (CH), 83.5 (C); MS (EI): calcd for
C21H41N120Sn: 427.2261; found 427.2250 [M] ; m/z (%): 427 (6) [M] , 368
(42), 134 (100); elemental analysis calcd (%) for C21H41NSn (426.3): C
59.17, H 9.69, N 3.29; found: C 59.43, H 10.13, N 3.21.
Sn(CH2CH2CH2)3], 1.43 1.58 [m, 6H; Sn(CH2CH2)3], 1.70 1.90 (m, 3H;
4
ꢁ
3  CH), 1.96 2.10 (m, 1H; CH), 2.18 (t, J(H,H) ˆ 2.5 Hz, 1H; CH), 2.26
(q, 3J(H,H) ˆ 8.5 Hz, 1H; CH), 2.47 2.53 (m, 1H; CH), 2.93 3.00 (m, 1H;
CH), 3.36 (dd, 2,4J(H,H) ˆ 17, 2.5 Hz, 1H; NCH H C C), 3.64 (dd,
A
B
ꢁ
‡
‡
2,4
A
B
J(H,H) ˆ 17, 2.5 Hz, 1H; NCH H C C); 13C NMR (75 MHz, CDCl3,
ꢁ
258C): d ˆ 8.7 (CH2), 13.7 (CH3), 24.8 (CH2), 27.5 (CH2), 29.3 (CH2), 29.9
(CH2), 43.0 (CH2), 53.0 (CH2), 53.7 (CH), 72.6 (CH), 79.2 (C); MS (CI):
calcd for C19H38N120Sn: 400.2026; found: 400.2028 [M‡H] ; m/z (%): 400
‡
(2S)-N-(5-Phenylthiopent-4-ynyl)-2-(tributylstannyl)pyrrolidine
(18):
‡
‡
‡
(2.8) [M‡H] , 308 (3.0), 108 (13) [M À SnBu3] , 70 (100) [C4H8N] .
nBuLi (0.39 mL, 0.98 mmol, 2.5m in hexanes) was added at 08C to a
solution of the alkyne 17 (378 mg, 0.89 mmol) in Et2O (5 mL). After
90 min, a pre-mixed solution of PhSSPh (243 mg, 1.07 mmol) and MeI
(0.06 mL, 0.98 mmol) in THF (10 mL) was added. The mixture was allowed
to warm to room temperature. After 16 h, the mixture was absorbed on
alumina and purified by column chromatography on alumina, eluting with
petrol/EtOAc 10:1 to give the alkyne 18 (312 mg, 66%) as an oil. Rf ˆ 0.14
(petrol/EtOAc 4:1); [a]2D2 ˆ ‡36.5 (c ˆ 1.04 in CHCl3); IR: nÄ ˆ 1595,
1480 cmÀ1 (Ar); 1H NMR (300 MHz, CDCl3, 258C): d ˆ 0.81 0.96 [m,
15H; Sn(CH2CH2CH2CH3)3], 1.21 1.39 [m, 6H; Sn(CH2CH2CH2)3],
1.41 1.55 [m, 6H; Sn(CH2CH2)3], 1.61 2.23 (m, 8H; 3 Â CH2, 2 Â CH),
(2S)-N-[3-(Phenylthio)prop-2-ynyl]-2-(tributylstannyl)pyrrolidine (25): In
the same way as the sulfide 18, the alkyne 24 (329 mg, 0.83 mmol) in Et2O
(6.5 mL), PhSSPh (230 mg, 1.0 mmol) and MeI (0.057 mL, 0.91 mmol) in
THF (3.5 mL) gave, after allowing to warm to room temperature for 1 h
and purification by column chromatography on alumina, eluting with
petrol/EtOAc 100:1 to 9:1, the alkyne 25 (275 mg, 65%) as an oil. Rf ˆ 0.65
(petrol/EtOAc 4:1); [a]2D2 ˆ ‡88.8 (c ˆ 1.1 in CHCl3); IR: nÄ ˆ 1585,
1485 cmÀ1 (Ar); 1H NMR (300 MHz, CDCl3, 258C): d ˆ 0.89 0.98 [m,
15H; Sn(CH2CH2CH2CH3)3], 1.35 [sextet, 3J(H,H) ˆ 7Hz, 6H;
Sn(CH2CH2CH2)3], 1.49 1.59 [m, 6H; Sn(CH2CH2)3], 1.78 2.13 (m, 4H;
4  CH), 2.38 (q, 3J(H,H) ˆ 8.5 Hz, 1H; CH), 2.59 (t, 3J(H,H) ˆ 8.5 Hz,
1H; CH), 2.97 3.04 (m, 1H; CH), 3.65 (d, 2J(H,H) ˆ 18 Hz, 1H;
ꢁ
2.38 2.57 (m, 3H; CH2C , NCH), 2.80 2.99 (m, 2H; 2 Â NCH), 7.19 (t,
3J(H,H) ˆ 7 Hz, 1H; Ar), 7.31 (t, 3J(H,H) ˆ 7 Hz, 2H; Ar), 7.41 (t,
3J(H,H) ˆ 7 Hz, 2H; Ar); 13C NMR (75 MHz, CDCl3, 258C): d ˆ 9.1
(CH2), 13.6 (CH3), 14.2 (CH2), 18.4 (CH2), 24.5 (CH2), 27.5 (CH2), 29.3
(CH2), 29.4 (CH2), 54.0 (CH2), 55.9 (CH2), 57.7 (CH), 60.4 (C), 99.2 (C),
125.7 (CH), 126.0 (CH), 129.0 (CH), 134.6 (C); MS (CI): calcd for
A
B
2
A
B
ꢁ
ꢁ
NCH H C C), 3.88 (d, J(H,H) ˆ 18 Hz, 1H; NCH H C C), 7.24 7.45
(m, 5H; Ar); 13C NMR (75 MHz, CDCl3, 258C): d ˆ 8.8 (CH2), 13.7 (CH3),
24.9 (CH2), 27.6 (CH2), 29.3 (CH2), 30.0 (CH2), 44.5 (CH2), 53.2 (CH2), 53.8
(CH), 70.3 (C), 95.4 (C), 126.0 (CH), 126.3 (CH), 129.1 (CH), 133.2 (C); MS
‡
‡
C27H45NS120Sn: 536.2373; found: 536.2373 [M‡H] ; m/z (%): 536 (7)
(CI): calcd for C25H42NS120Sn: 508.2060; found: 508.2065 [M‡H] ; m/z
‡
‡
‡
[M‡H] , 308 (50), 84 (100); elemental analysis calcd (%) for C27H45NSSn
(%): 508 (1.3) [M‡H] , 308 (3.0), 216 (2.7) [M À SnBu3] , 108 (13) [M À
‡ ‡
(534.4): C 60.68, H 8.49, N 2.62; found: C 60.73, H 8.88, N 2.33.
SPh À SnBu3] , 70 (100) [C4H8N] .
Cyclization of the stannane E-15: The stannane E-15 (1.16 g, 2.16 mmol) in
hexane/Et2O (25 mL, 4:1) was treated with n-butyllithium (2.6 mL,
6.50 mmol, 2.5m in hexanes) at room temperature. After 2 h, MeOH
(2 mL) was added, the solvent was removed under reduced pressure and
the residue was purified by column chromatography on alumina, eluting
with petrol-EtOAc (1:0 to 4:1) to give the amines 19 and 20 (409 mg, 77%)
as a 7:3 ratio of diastereomers as an oil. IR: nÄ ˆ 3020, 2935 cmÀ1 (C-H);
1H NMR (400 MHz, CDCl3, 258C): d ˆ 1.25 2.21 (m, 12H; 4  CH2, 4 Â
CH), 2.46 2.50 (m, 0.3H; CHAHBN), 2.62 (dd, 2,3J(H,H) ˆ 12, 8.5 Hz,
0.3H; CHAHBS), 2.93 3.03 (m, 1.7H; CHAHBN, CHCHDN), 3.05 (dd,
2,3J(H,H) ˆ 12, 3.5 Hz, 0.3H; CHAHBS), 3.19 (dd, 2,J(H,H) ˆ 12.5, 9 Hz,
0.7H; CHAHBS), 3.32 (dd, 2,3J(H,H) ˆ 12.5, 4.5 Hz, 0.7H; CHAHBS), 6.98
7.04 (m, 1H; Ar), 7.09 7.14 (m, 2H; Ar), 7.38 7.43 (m, 2H; Ar); 13C NMR
(100 MHz, CDCl3, 258C): d ˆ 20.8 (CH2), 21.1 (CH2), 25.7 (CH2), 26.3
E-(2S)-N-[3-(Phenylthio)prop-2-enyl]-2-(tributylstannyl)pyrrolidine (26):
In the same way as the alkene E-13, LiAlH4 (55 mg, 1.45 mmol) and the
alkyne 25 (210 mg, 0.42 mmol) in THF (2 mL) gave, after 1.5 h at 458C and
purification by column chromatography on alumina, eluting with petrol/
EtOAc 1:0 to 4:1, the stannane E-26 (172 mg, 80%) as an oil. Rf ˆ 0.22
(petrol/EtOAc 4:1); [a]2D2 ˆ ‡34.0 (c ˆ 2.0 in CHCl3); IR: nÄ ˆ 1585,
1480 cmÀ1 (Ar); 1H NMR (300 MHz, CDCl3, 258C): d ˆ 0.82 0.95 [m,
15H; Sn(CH2CH2CH2CH3)3], 1.35 [sextet, 3J(H,H) ˆ 7 Hz, 6H;
Sn(CH2CH2CH2)3], 1.42 1.58 [m, 6H; Sn(CH2CH2)3], 1.62 2.08 (m, 5H;
5  CH), 2.40 (t, 3J(H,H) ˆ 8.5 Hz, 1H; CH), 2.74 2.88 (m, 1H; CH),
2.90 3.05 (m, 1H; CH), 3.49 (dd, 3,3J(H,H) ˆ 13.5, 6.5 Hz, 1H; CH), 5.99
(dt, 3,3J(H,H) ˆ 14, 7 Hz, 1H; CH ˆ CHS), 6.35 (d, 3J(H,H) ˆ 14 Hz, 1H; ˆ
CHS), 7.17 7.36 (m, 5H; Ar); 13C NMR (75 MHz, CDCl3, 258C): d ˆ 9.1
(CH2), 13.7 (CH3), 24.6 (CH2), 27.6 (CH2), 29.3 (CH2), 29.6 (CH2), 54.4
Chem. Eur. J. 2002, 8, No. 1
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205

I. Coldham et al.
FULL PAPER
(CH2), 56.9 (CH), 58.4 (CH2), 124.3 (CH), 126.5 (CH), 129.0 (CH), 129.4
(CH), 132.2 (CH), 135.6 (C); MS (CI): calcd for C25H44NS120Sn: 510.2216;
the mixture was filtered and picric acid (1.5 mL, 0.32 mmol, 0.2m in EtOH)
was added. The solution was absorbed on silica gel and purified by column
chromatography on silica gel, eluting with CH2Cl2/MeOH 1:0 to 50:1, to
give the picrate salts of the amines 30 ‡ 31 (77 mg, 71%) as a 1:1 mixture of
diastereomers as a solid. Rf ˆ 0.40 (CH2Cl2/MeOH 9:1); IR (picrate salt,
CHCl3): nÄ ˆ 1620 (Ar), 1575, 1320 cmÀ1 (NO2); 1H NMR (300 MHz,
CDCl3, 258C, picrate salt): d ˆ 1.15 (d, 3J(H,H) ˆ 7.5 Hz, 3H; CH3), 1.39 (d,
3J(H,H) ˆ 7.5 Hz, 3 H ; CH3), 2.07 2.56 (m, 10H; 10  CH), 3.17 3.42 (m,
5H; 5  CH), 3.61 3.71 (m, 1H; CH), 4.21 (dt, 2,3J(H,H) ˆ 12, 7.5 Hz, 1H;
CH), 4.58 4.71 (m, 2H; 2  CH), 5.05 (q, 3J(H,H) ˆ 7.5 Hz, 1H; CH), 9.04
(s, 4H; 2  Ar); 13C NMR (75 MHz, CDCl3, 258C, picrate salt): d ˆ 13.0
(CH3), 18.4 (CH3), 24.5 (CH2), 25.2 (CH2), 25.7 (CH2), 25.7 (CH), 30.4
(CH), 30.6 (CH2), 52.9 (CH2), 53.2 (CH2), 57.6 (CH2), 58.6 (CH2), 70.5
(CH), 74.2 (CH), 126.6 (CH), 128.2 (C), 141.6 (C), 162.2 (C); MS (ES):
‡
‡
found: 510.2217 [M‡H] ; m/z (%): 510 (24) [M‡H] , 308 (26), 218 (86)
‡
‡
[M À SnBu3] , 70 (100) [C4H8N] ; elemental analysis calcd (%) for
C25H43NSSn (508.4): C 59.06, H 8.53, N 2.76; found: C 58.88, H 8.76, N 2.52.
6-Phenylthiomethyl-1-azabicyclo[3.2.0]heptane (27 ‡ 28): The stannane E-
26 (116 mg, 0.23 mmol) in hexane/Et2O (3.2 mL, 4:1) was treated with n-
butyllithium (0.23 mL, 0.58 mmol, 2.5m in hexanes) at room temperature.
After 30 min, MeOH (0.2 mL) and picric acid (1.1 mL, 0.23 mmol, 0.2m in
EtOH) were added and the mixture was absorbed on silica gel. Purification
by column chromatography on silica gel, eluting with CH2Cl2/MeOH 1:0 to
50:1 gave the picrate salts of the amines 27 and 28 (52 mg, 52%) as a 10:1
ratio of diastereomers as a solid. M.p. (decomp.) 1348C; Rf ˆ 0.45 (CH2Cl2/
MeOH 9:1); [a]1D8 ˆ À1.1 (c ˆ 1.3 in CHCl3); IR (picrate salt, CHCl3): nÄ ˆ
1630, 1615 (Ar), 1560, 1320 cmÀ1 (NO2); 1H NMR (400 MHz, CDCl3, 258C,
picrate salt, major product): d ˆ 1.99 2.04 (m, 1H; NCHCHEHF), 2.13
2.23 (m, 1H; NCHCHEHF), 2.34 2.42 (m, 2H; NCH2CH2), 2.52 (sextet,
3J(H,H) ˆ 7.5 Hz, 1H; NCH2CH), 3.24 3.29 (m, 1H; NCHCHDCH2), 3.33
(d, 3J(H,H) ˆ 8 Hz, 2H; CH2S), 3.32 3.41 (m, 1H; NCHCHDCH2), 3.56
(dd, 2,3J(H,H) ˆ 11.5, 10 Hz, 1H; NCHAHBCH), 4.30 (dd, 2,3J(H,H) ˆ 11.5,
7.5 Hz, 1H; NCHAHBCH), 4.76 (t, 3J(H,H) ˆ 7 Hz, 1H; NCH), 7.24 7.36
(m, 5H; Ph), 8.85 (s, 2H; Ar); 13C NMR (100 MHz, CDCl3, 258C, picrate
salt, major product) d ˆ 24.5 (CH2), 30.7 (CH2), 35.1 (CH), 36.7 (CH2), 53.2
(CH2), 55.6 (CH2), 72.2 (CH), 126.6 (CH), 127.4 (CH), 128.2 (C), 129.3
(CH), 130.8 (CH), 133.7 (C), 141.7 (C), 162.4 (C); MS (CI): calcd for
‡
calcd for C7H14N: 112.1126; found: 112.1124 [M‡H] ; m/z (%): 112 (100)
‡
[M‡H] .
Alternatively, the free base of the amines 30 ‡ 31 (10:1) could be prepared:
To a suspension of Raney nickel (1.0 g) in EtOH (2 mL) was added sulfide
27 ‡ 28 (82 mg, 0.37 mmol, 10:1) in EtOH (2 mL) at 608C. After 1 h, the
mixture was filtered and evaporated to give the amines 30 ‡ 31 (23 mg,
54%) as a 10:1 mixture of diastereomers as an oil. 1H NMR (300 MHz,
CDCl3, 258C, major diastereomer): d ˆ 1.26 (d, 3J(H,H) ˆ 7.5 Hz, 3H;
CH3), 1.92 2.00 (m, 2H; 2 Â CH), 2.15 2.40 (m, 3H; 3 Â CH), 2.98 3.15
(m, 2H; 2  CH), 3.40 (dd, 2,3J(H,H) ˆ 10 Hz, 1H; CH), 3.95 (dd,
2,3J(H,H) ˆ 10, 7.5 Hz, 1H; CH), 4.44 (t, 3J(H,H) ˆ 6 Hz, 1H; CH);
13C NMR (75 MHz, CDCl3, 258C): d ˆ 18.4 (CH3), 24.5 (CH2), 30.4
(CH), 30.7 (CH2), 52.3 (CH2), 56.4 (CH2), 72.4 (CH); MS (CI): calcd for
‡
C13H18NS: 220.1160; found: 220.1159 [M‡H] ; m/z (%): 220 (100)
‡
[M‡H] , 110 (23); elemental analysis calcd (%) for C19H20N4O7S (448.5):
‡
‡
C7H14N: 112.1126; found: 112.1126 [M‡H] ; m/z (%): 112 (100) [M‡H] .
C 50.89, H 4.50, N 12.49; found: C 50.55, H 4.30, N 12.30. In addition, the
picrate salt of the stannane 26 (61 mg, 36%) was isolated.
The enantioselectivity of the cyclization reaction was determined by
measuring (1H NMR) the relative peak areas of the methyl doublets of the
amines 30 ‡ 31 (as their free bases) in the presence of the chiral solvating
agent (R)-(À)-2,2,2-trifluoro-1-(9-anthryl)ethanol.[17]
Alternatively, the amines 27 and 28 could be prepared from 26 in THF: The
stannane E-26 (76 mg, 0.15 mmol) in THF (2 mL) was treated over 1 min
with n-butyllithium (0.15 mL, 0.38 mmol, 2.5m in hexanes) at À788C. After
a further 1 min, MeOH (0.2 mL) and picric acid (0.73 mL, 0.15 mmol, 0.2m
in EtOH) were added and the mixture was warmed to room temperature
and absorbed on silica gel. Purification by column chromatography on silica
gel, eluting with CH2Cl2/MeOH 1:0 to 50:1 gave the picrate salts of the
amines 27 and 28 (59 mg, 86%) as a 1:1 ratio of diastereomers as a solid.
Data as above but 1H NMR (300 MHz, CDCl3, 258C, picrate salt): d ˆ
1.98 2.57 (m, 10H; 10 Â CH), 2.93 3.06 (m, 2H; 2 Â CH), 3.20 3.40 (m,
7H; 7  CH), 3.56 (dd, 2,3J(H,H) ˆ 11.5, 10 Hz, 1H; CH), 4.30 (dd,
2,3J(H,H) ˆ 11.5, 7.5 Hz, 1H; CH), 4.48 4.63 (m, 1H; CH), 4.76 (t,
3J(H,H) ˆ 7 Hz, 1H; CH), 5.00 (t, 3J(H,H) ˆ 8 Hz, 1H; CH), 7.20 7.38
(m, 10H; 2 Â SPh), 8.80 (s, 4H; 2 Â Ar); 13C NMR (75 MHz, CDCl3, 258C,
picrate salt): d ˆ 24.5 (CH2), 25.5 (CH2), 25.8 (CH2), 30.4 (CH), 30.7 (CH2),
32.8 (CH2), 35.1 (CH), 36.7 (CH2), 53.1 (CH2), 53.2 (CH2), 55.6 (CH2), 56.8
(CH2), 69.7 (CH), 72.2 (CH), 126.6 (CH), 127.4 (CH), 127.7 (CH), 128.2 (C),
129.3 (CH), 129.5 (CH), 130.8 (CH), 131.3 (CH), 133.3 (C), 133.7 (C), 141.7
(C), 162.4 (C).
E- and Z-6-Phenylthiomethylene-1-azabicyclo[3.2.0]heptane (32): n-Bu-
tyllithium (0.3 mL, 0.68 mmol, 2.5m in hexanes) was added to the stannane
24 (139 mg, 0.27 mmol) in THF (2.5 mL) at À788C. After 1.5 h, MeOH
(0.5 mL) was added and the mixture was absorbed on alumina. Purification
by column chromatography on alumina, eluting with petrol/EtOAc 1:0 to
0:1 then EtOAc/MeOH 50:1 to 5:1, gave the amines E- and Z-32 (45 mg,
78%) as a 1:1 mixture of geometrical isomers as an oil. Rf ˆ 0.07 (MeOH);
IR: nÄ ˆ 1585, 1485 cmÀ1 (Ar); 1H NMR (300 MHz, CDCl3, 258C): d ˆ
1.76 2.15 (m, 8H; 2 Â NCH2CH2CH2), 2.66 2.87 (m, 4H; 2 Â
2,4
A
B
ˆ
NCH2CH2), 3.44 (dt, J(H,H) ˆ 15, 3.0 Hz, 1H; NCH H C ), 3.55 (ddd,
J(H,H) ˆ 15, 3.5, 2.5 Hz, 1H; NCH H C ), 4.23 (dd, 2,4J(H,H) ˆ 15,
2,4,4
A
B
ˆ
A
B
2.5 Hz, 1H; NCH H C ), 4.29 (dd, 2,4J(H,H) ˆ 15, 1.5 Hz, 1H;
ˆ
NCH H C ), 4.57 4.66 (m, 2H; 2  NCH), 5.87 (q, 4J(H,H) ˆ 1.0 Hz,
1H; CHS), 5.92 (q, 4J(H,H) ˆ 1.0 Hz, 1H; CHS), 7.14 7.32 (m, 10H; 2 Â
Ar); 13C NMR (75 MHz, CDCl3, 258C): d ˆ 23.9 (CH2), 23.9 (CH2), 30.8
(CH2), 32.7 (CH2), 55.9 (CH2), 56.0 (CH2), 60.2 (CH2), 60.8 (CH2), 72.6
(CH), 73.0 (CH), 111.5 (2 Â CH), 126.0 (CH), 126.1 (CH), 128.1 (CH), 128.3
(CH), 129.0 (CH), 136.0 (C), 136.4 (C), 145.6 (C), 146.3 (C); MS (CI): calcd
A
B
ˆ
E-(2S)-N-[3-Deuterio-3-(phenylthio)prop-2-enyl]-2-(tributylstannyl)pyr-
rolidine (29): In the same way as the amines 27 ‡ 28, prepared in hexane/
Et2O 4:1, the stannane 26 (120 mg, 0.24 mmol) and nBuLi (0.24 mL,
0.60 mmol, 2.5m in hexanes), gave, after quenching with MeOD (0.2 mL),
addition of picric acid (1.2 mL, 0.24 mmol, 0.2m in EtOH) and purification
by column chromatography on silica gel, eluting with CH2Cl2/MeOH 1:0 to
50:1, the picrate salt of the stannane 29 (59 mg, 33%) as an oil. Rf ˆ 0.85
(CH2Cl2/MeOH 9:1); IR (picrate salt, CHCl3): nÄ ˆ 1630, 1615 (Ar), 1570,
1330 cmÀ1 (NO2); 1H NMR (300 MHz, CDCl3, 258C, picrate salt): d ˆ
0.79 1.08 [m, 15H; Sn(CH2CH2CH2CH3)3], 1.18 1.54 [m, 12H;
Sn(CH2CH2CH2)3], 1.96 2.08 (m, 1H; CH), 2.19 2.36 (m, 3H; 3 Â CH),
2.56 2.68 (m, 1H; CH), 2.78 2.92 (m, 1H; CH), 3.50 (dt, 2,3J(H,H) ˆ 13,
6.5 Hz, 1H; CH), 3.60 3.74 (m, 1H; CH), 4.08 (dd, 2,3J(H,H) ˆ 13, 6.5 Hz,
1H; CH), 5.55 (t, 3J(H,H) ˆ 7.5 Hz, 1H; CH ˆ CS), 7.22 7.40 (m, 5H; Ar),
8.87 (s, 2H; Ar); 13C NMR (75 MHz, CDCl3, 258C, picrate salt): d ˆ 9.9
(CH2), 13.6 (CH3), 23.9 (CH2), 27.3 (CH2), 28.9 (CH2), 29.4 (CH2), 54.2
(CH2), 55.3 (CH), 56.8 (CH2), 115.7 (CH), 126.7 (CH), 128.0 (C), 128.4
(CH), 129.5 (CH), 131.7 (C), 132.0 (CH), 141.5 (C), 162.0 (C); MS (FAB):
‡
for C13H16NS: 218.1003; found: 218.1002 [M‡H] ; m/z (%): 218 (43) [M ‡
‡
H] , 110 (100).
Acknowledgement
The Leverhulme Trust and EPSRC are thanked for support of this work.
We acknowledge the use of the EPSRC mass spectrometry service at the
University of Wales Swansea. We thank Dr. John P. B. Sandall for help with
the kinetic data.
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calcd for C25H43DNS120Sn: 511.2273; found: 511.2279 [M‡H] ; m/z (%):
‡
‡
511 (57) [M‡H] , 219 (40) [M À SnBu3] , 150 (100).
¬
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206
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Chem. Eur. J. 2002, 8, No. 1

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[28] The absolute configuration of both diastereomers 27 and 28 is
unknown; in all cases studied with a variety of different solvents and
reaction conditions, the same major enantiomer of the diastereomer
27 is formed. However, in the few cases [using the solvent system
hexane/Et2O 2:1, which occurred with reasonable yield (58%) and
diastereoselectivity (27:28 10:1) but lower enantioselectivity (31
34% ee) or using the solvent THF] where it has been possible to
observe [1H NMR in the presence of (R)-(À)-2,2,2-trifluoro-1-(9-
anthryl)ethanol] the splitting of the methyl doublets of both 30 and 31
in the mixture of 30 ‡ 31 derived from 27 ‡ 28, it appears that a
different major enantiomer of the diastereomer 28 may have been
formed in hexane/Et2O 2:1 from that formed in THF as the solvent.
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6775.
Received: June 26, 2001 [F3368]
Chem. Eur. J. 2002, 8, No. 1
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0947-6539/02/0801-0207 $ 17.50+.50/0
207