Studies towards the enantioselective synthesis of 5,6,8-trisubstituted amphibian indolizidine alkaloids via enaminone intermediates

Article abstract of DOI:10.1039/b418062c

Investigations aimed at the enantioselective total synthesis of indolizidine 223A, a recently described 5,6,8-trisubstituted indolizidine alkaloid from a dendrobatid frog, are described. tert-Butyl (2R,3R)-3-amino-2- ethylhexanoate and its (2S,3R)-diaster

Full text of DOI:10.1039/b418062c

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A R T I C L E
Studies towards the enantioselective synthesis of 5,6,8-trisubstituted
amphibian indolizidine alkaloids via enaminone intermediates
Joseph P. Michael,* Charles B. de Koning and Christiaan W. van der Westhuyzen
Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand,
Johannesburg, P.O. Wits 2050, South Africa. E-mail: jmichael@aurum.wits.ac.za;
Fax: +27 (0)11 717-6749; Tel: +27 (0)11 717-6753
Received 1st December 2004, Accepted 6th January 2005
First published as an Advance Article on the web 31st January 2005
Investigations aimed at the enantioselective total synthesis of indolizidine 223A, a recently described
5,6,8-trisubstituted indolizidine alkaloid from a dendrobatid frog, are described. tert-Butyl (2R,3R)-3-
amino-2-ethylhexanoate and its (2S,3R)-diastereomer, prepared in several steps from lithium N-benzyl-N-
[(1R)-1-phenylethyl]amide and tert-butyl (2E)-hex-2-enoate by the Davies protocol, served as chiral building blocks
from which two complementary suites of diastereomeric intermediates were made en route to pivotal tert-butyl
3-[2-(alkoxycarbonylmethylene)pyrrolidin-1-yl]-2-ethylhexanoate intermediates 20 and 21. Cyclisation of these
enaminones, achieved by acid hydrolysis of the tert-butyl esters and activation of the liberated carboxylic acids as
mixed anhydrides, afforded 6-ethyl-7-oxo-5-propyl-1,2,3,5,6,7-hexahydroindolizine-8-carboxylate esters 28 and 29.
Several further transformations of these potential scaffolds for the synthesis of the target alkaloidal systems are also
reported.
Introduction
Over 500 alkaloids belonging to a variety of structural classes
have been isolated from the skins of amphibians.1,2 Among the
most numerous are the indolizidine alkaloids,3 which appear to
be sequestered by the animals from dietary sources, especially
arthropods.4 This group of alkaloids includes relatively simple
3,5- and 5,8-disubstituted indolizidines as well as the structurally
and stereochemically more complex pumiliotoxins and allo-
pumiliotoxins. Indolizidine 223A, the first naturally occurring
5,6,8-trisubstituted indolizidine alkaloid, was reported in 1997
as a major component of skin extracts from a Panamanian
population of the frog Dendrobates pumilio.5 Enough material
1
was isolated for quite extensive FTIR, EIMS and H NMR
spectroscopic studies, on the strength of which the structure and
relative stereochemistry shown in 1 were proposed, although the
optical rotation was not measured and the absolute stereochem-
istry was not determined. Toyooka et al. set out to confirm the
structure of indolizidine 223A by synthesis, and succeeded in
preparing the dextrorotatory enantiomer ent-1.6 However, the
spectra obtained did not match those of the natural product,
which aroused the suspicion that the alkaloid was probably
a diastereomer of 1. In the interim, another trisubstituted
indolizidine, alkaloid 249H, had been thoroughly characterised,
and was shown to possess a cis-arrangement of substituents at C-
5 and C-6, as shown in 2.7 The synthetic route was thus modified
to produce the 5,6-cis-disubstituted analogue of 1.6 The product,
(5R,6R,8R,8aS)-(−)-3, was identical in all spectroscopic respects
to the natural product, thereby necessitating a structural revision
of indolizidine 223A. While the absolute configuration of
the alkaloid still remains unknown, the structure shown as
(−)-3 appears to be highly probable since it ties in with that
unambiguously ascertained for better-known 5,8-disubstituted
indolizidine alkaloids such as (−)-indolizidine 207A 4 and
(−)-indolizidine 209B 5. Racemic 6-epi-indolizidine 223A,
( )-1, has subsequently been synthesised by Harris and Padwa;8
while Pu and Ma have reported syntheses of both (−)-6-epi-
indolizidine 223A and (−)-indolizidine 223A.9 Additional 5,6,8-
trisubstituted indolizidine alkaloids have been detected in trace
amounts in amphibian skin extracts, but only tentative structures
have been proposed at this stage.2,5
Our continuing investigations into the use of b-acylated
enamines (‘enaminones’ in general) and related compounds as
intermediates in alkaloid synthesis10,11 take advantage of their
ability to function either as ambident nucleophiles or as am-
bident electrophiles depending on the synthetic strategy envis-
aged. These readily prepared compounds are easily incorporated
into structures that contain the gross skeletal features found in
many alkaloidal systems, and they also offer ample opportunity
for controlling diastereoselectivity and enantioselectivity. A
case in point is our reported enantioselective synthesis12 of
(−)-indolizidine 209B 5, the key steps in which are shown in
Scheme 1. The chiral amine (R)-(−)-6, prepared from lithium N-
benzyl-N-[(1R)-1-phenylethyl]amide and tert-butyl (2E)-oct-2-
enoate by the powerful Davies protocol,13 was converted in three
steps into the pyrrolidine-2-thione (+)-7, from which the enam-
inone (+)-8 (a vinylogous urethane) was readily prepared by the
Eschenmoser sulfide contraction.14 Chemoselective reduction of
the saturated ester to the alcohol (−)-9 followed by cyclisation
via the corresponding iodide produced the hexahydroindolizine
(+)-10, which is itself an enaminone. Diastereoselective reduc-
tion of 10 yielded (−)-11, which was converted by standard
methods into the target alkaloid (−)-5. We envisaged that this
route could be adapted for the enantioselective synthesis of
5,6,8-trisubstituted indolizidines such as 1 and 3. However,
8 3 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 3 6 – 8 4 7
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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Scheme 1 Reagents and conditions: i, Cl(CH2)3COCl, NaHCO3,
CHCl3, reflux; ii, KOBut, ButOH, rt; iii, Lawesson’s reagent, PhMe,
reflux (73% over 3 steps); iv, BrCH2CO2Et, MeCN, rt; v, Ph3P, Et3N,
MeCN, rt (94% over 2 steps); vi, LiAlH4, THF, rt (88%); vii, I2, imidazole,
Ph3P, PhMe, 110 ◦C (81%); viii, H2 (1 atm), PtO2, AcOH, rt; ix, NaOEt
(cat.), EtOH, reflux (30% over 2 steps).
two important additional features would need to be addressed.
Firstly, instead of the chiral amine 6, a chiral a-alkyl b-amino
ester 12 containing two contiguous stereocentres of known
absolute configuration would be required from the outset.
Secondly, manipulation of the ethoxycarbonyl substituent in
late intermediates such as 11 becomes necessary in order to
elaborate the alkyl substituent at C-8. The extent to which our
expectations were realised is described in this paper.
Scheme 2 Reagents and conditions: i, 14 + n-BuLi, THF, −78 ◦C,
30 min, then add 13, 3 h; ii, EtI, −78 ◦C to rt, 18 h (12a + 12b, 58 :
42, 36% over 2 steps); iii, LDA, THF, −78 ◦C, 1 h, then EtI, −78 ◦C,
1h, −78 ◦C to rt, 18 h (12a + 12b, 56 : 44, 88%); iv, H2 (7 atm), 10%
Pd/C, AcOH, rt, 72 h; v, Cl(CH2)3COCl, NaHCO3, CHCl3, rt, 18 h; vi,
ButOK, ButOH, rt, 36 h, then separation by chromatography (18a, 39%
over 3 steps; 18b, 24% over 3 steps).
Results and discussion
the ratio of diastereomers was essentially the same (56 : 44).
The identity of the major isomer could not be established at
this stage, but later results (vide infra) proved that it was indeed
the expected anti product. It is worth noting that Pu and Ma
were able to prepare the syn-adduct 12b in 67% yield and 98%
diastereomeric excess from the (R)-(+)-amine 14 and tert-butyl
(2E)-2-ethylhex-2-enoate.9 The 13C NMR spectrum reported for
this diastereomer corresponds quite closely with that of our
minor diastereomer.
The Davies group has achieved the stereocontrolled synthesis of
chiral a-alkyl b-amino esters by three modifications of their basic
strategy: using a trisubstituted alkenoate of defined geometry
in place of the trans-disubstituted alkenoate; trapping the
intermediate enolate formed in the conjugate addition to trans-
disubstituted alkenoates in situ with suitable electrophiles (the
tandem approach); or treating ester enolates generated from pre-
formed chiral b-amino esters with electrophiles (the consecutive
approach). The first strategy has been applied to cycloalkene-
1-carboxylates, where the amine and ester end up syn to
each other on the ring;15 and to (E)-2-alkylalk-2-enoates, in
which case the amine and 2-alkyl substituents are preferentially
syn.16 The tandem and consecutive approaches give yields and
diastereoselectivities that depend quite substantially on the
reaction conditions, substrate structure and steric effects of the
alkylating agent, although in general there is a preference for an
anti orientation of the 2-alkyl and amine substituents.17 Because
the commencement of our investigations, like those of Padwa
and Ma, antedated the structural revision of indolizidine 223A,
we believed that we required the anti a-alkyl b-amino ester 12a.
We accordingly chose to investigate tandem and consecutive
approaches to 12 with tert-butyl (2E)-hex-2-enoate 18 13 and
(+)-N-benzyl-N-[(1R)-1-phenylethyl]amine 14 as precursors.
The tandem method entailed adding the alkenoate over 30 min
to the amide anion, generated by treating the parent amine 14
with n-butyllithium in THF at −78 ◦C (Scheme 2). After 3 h, an
excess of iodoethane was added, and the reaction mixture was
allowed to stand at ambient temperature for 18 h. An inseparable
mixture of two diastereomers 12a,b in a ratio of about 58 : 42
(established both by NMR spectroscopy and by HPLC) was
isolated in a poor yield of 36%, a result consistent with similar
Debenzylating the diastereomeric mixture 12a,b to give the
primary amines 16a,b was accomplished by hydrogenolysis
under pressure (7 atm) over palladium catalysts (Scheme 2).
When a solution of isomers 12 in methanol was hydrogenated
over Pearlman’s catalyst (20% palladium hydroxide on charcoal),
the primary amines 16 could be isolated after work-up, but
attempted purification resulted in drastically diminished yields
as reaction with atmospheric carbon dioxide rapidly resulted in
the formation of solid products, presumably carbonate and/or
carbamate salts.19 Hydrogenolysis in acetic acid over 10%
palladium on charcoal was more successful, since the amines
could be preserved in solution in protonated form until required.
However, even after prompt neutralisation and purification, the
isolated yield of primary amines was 47% at best. The ratio of
diastereomers (56 : 44) was similar to that in the precursors.
Since speedy conversion into more robust intermediates was
clearly advisable at this stage, the mixture of primary amines 16
was acylated with 4-chlorobutanoyl chloride to give amides 17a
and 17b, which could be separated by column chromatography
on silica gel. However, even these compounds were found to
decompose rather rapidly. In the end, our most successful
strategy involved a sequential procedure in which the crude
primary amines formed by hydrogenolysis in acetic acid were
immediately treated with 4-chlorobutanoyl chloride, after which
the unpurified mixture of amide diastereomers 17 was cyclised
by treatment with potassium tert-butoxide in tert-butyl alcohol
to give the separable lactams 18a and 18b in variable yields (ca.
65% overall). Once again, unambiguous confirmation of the
17b
findings by Davies and Walters. In the consecutive approach,
when pre-formed (+)-tert-butyl (3R)-3-[N-benzyl-N-(1R)-1-
phenylethyl]aminohexanoate 9,18 15 was treated with LDA in
THF at −78 ◦C followed by the addition of excess iodoethane,
the isolated yield of 12a,b was improved to 88%, although
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 3 6 – 8 4 7
8 3 7

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relative stereochemistry of these two products was not possible,
but was inferred with hindsight from products formed later in
the reaction sequence. The 1H and 13C NMR spectra of the two
isomers were very similar, but the specific rotations had opposite
signs. (In general in these investigations, compounds of the anti
series proved to be dextrotatory, while those of the syn series were
laevorotatory.) A noteworthy observation is that the strongly
basic conditions required for cyclisation effected a degree of
epimerisation at the enolisable a-position. This was confirmed
by subjecting the individual uncyclised amides 17a and 17b to
the basic cyclisation conditions; in either case, a mixture of
diastereomeric lactams was formed, with the anti product 18a
again being dominant. Davies et al. have reported similar base-
aluminium hydride in THF to give alcohols 23, the precursors
for alkylative cyclisation to create the indolizidine core. To our
consternation, repeated attempts to achieve this transformation
with the ethyl esters 20 failed, no matter how we varied the
solvent, temperature or reductant. The quality of the reagent
and solvent was not at fault since, when we repeated the reported
transformation 8 → 9 in parallel with the attempted reductions
of 20 using exactly the same batch of reactant and solvent, the
former proceeded smoothly while the latter returned only the
starting material. It appears that the additional ethyl substituent
a to the tert-butyl ester in 20 increases steric hindrance at the
carbonyl group to such an extent that reduction cannot proceed.
At this stage a change in strategy was indicated. We reasoned
that, if we could hydrolyse the tert-butyl esters in compounds 20
to the corresponding carboxylic acids, we should be able to carry
out an acylative cyclisation to form 2,3,5,6-tetrahydroindolizin-
7(1H)-ones, which could then be deoxygenated at a later stage.
The reason for our optimism lay in our reported synthesis of the
simple alkaloid indolizidine 167B 24, among others, one step
of which entailed acid- or base-induced hydrolysis of ethyl, tert-
butyl or (−)-menthyl esters 25 and cyclisation of the carboxylic
acid intermediate via a mixed anhydride to yield the product 26
in overall yields of up to 89%.18,22
15a
induced epimerisation with 2-aminocycloalkanecarboxylates.
Thionation of lactams 18a and 18b, accomplished with
Lawesson’s reagent in boiling toluene, produced the thiolactams
19a and 19b in yields of 81 and 95%, respectively, thereby
opening the way to forming the pivotal enaminone intermediates
by the Eschenmoser sulfide contraction procedure (Scheme 3).
Reaction between each thiolactam and ethyl bromoacetate or
benzyl bromoacetate in acetonitrile smoothly produced S-alkyl
salts, from which the desired vinylogous urethanes 20 and
21 were generated by treatment with triphenylphosphine and
triethylamine. The ethyl esters 20a and 20b were isolated in
better than 96% yield, while the yields of benzyl esters 21a
and 21b were somewhat lower (90 and 81%, respectively). In
all cases the (E)-geometry of the newly formed double bond was
inferred from the through-space deshielding of the methylene
14a
protons on C-3 by the carbonyl group (dH >3.0). No useful
products were obtained when bromoacetone was used as the
alkylating agent – an unfortunate failure, since this reactant
would have introduced a carbon chain of the correct length
for the 8-ethylindolizidine target. We also considered Weinreb
amides20 as possible candidates for late-stage chain extension,
and to this end performed the sulfide contraction between the
major thione 19a and N-methoxy-N-methyl-2-bromoacetamide
21
to give the vinylogous urea 22 in 91% yield. This appears to
be only the second time in which an enaminone incorporating a
Weinreb amide has been reported.21
In the event, when solutions of 20a and 20b in triflu-
oroacetic acid were maintained at ambient temperature for
3 h before neutralisation and work-up, (2R,3R)-3-[(2E)-(2-
ethoxycarbonylmethylene)pyrrolidin-1-yl]-2-ethylhexanoic acid
27a and its (2S,3R)-isomer 27b could be isolated and
characterised (Scheme 4), although attempts at purification
Scheme 3 Reagents and conditions: i, Lawesson’s reagent, toluene,
reflux, 18 h (19a, 81%; 19b, 95%); ii, BrCH2CO2Et, MeCN, rt, 76 h,
then PPh3, NEt3, rt, 3–5 h (20a, 97%; 20b, 96%); iii, BrCH2CO2Bn,
MeCN, rt, 18 h, then PPh3, NEt3, rt, 3–5 h (21a, 90%; 21b, 81%); iv,
BrCH2CON(OMe)Me, MeCN, rt, 40 h, then PPh3, NEt3, rt, 3–5 h (22,
91%).
Scheme
4
Reagents and conditions: i, CF3CO2H, rt, 3 h; ii,
Ac2O, K2CO3, MeCN, rt, 18 h, then reflux, 3 h. [Yields from
(2R,3R)-precursors: 28a, 85% over 2 steps; 29a, 80% over 2 steps; 30,
83% over 2 steps. Yields from (2S,3R)-precursors: 28a + 28b, 52%, ca.
3 : 1, over 2 steps; 29a + 29b + mixed fraction, 32% + 12% + 9% over
2 steps.]
Following the precedent established in our synthesis of
indolizidine 209B (cf. 8 → 9, Scheme 1), the next step to be
carried out was the chemoselective reduction of the saturated
tert-butyl ester in the enaminone intermediates 20 with lithium
8 3 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 3 6 – 8 4 7

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resulted in poor recovery of products. In general, it was
not necessary to purify these acids; simply evaporating the
trifluoroacetic acid and then treating the crude product
with acetic anhydride and potassium carbonate in dry ace-
tonitrile yielded ethyl 7-oxo-1,2,3,5,6,7-hexahydroindolizine-8-
carboxylates. However, in this case the two diastereomeric
precursors showed an unexpected difference in behaviour, with
reaction temperature also playing a crucial role. The vinylogous
urethane 20a consistently produced the expected 5,6-trans-
disubstituted product, ethyl (5R,6R)-6-ethyl-7-oxo-5-propyl-
1,2,3,5,6,7-hexahydroindolizine-8-carboxylate 28a, in 85% yield
after 24 h of stirring at room temperature, followed by 3 h
of heating under reflux. By contrast, the vinylogous urethane
20b produced a mixture of the 5,6-trans- and cis-disubstituted
products 28a and 28b in about 52% overall yield when warmed
at 50 ◦C for the same period. If we started with the purified
(2S,3R)-carboxylic acid 27b and heated the cyclisation reaction
mixture under reflux for 18 h, the sole product isolated, in
about the same modest yield, was the 5,6-trans-disubstituted
product 28a. In other words, under these conditions, the ethyl
group in the (2S,3R)-series undergoes epimerisation at the
enolisable position during or after the cyclisation, no doubt
induced by the base present in the reaction medium (either
potassium carbonate, or the potassium acetate generated). Since
the isolated products maintained optical activity, alternative
explanations for the stereochemical inversion involving retro-
Mannich or retro-Michael ring opening/ring closing equilibria23
seem not to be tenable, as both would also have led to racemi-
sation. The relative stereochemistry of the cyclised product
28a was confirmed by NOESY spectroscopy, which showed no
interaction between the trans-disposed protons at C-5 and C-6,
but a clear interaction between 5-H and both sets of protons on
the ethyl substituent attached to C-6. This result also supports
the relative stereochemistry assigned to all precursors leading
up to these products.
To confirm that the isomerisation of the C-6 ethyl group
was indeed occurring, we repeated the two-step hydroly-
sis/intramolecular acylation sequence with the benzyl esters 21a
and 21b. Following room-temperature cleavage of the tert-butyl
group with trifluoroacetic acid, the unpurified carboxylic acid
intermediates were heated under reflux in acetonitrile containing
acetic anhydride and potassium carbonate for 18 h. From the
(2R,3R)-precursor 21a, benzyl (5R,6R)-6-ethyl-7-oxo-5-propyl-
1,2,3,5,6,7-hexahydroindolizine-8-carboxylate 29a was isolated
as the sole isomer in 80% yield. Its NMR spectra matched
those obtained for the corresponding ethyl ester 28a. The
diastereomeric vinylogous urethane 21b, on the other hand,
produced the epimerised product 29a as the major isomer
in 32% isolated yield, together with a mixed fraction (9%)
and 12% of the minor isomer, benzyl (5R,6S)-6-ethyl-7-oxo-
5-propyl-1,2,3,5,6,7-hexahydroindolizine-8-carboxylate 29b. Fi-
nally, hydrolysis and cyclisation of the (2R,3R)-vinylogous urea
22 produced only the expected indolizinone 30 in 83% yield,
without apparent deleterious effect on the Weinreb amide.
A fortuitous consequence of the cyclisation studies is that the
problem we encountered right at the outset of the synthesis,
viz. the formation of diastereomers, was no longer of any
consequence, since in principle the cyclisation step allows the two
diastereomers to converge, forming a single, thermodynamically
stable product – unfortunately, the wrong one for ultimate
conversion into indolizidine 223A. However, the structure of
the natural product had not yet been revised when we obtained
these results, and so we were encouraged to proceed with the
synthesis. With two of the putative target’s stereogenic centres in
place, the next objective was to introduce the remaining two by
a stereoselective reduction of the carbon–carbon double bond
of the enaminone unit, a task for which we had established
ample precedent in a variety of previous syntheses.12,18,22,24 Our
experience has been that steric factors favour the preferential
delivery of hydride reductants to the bridgehead position C-8a
on the face of the double bond anti to the substituent at C-
5 (the re face in this case); isomeric mixtures may be formed
at C-8, but base-mediated epimerisation facilitates conversion
into the isomer containing the equatorial C-8 substituent.
Catalytic hydrogenation also occurs on the face of the double
bond opposite to the C-5 substituent, with the expected cis-
stereocontrol at both C-8 and C-8a. In the present case, however,
the additional substituent at C-6 lies within the same topos as the
incoming reductant, thereby introducing a further steric factor
whose effect on the stereochemical outcome of the double bond
reduction is likely to be significant.
Our normally successful conditions for catalytic hydrogena-
tion with acetic acid as solvent and platinum dioxide as catalyst
failed to reduce the double bond of 28a. However, following a
good precedent for the stereoselective reduction of the alkene
bond in bicyclic b-keto esters similar to 28a,25 we achieved
a chemoselective reduction of the double bond with lithium
aluminium hydride in tetrahydrofuran at −78 ◦C (Scheme 5).
Two isomeric octahydroindolizinones were obtained in a ratio of
3 : 1 and an overall yield of 79%. 13C NMR spectroscopic signals
for the saturated ketone and ester groups in the major isomer
at d 205.7 and 168.6 (d 208.5 and 169.0 in the minor isomer),
respectively, attested to the preservation of both carbonyl
groups under the reaction conditions. Spectroscopic evidence
points to structure 31, i.e. ethyl (5R,6R,8S,8aS)-6-ethyl-7-oxo-5-
propyloctahydroindolizine-8-carboxylate, as the major isomer.
Support for a cis-relationship of the hydrogen atoms at positions
C-5 and C-8a was provided by a strong Bohlmann band26 at
2801 cm−1 in the FTIR spectrum, a feature that arises from
the antiperiplanar alignment of these hydrogen atoms with
the lone pair on nitrogen, and which also implies a trans-
fused indolizidine ring system. Most importantly, diagnostic
new signals for the methine protons at C-8 and C-8a in the
1H NMR spectrum also support the proposed stereochemistry.
The signal for 8-H, a doublet at d 3.31, shows a coupling
constant of 11 Hz, which suggests a trans-diaxial relationship
with its neighbour, and an equatorial disposition of the ester
substituent. The matching coupling constant of 11 Hz for 8a-
H is found in the double double doublet signal at d 2.73. The
identity of the minor isomer is less certain because most of its
signals in the 1H NMR spectrum were obscured by those of the
major isomer. However, two well-separated signals – a doublet
(J ≈ 10.3 Hz) at d 3.29 and a broad doublet (J ≈ 11 Hz) with
unresolved fine coupling at d 2.98 – appear to be due to 8-H
and 8a-H, respectively. If these assignments are correct and 8-H
Scheme 5 Reagents and conditions: i, LiAlH4, THF, −78 ◦C, 2.5 h, then
work-up (yield from 28a: 31 + 32, ca. 3 : 1, 79%; yield from 28b :31 +
32, ca. 4 : 1, 65%; yield from 29a: 33 + 34, ca. 3 : 1, 73%); ii, NaH, THF,
0 ◦C, 1.5 h, then EtI, rt, 7 d (35, ca. 4 : 1 mixture of isomers, 35%); iii,
H2 (1 atm), 10% Pd/C, EtOH, rt, 18 h (36, mixture of isomers, 52%); iv,
aq. NaOH (1 M), reflux, 1.5 h, then conc. HCl, reflux, 30 min (37, 84%).
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 3 6 – 8 4 7
8 3 9

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and 8a-H are also trans to each other, then the minor isomer
is likely to have the (5R,6R,8R,8aR) configuration as shown
in 32, and the ring fusion in the indolizidine system can only
be cis, with the lone pair and 8a-H cis to each other. In this
case, hydride must be delivered to C-8a from the si face of the
double bond, probably as a result of steric hindrance to the re
face by the C-6 ethyl substituent. Remarkably, when the hydride
reduction was repeated with ethyl (5R,6S)-6-ethyl-7-oxo-5-
propyl-1,2,3,5,6,7-hexahydroindolizine-8-carboxylate 28b (that
is, the minor isomer of the bicyclic vinylogous urethane, with
the C-5 and C-6 substituents cis to each other), exactly the same
pair of indolizidine isomers was obtained in 65% yield and a ratio
of 4 : 1. In other words, the ethyl substituent at the enolisable
C-6 position appears to have epimerised once again under
the basic reaction (or work-up) conditions. For comparison, the
(5R,6R)-benzyl ester 29a was also reduced under comparable
conditions. Two principal inseparable isomers (ratio 3 : 1, by
NMR spectroscopy) were obtained in an overall yield of 73%.
Since the spectroscopic properties paralleled those of the ethyl
esters, structures 33 and 34 are tentatively proposed. Attempted
reduction of the hexahydroindolizinone 30 incorporating the
Weinreb amide yielded unidentifiable products.
If the route described thus far is to be generally suitable for
making natural or unnatural 5,6,8-trialkyl indolizidines, then a
final suite of transformations must still be explored: introduction
of an alkyl substituent at C-8, and defunctionalisation of the
carbonyl group at C-7. Attempts to achieve the first of these tasks
met with mixed success. Although the ester group of 31 might be
viewed as the obvious forerunner of the two-carbon chain in the
desired target alkaloids (e.g. by reduction and chain extension),
several operationally simpler, more direct approaches were
selected for initial investigation. Firstly, since compounds 31–
34 are b-keto esters, we explored the feasibility of a-alkylation
followed by ester hydrolysis and decarboxylation. We found that
the isomer mixture 31/32 was readily deprotonated with sodium
hydride in THF, but subsequent reaction with iodoethane was
inefficient, producing a mixture of isomeric products 35 in
modest yield (30–40%; ca. 4 : 1 by NMR spectroscopy). Apart
from obvious NMR spectroscopic signals for the additional
ethyl substituent and the loss of the signal for 8-H, the only other
notable spectroscopic feature was a Bohlmann band at 2796 cm−1
in the infrared spectrum, which suggests the retention of a trans-
fused ring junction in the product. Unfortunately, all attempts
to hydrolyse and decarboxylate the ester group in this crowded
system under a variety of conditions (including boiling with 1 M
aqueous sodium hydroxide or 48% hydrobromic acid, or with
sodium chloride in DMSO) failed. Ethylation of the mixture
of benzyl esters 33/34 was even poorer; moreover, subsequent
attempts to cleave the benzyl ester by hydrogenolysis over
palladium on carbon left the ethylated intermediate untouched.
Changing the order of the steps also proved to be futile; while
the benzyl ester could be removed from the isomer mixture
33/34 by hydrogenolysis over palladium on carbon followed by
decarboxylation, attempts to generate and ethylate an enolate
from the resulting unstable product 36 under kinetic conditions
(LDA, THF, −78 ◦C) failed dismally. Finally, the bicyclic vinylo-
gous urethane 28a could be hydrolysed and decarboxylated quite
readily to give the enaminone 37 in good yield (84%). However,
attempts to alkylate this nucleophilic intermediate exclusively
on the enamine carbon atom gave inconclusive results.
group of 20 is effectively the Trojan horse in our approach: while
the acylative cyclisation 20 → 28 was excellent for creating the
indolizidine nucleus, it necessarily resulted in the formation of a
ketone buttressed on both sides, and therefore far less susceptible
to attack by nucleophiles.
In conclusion, although the strategy described in this paper
was ultimately unsuitable for the synthesis of indolizidine 223A
itself, the results obtained provide valuable insights into the
synthesis and reactivity of multiply-substituted indolizidin-7-
ones. Furthermore, our original plan of proceeding by way of
an alkylative cyclisation, which would avoid the troublesome
carbonyl group at C-7, still presents tantalising prospects for fu-
ture investigations provided that we can devise viable alternative
routes to cyclisation precursors such as the alcohols 23. We are
currently exploring routes involving the preparation of stereo-
chemically unambiguous enaminone intermediates related to 23
from derivatives of homochiral 3-amino-2-ethylhexan-1-ols.28
Experimental
All solvents used for reactions and chromatography were
distilled before use. Tetrahydrofuran (THF) was distilled from
Na/benzophenone; dichloromethane, acetonitrile and triethy-
lamine from CaH2; and toluene from Na metal. Commercially
available chemicals were used as received. Melting points,
recorded on a Reichert hot-stage microscope apparatus, are
uncorrected. TLC was performed on aluminium-backed Alu-
gram Sil G/UV254 plates pre-coated with 0.25 mm silica gel
60. Column chromatography was carried out on silica gel
60, particle size 0.063–0.200 mm (conventional columns) or
Whatman Partisil Prep 40, particle size 0.040–0.063 mm (flash
columns). FTIR spectra were recorded on Bruker Vector 22 or
Bruker IFS 25 spectrometers. NMR spectra were recorded on
Bruker AC-200 (200.13 MHz for 1H, 50.32 MHz for 13C), Bruker
300 (300.139 MHz for 1H, 75.035 MHz for 13C) or Bruker DRX
400 (400.132 MHz for 1H, 100.625 MHz for 13C) spectrometers.
CDCl3 was used as solvent and TMS as internal standard. DEPT
and CH-correlated spectra were routinely used for assignment of
signals. J values are given in Hz. Optical rotations were measured
on a Jasco DIP-370 polarimeter; [a]D values are given in 10−1
deg cm2 g−1. High-resolution mass spectra were recorded at
70 eV on a VG 70 SEQ mass spectrometer with a MASPEC
II data system.
tert-Butyl (2R,3R)-3-{N-Benzyl-N-[(1R)-1-phenylethyl]amino}-
2-ethylhexanoate 12a and its (2S,3R) epimer 12b
(a) Tandem approach. A solution of (1R)-N-benzyl-a-
methylbenzylamine 14 (Aldrich; 0.30 cm3, 300 mg, 1.42 mmol)
in dry THF (6 cm3) in a◦flame-dried, nitrogen-purged 3-necked
flask was cooled to −78 C. n-BuLi (1.45 M in hexane, 0.89 cm3,
1.29 mmol) was added dropwise, and the deep purple solution
obtained was stirred for 30 min. tert-Butyl (2E)-hex-2-enoate18
13 (203 mg, 1.19 mmol) in THF (1 cm3) was added dropwise
over 30 min,◦ and the resulting solution was left to react for
3 h at −78 C. Iodoethane (0.42 cm3, 819 mg, 5.25 mmol)
was added by syringe. The mixture was kept at −78 ◦C for
30 min, then allowed to warm to rt over 18 h, affording a deep
yellow solution. Saturated aq. NH4Cl solution (10 cm3) was
added dropwise, and the organic components were extracted
with Et2O, then CH2Cl2. The combined organic extracts were
dried (MgSO4) and evaporated in vacuo to yield a yellow oil.
Column chromatography on silica gel with EtOAc–hexane (1 :
200 to 1 : 50) as mobile phase yielded an inseparable mixture (ca.
58 : 42, by NMR spectroscopy and HPLC) of tert-butyl (2R,3R)-
3-[N-benzyl-N-(1R)-1-phenylethyl]amino-2-ethylhexanoate 12a
and its (2S,3R)-epimer 12b (174 mg, 36% over two steps) as a
light yellow oil, Rf 0.56 (EtOAc–hexane, 1 : 20); mmax(film)/cm−1
3062 (w), 3028 (w), 2965 (s), 2873 (s), 1725 (s), 1456 (m), 1368
(m), 1254 (m), 1151 (s), 752 (m) and 700 (m); m/z (EI) 409 (M+,
In the final analysis, the synthetic approach adopted in this
work was scuppered by a more serious problem: the inability
to remove the carbonyl group at C-7. All attempts to prepare
suitable derivatives of 31 for defunctionalisation, including
the 1,3-dithiane and p-toluenesulfonylhydrazone, were fruitless.
Since we have previously been able to form derivatives of related
5-alkylindolizidin-7-ones unsubstituted at C-6,18,22,27 it seems
that the additional substituent at this site in 31 once again
provides a formidable steric check to further reaction, as it did in
the attempted reduction of 20 to 23. The electrophilic carbonyl
8 4 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 3 6 – 8 4 7

View Article Online
ꢀ1%), 267 (21), 266 (100), 206 (13), 163 (10), 162 (86), 160 (11),
105 (82), 104 (19) and 103 (10) [found: PrCHN(CHMePh)Bn+,
266.1908. C19H24N requires 266.1909]. The signals due to the
individual isomers were distinguishable by NMR spectroscopy.
Major isomer 12a: dH (400 MHz; CDCl3; Me4Si) 7.60–7.40 (10H,
m, ArH), 3.98 (1H, q, J 6.9, NCHMePh), 3.91 and 3.78 (2H, AB
system, J 15.0, NCH2Ph), 2.97 (1H, br q, J ca. 5.9, NCHPr), 2.28
(1H, ddd, J 10.8, 5.9 and 3.8, CHCO2But), 1.43 (9H, s, OCMe3),
1.26 (3H, d, J 6.8, NCHMePh), 1.58–1.21 (6H, m, remaining
CH2), 0.79 and 0.69 (6H, 2 × t, J 7.2 and 7.4, 2 × Me); dC
dH (400 MHz; CDCl3; Me4Si) 2.90–2.85 and 2.85–2.78 (1H, 2 ×
m, CHNH2 of minor and major isomers, respectively), 2.18–
2.13 and 2.13–2.07 (H, 2 × m, CHCO2But of major and minor
isomers, respectively), 1.72–1.30, 1.47 and 1.46 (17H, m and
2 × s, remaining CH2 and NH2 with OCMe3 of major and
minor isomers, respectively) and 0.92 (6H, br t, J ca. 7.3, 2 ×
Me); m/z (EI) 215 (M+, 0.17%), 158 (4), 116 (26), 98 (7) and
72 (100) (found: M+, 215.1878. C12H15NO2 requires 215.1885).
The signals due to the individual isomers were distinguishable
by 13C NMR spectroscopy. Major isomer 16a: dC (100 MHz;
=
=
(100 MHz; CDCl3) 174.8 (C O), 144.7 and 142.5 (ArC), 128.3,
CDCl3) 174.4 (C O), 80.2 (OCMe3), 54.3 and 52.7 (NCH and
128.1, 127.9, 127.7, 126.5 and 126.3 (ArCH), 79.8 (OCMe3),
60.2 and 59.4 (NCHPh and NCHPr), 51.3 and 50.8 (NCH2Ph
and CHCO2But), 32.0 (NCHCH2Et), 28.1 (OCMe3), 22.5 and
21.2 (remaining CH2), 18.3 (NCHMePh), 14.3 and 12.2 (2 ×
Me). Minor isomer 12b: dH (400 MHz; CDCl3; Me4Si) 7.60–7.40
(10H, m, ArH), 3.99 (1H, q, J 6.8, NCHMePh), 3.82 and 3.75
(2H, AB system, J 15.0, NCH2Ph), 2.76 (1H, ddd, J 8.0, 6.4 and
4.0, NCHPr), 2.18 (1H, ddd, J 10.9, 6.6 and 4.2, CHCO2But),
1.41 (9H, s, OCMe3), 1.27 (3H, d, J 6.8, NCHMePh), 1.58–1.21
(6H, m, remaining CH2), 0.82 and 0.74 (6H, 2 × t, J 6.9 and 7.3,
CHCO2But), 37.9 (NCHCH2Et), 28.1 (OCMe3), 22.7 and 19.3
(remaining CH2), 14.0 and 11.9 (2 × Me). Minor isomer 16b: dC
=
(100 MHz; CDCl3) 174.5 (C O), 80.1 (OCMe3), 55.0 and 52.7
(NCH and CHCO2But), 37.6 (NCHCH2Et), 28.0 (OCMe3), 20.9
and 19.4 (remaining CH2), 14.0 and 12.0 (2 × Me).
tert-Butyl (−)-(2R,3R)-3-(2-oxopyrrolidin-1-yl)-2-
ethylhexanoate 18a and tert-butyl (+)-(2S,3R)-3-
(2-oxopyrrolidin-1-yl)-2-ethylhexanoate 18b
=
2 × Me); dC (100 MHz; CDCl3) 175.1 (C O), 144.9 and 142.7
(a) A solution of tert-butyl 3-[N-benzyl-N-(1R)-1-phenylethyl]-
amino-2-ethylhexanoate diastereomers 12a and 12b (1.00 g,
2.44 mmol) in glacial acetic acid (25 cm3) containing a suspen-
sion of 10% palladium on charcoal (200 mg) was hydrogenated
in an autoclave (7 atm) as described above. The catalyst was
removed by filtration through celite, the plug washed with EtOH,
and all solvent removed under vacuum to afford amines 16
as a yellow oil. The oil was purged with N2, and dissolved
in CHCl3 (25 cm3). NaHCO3 (623 mg, 7.42 mmol) and 4-
chlorobutyryl chloride (1.07 cm3, 1.35 g, 9.57 mmol) were added,
and the resulting mixture was stirred at rt for 18 h. Inorganic
solids were removed by filtration and washed with CHCl3. The
filtrate and washings were concentrated under vacuum to yield
a mixture of the crude amides 17a and 17b (vide infra) as a
brown oil. This oil was purged with N2, then dissolved in dry
ButOH (10 cm3) under an atmosphere of N2. ButOK (542 mg,
4.83 mmol) was added, giving a salmon-pink suspension. The
mixture was stirred at rt for 18 h before being neutralised with
glacial acetic acid, diluted with water (10 cm3) and extracted
with CH2Cl2. As the reaction appeared to be incomplete,
the organic extracts were dried (MgSO4) and evaporated to
dryness. The resulting orange oil was dissolved in fresh ButOH
(10 cm3) containing ButOK (539 mg, 4.80 mmol), and stirred
at rt for a further 18 h. Work-up as described before yielded
an orange oil, which was purified by flash chromatography
on silica gel with EtOAc–hexane (1 : 5) as mobile phase to
yield two oils, (+)-tert-butyl (2R,3R)-3-(2-oxopyrrolidin-1-yl)-2-
ethylhexanoate 18a (165 mg, 24%), and (−)-tert-butyl (2S,3R)-
3-(2-oxopyrrolidin-1-yl)-2-ethylhexanoate 18b (270 mg, 39%), as
well as a mixed fraction (17 mg, 2.5%).
(ArC), 128.5, 128.1, 128.0, 127.8, 126.7 and 126.3 (ArC), 79.9
(OCMe3), 60.2 and 59.3 (NCHPh and NCHPr), 51.8 and 51.2
(NCH2Ph and CHCO2But), 32.9 (NCHCH2Et), 28.0 (OCMe3),
25.0 and 21.1 (remaining CH2), 20.0 (NCHMePh), 14.3 and 11.9
(2 × Me).
(b) Consecutive approach. n-BuLi (1.25 M in hexane,
11.6 cm3, 14.5 mmol) was added dropwise to a solution of
diisopropylamine (2.03 cm3, 1.47 g, 14.5 mmol) in dry
THF (50 cm3) under an atmosphere of N2 at −78 ◦C. Af-
ter 15 min, (+)-tert-butyl (3R)-3-[N-benzyl-N-(1R)-1-phenyl-
ethyl]aminohexanoate9,18 15 (3.69 g, 9.67 mmol) in dry THF
(30 cm3) was added dropwise over 30 min, and the reaction
mixture was stirred for a further 1 h. A solution of iodoethane
(3.55 cm3, 6.92 g, 44.4 mmol) in THF (30 cm3) was then
added. The temperature was maintained at −78 ◦C for 1 h,
after which the mixture was allowed to warm to rt over 18 h.
Saturated aq. NH4Cl solution (20 cm3) was added dropwise.
After 1 h, the reaction mixture was extracted with CH2Cl2.
After drying (MgSO4) and removal of solvent in vacuo, the
yellow oil obtained was purified by column chromatography
on silica gel as described above to yield an inseparable mixture
(ca. 56 : 44, by NMR spectroscopy) of tert-butyl (2R,3R)-
3-[N-benzyl-N-(1R)-1-phenylethyl]amino-2-ethylhexanoate 12a
and its (2S,3R)-epimer 12b (3.49 g, 88%); characterisation as
described above.
tert-Butyl (2R,3R)-3-amino-2-ethylhexanoate 16a and its
(2S,3R) epimer 16b
19
A solution of tert-butyl 3-[N-benzyl-N-(1R)-1-phenylethyl]-
amino-2-ethylhexanoate diastereomers 12a and 12b (188 mg,
0.46 mmol) in glacial acetic acid (5 cm3) containing a suspension
of 10% palladium on charcoal (56 mg) was placed in an
autoclave. The sealed vessel was purged four times with H2
(1 atm), and then left to stir under H2 (7 atm) for 72 h at rt. The
catalyst was removed by filtration over celite, the plug washed
with MeOH, and the filtrate reduced in volume. The resulting
concentrated solution was made basic with aq. NaHCO3
solution (10%), and the mixture was extracted with CH2Cl2. The
organic phase was dried (Na2SO4) and concentrated to yield a
yellow oil. Silica column chromatography with MeOH–EtOAc
(1 : 200) afforded an inseparable mixture (56 : 44) of tert-butyl
(2R,3R)-3-amino-2-ethylhexanoate 16a and its (2S,3R)-epimer
16b (47 mg, 47%) as a yellow oil; Rf 0.19 (EtOAc). The unstable
free amines were rapidly converted into solids on exposure to
the atmosphere, but the following spectroscopic data could be
obtained: mmax(film)/cm−1 3400–3200 (w, br), 2963 (s), 2933 (s),
2874 (s), 1725 (s), 1460 (m), 1368 (m), 1254 (m) and 1155 (s);
18a: Rf 0.50 (EtOAc–hexane, 1 : 2); [a]D +52.7 (c 1.35,
EtOH); mmax(film)/cm−1 2966 (s), 2875 (s), 1725 (s), 1692 (s), 1461
(m), 1423 (m), 1367 (m), 1287 (m) and 1158 (m); dH (400 MHz;
CDCl3; Me4Si) 4.21 (1H, td, J 10.7 and 3.7, NCHPr), 3.48
(1H, dt, J 9.3 and 6.6, NCHaHb), 3.20 (1H, td, J 9.3 and 7.3,
NCHaHb), 2.39–2.31 (3H, m, CHCO2But and ring COCH2),
1.96 (2H, quintet, J ca. 7.6, ring NCH2CH2), 1.62–1.51 and
1.58 (3H, overlapping m and t, J 7.4, chain NCHCH2 and
COCHCHaHb), 1.45–1.35 and 1.40 (10H, overlapping m and s,
COCHCHaHb and OCMe3), 1.26–1.16 (2H, m, remaining CH2),
0.92 and 0.91 (6H, 2 × t, J ca. 7.3, 2 × Me); dC (100 MHz; CDCl3)
=
174.7 and 172.7 (2 × C O), 80.3 (OCMe3), 52.6 and 52.5 (NCH
and CHCO2But), 42.6 (NCH2), 31.6 and 31.1 (NCHCH2Et and
COCH2), 27.6 (OCMe3), 22.8, 19.0 and 18.2 (remaining CH2),
13.7 and 11.5 (2 × Me); m/z (EI) 283 (M+, 1.1%), 227 (4), 210
(8), 184 (4), 141 (13), 140 (100), 98 (13), 86 (9) and 57 (10)
(found: M+, 283.2157. C16H29NO3 requires 283.2147).
19
18b: Rf 0.42 (EtOAc–hexane, 1 : 2); [a]D −16.8 (c 1.43,
EtOH); mmax(film)/cm−1 2965 (s), 2875 (s), 1727 (s), 1690 (s), 1461
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 3 6 – 8 4 7
8 4 1

View Article Online
(m), 1423 (m), 1369 (m), 1266 (m) and 1150 (m); dH (400 MHz;
CDCl3; Me4Si) 4.22 (1H, td, J 11.0 and 3.1, NCHPr), 3.24
(1H, dt, J 9.6 and 7.0, NCHaHb), 3.15 (1H, dt, J 9.6 and
6.9, NCHaHb), 2.41 (2H, t, J 8.0, ring COCH2), 2.28 (1H,
td, J 10.6 and 3.8, CHCO2But), 2.00 (2H, quintet, J ca. 7.5,
ring NCH2CH2), 1.59–1.50 (2H, m, chain NCHCH2), 1.47
(9H, s, OCMe3), 1.42–1.30 and 1.28–1.17 (2 × 2H, 2 × m,
remaining CH2), 0.90 and 0.88 (6H, 2 × t, J ca. 7.4, 2 × Me); dC
52.4 and 51.7 (NCH and CHCO2But), 42.4 (NCH2), 32.1 and
31.3 (NCHCH2Et and COCH2), 28.0 (OCMe3), 23.0, 19.2 and
18.4 (remaining CH2), 13.7 and 11.4 (2 × Me); m/z (EI) 283
(M+, 1.1%), 227 (4), 210 (8), 184 (4), 141 (12), 140 (100), 98 (11),
86 (8) and 57 (9) (found: M+, 283.2139. C16H29NO3 requires
283.2147).
(s), 1642 (s), 1455 (m), 1291 (m), 1196 (m) and 755 (m); dH
(200 MHz; CDCl3; Me4Si) 5.19 (1H, br t, J ca. 7.1, NCHPr),
3.84 (1H, dt, J 10.8 and 6.8, NCHaHb), 3.48 (1H, dt, J 10.8
and 7.5, NCHaHb), 2.97 (2H, t, J 7.8, CSCH2), 2.41 (1H, br
q, J ca. 9.6, CHCO2But), 1.99 (2H, quintet, J ca. 7.6, ring
NCH2CH2), 1.80–1.52 and 1.65 (3H, overlapping m and t, J
7.4, COCHCHaHb and chain NCHCH2), 1.52–1.10 and 1.43
(12H, overlapping m and s, remaining CH2 and OCMe3), 0.94
and 0.92 (6H, 2 × t, J 7.4 and 7.1 2 × Me); dC (50 MHz; CDCl3)
=
(100 MHz; CDCl3) 175.5 and 173.1 (2 × C O), 80.7 (OCMe3),
=
=
202.4 (C S), 172.2 (ester C O), 81.0 (OCMe3), 57.3 (NCHPr),
t
=
53.0 (CHCO2Bu ), 49.3 (br, NCH2), 45.1 (CH2C S), 32.7
(NCHCH2Et), 27.7 (OCMe3), 22.8, 20.1 and 19.0 (remaining
CH2), 14.1 and 11.6 (2 × Me); m/z (EI) 300 (14%), 299 (M+,
71), 266 (10), 243 (16), 242 (67), 226 (35), 214 (12), 210 (62), 198
(30), 157 (51), 156 (53), 125 (29), 124 (32), 115 (55), 102 (100),
101 (12), 85 (18), 57 (28) and 55 (35) (found: M+, 299.1916.
C16H29NO2S requires 299.1919).
(b) In a separate experiment, the unstable intermediate amides
17 were separated for characterisation by flash chromatography
on silica gel with EtOAc–hexane (1 : 5) as the mobile phase. The
following data were recorded.
(b) (−)-tert-Butyl (2S,3R)-3-(2-thioxopyrrolidin-1-yl)-2-
ethylhexanoate 19b. The above procedure was repeated with
(+)-tert-Butyl (3R)-3-[N-(4-chloro-1-oxo)butyl]amino-(2R)-
(−)-tert-butyl
(2S,3R)-3-(2-oxopyrrolidin-1-yl)-2-ethylhexa-
2-ethylhexanoate 17a: beige oil, Rf 0.43 (EtOAc–hexane, 1 : 5);
noate 18b (370 mg, 1.31 mmol) and Lawesson’s reagent (340 mg,
0.84 mmol) in dry toluene (25 cm3). After column chromato-
graphy, thiolactam 19b was obtained as a chromatographically
pure reddish solid (373 mg, 95%), Rf 0.52 (EtOAc–hexane, 3 :
7). Subsequent recrystallisation afforded colourless needles, mp
21
[a]D +228 (c 0.14, hexane); mmax(film)/cm−1 3308 (m, br), 2964
(s), 2934 (s), 2874 (s), 1726 (s), 1651 (s), 1517 (m), 1460 (m), 1369
(m), 1252 (m) and 1155 (s); dH (400 MHz; CDCl3; Me4Si) 6.48
(1H, br d, J ca. 9.3, NH), 4.15–4.11 (1H, m, NCHPr), 3.60 (2H,
t, J 6.3, CH2Cl), 2.38 and 2.37–2.32 (3H, overlapping t, J 7.4,
and m, NHCOCH2 and CHCO2But), 2.12 (2H, quintet, J ca 6.7,
CH2CH2Cl), 1.68–1.60 (1H, m, CHCHaHb), 1.53–1.32 and 1.50
(14H, overlapping m and s, remaining CH2 and OCMe3), 0.94
and 0.91 (6H, 2 × t, J 7.5 and 7.1, 2 × Me); dC (100 MHz; CDCl3)
◦
116–117.5 C (from EtOH–H2O) (found: C, 64.64; H, 9.90; N,
4.67; S, 11.22. C16H29NO2S requires C, 64.17; H, 9.76; N, 4.68;
S, 10.71%); [a]D −139.0 (c 0.26, abs. EtOH); mmax(film)/cm−1
19
2963 (s), 2928 (m), 2872 (m), 1724 (s), 1499 (m), 1451 (m), 1320
(m), 1282 (m) and 1163 (m); dH (400 MHz; CDCl3; Me4Si) 5.25
(1H, br s, NCHPr), 3.55 (1H, dt, J 10.9 and 7.3, NCHaHb),
3.47 (1H, dt, J 10.9 and 7.1, NCHaHb), 3.04 (2H, t, J 7.8,
CSCH2), 2.37 (1H, br s, CHCO2But), 2.05 (2H, quintet, J ca.
7.5, ring NCH2CH2), 1.70–1.60 (2H, m, chain NCHCH2), 1.49
(9H, s, OCMe3), 1.37–1.31 and 1.31–1.16 (2 × 2H, 2 × m,
remaining CH2), 0.92 and 0.89 (6H, 2 × t, J 7.3 and 7.4, 2 ×
=
175.2 and 171.2 (2 × C O), 81.3 (OCMe3), 50.3 and 49.2 (NCH
and CHCO2But), 44.4 (CH2Cl), 36.6 and 33.5 (NCHCH2Et and
NHCOCH2), 28.2 (CH2CH2Cl), 28.1 (OCMe3), 23.6 and 19.4
(remaining CH2), 13.9 and 11.9 (2 × Me); m/z (EI) 319 (M+,
<1%), 276 (9), 246 (14), 222 (13), 220 (38), 178 (15), 177 (11),
176 (46), 140 (12), 116 (75), 72 (100) and 57 (34) (found: M+,
319.1924. C16H30ClNO3 requires 319.1914).
=
=
Me); dC (100 MHz; CDCl3) 203.2 (C S), 172.5 (ester C O),
(−)-tert-Butyl (3R)-3-[N-(4-chloro-1-oxo)butyl]amino-(2S)-
80.9 (OCMe3), 56.9 (br, NCHPr), 51.9 (CHCO2But), 48.8 (br,
=
2-ethylhexanoate 17b: beige oil, Rf 0.32 (EtOAc–hexane, 1 : 5);
NCH2), 45.0 (CH2C S), 32.3 (NCHCH2Et), 27.9 (OCMe3),
22.8, 20.2 and 19.0 (remaining CH2), 13.8 and 11.5 (2 × Me).
General procedure for sulfide contractions
[a]D −246 (c 0.06, hexane); mmax(film)/cm−1 3290 (m), 2965 (s),
21
2874 (s), 1726 (s), 1646 (s), 1548 (m), 1459 (m), 1369 (m), 1257
(m), 1156 (s) and 756 (m); dH (400 MHz; CDCl3; Me4Si) 5.68
(1H, br d, J ca. 7.6, NH), 4.22–4.10 (1H, m, NCHPr), 3.61 (2H,
t, J 6.1, CH2Cl), 2.36 (2H, t, J 7.1, NHCOCH2), 2.27 (1H, ddd,
J 9.9, 6.1 and 4.8, CHCO2But), 2.12 (2H, quintet, J ca. 6.6,
CH2CH2Cl), 1.69–1.63 (1H, m, CHCHaHb), 1.51–1.26 and 1.47
(14H, overlapping m and s, remaining CH2 and OCMe3), 0.93
and 0.91 (6H, 2 × t, J 7.4 and 7.1, 2 × Me); dC (100 MHz; CDCl3)
Solutions of the thiolactams 19a or 19b in MeCN (0.25 M)
were stirred at rt with the appropriate alkylating agent (ethyl
bromoacetate, benzyl bromoacetate or N-methoxy-N-methyl-
2-bromoacetamide, 1.7–1.8 equiv.) under N2 for the stipulated
period. The solvent and excess alkylating agent were removed in
vacuo, and the residue was dissolved in fresh MeCN (0.25 M
solution). PPh3 (1.5 equiv.) and then NEt3 (1.5 equiv.) were
added in that order, the reaction usually generating an exotherm.
The mixture was stirred at rt for 3–5 h. Precipitated solids were
removed by filtration through celite and washed with EtOAc–
hexane (1 : 1). The filtrate was evaporated in vacuo. Column
chromatography of the crude product mixture on silica gel was
performed with CH2Cl2 phosphorus-containing compounds,
after which the desired product was eluted with EtOAc–hexane
mixtures. The following results were recorded.
=
173.1 and 171.1 (2 × C O), 80.9 (OCMe3), 52.8 and 50.0 (NCH
and CHCO2But), 44.5 (CH2Cl), 34.0 and 33.5 (NCHCH2Et and
NHCOCH2), 28.2 (CH2CH2Cl), 28.1 (OCMe3), 22.0 and 19.4
(remaining CH2), 13.8 and 12.1 (2 × Me); m/z (EI) 319 (M+,
<1%), 246 (11), 220 (9), 178 (16), 176 (50), 140 (10), 116 (24), 72
(100) and 57 (31) (found: M+, 319.1913. C16H30ClNO3 requires
319.1914).
tert-Butyl 3-(2-thioxopyrrolidin-1-yl)-2-ethylhexanoate isomers
19a,b
(+)-tert-Butyl (2R,3R)-3-[(2E)-2-(ethoxycarbonylmethy-
(a) (+)-tert-Butyl (2R,3R)-3-(2-thioxopyrrolidin-1-yl)-2-ethyl-
hexanoate 19a. A solution of tert-butyl (+)-(2R,3R)-3-(2-
oxopyrrolidin-1-yl)-2-ethylhexanoate 18a (500 mg, 1.76 mmol)
in dry toluene (25 cm3) containing fresh, dry Lawesson’s reagent
(430 mg, 1.06 mmol) was heated at reflux under an atmosphere
of N2 for 18 h. The mixture was then concentrated in vacuo, and
the residue was purified by column chromatography on silica
gel with hexane–CH2Cl2 to remove Lawesson’s reagent residues,
followed by EtOAc–hexane (3 : 7). (+)-tert-Butyl (2R,3R)-3-(2-
thioxopyrrolidin-1-yl)-2-ethylhexanoate 19a (429 mg, 81%) was
lene)pyrrolidin-1-yl]-2-ethylhexanoate 20a (506 mg, 97%) was
obtained as
a
yellow oil from (+)-tert-butyl (2R,3R)-
3-(2-thioxopyrrolidin-1-yl)-2-ethylhexanoate 19a (444 mg,
1.48 mmol) and ethyl bromoacetate (0.28 cm3, 407 mg,
2.43 mmol) stirred in MeCN (6 cm3) for 76 h, followed by
evaporation, dissolution in fresh MeCN (5 cm3), and treatment
with PPh3 (592 mg, 2.26 mmol) and NEt3 (0.31 cm3, 224 mg,
23
2.21 mmol); yellow oil, Rf 0.17 (EtOAc–hexane, 1 : 19); [a]D
+49.2 (c 1.93, EtOH); mmax(film)/cm−1 2970 (m), 2877 (m), 1727
(s), ca. 1680 (m, shoulder), 1459 (m), 1370 (m), 1257 (m) and
19
=
obtained as a yellow oil; Rf 0.56 (EtOAc–hexane, 3 : 7); [a]D
1158 (m); dH (400 MHz; CDCl3; Me4Si) 4.69 (1H, s, CH), 4.11
and 4.03 (2H, AB system, JAB 10.8, further split into q, J 7.1,
+80.1 (c 1.36, EtOH); mmax(film)/cm−1 2965 (s), 2875 (s), 1721
8 4 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 3 6 – 8 4 7

View Article Online
OCH2Me), 3.74 (1H, br td, J 10.5 and 3.7, NCHPr), 3.39 (1H,
ddd, J 9.3, 7.7 and 5.2, NCHaHb), 3.30–3.10 (2H, m, NCHaHb
(10), 244 (18), 218 (57), 210 (12), 138 (15), 110 (17), 91 (100),
83 (12), 57 (26) and 55 (17) (found: M+, 415.2721. C25H37NO4
requires 415.2723).
=
=
and CCHaHb), 3.06 (1H, ca. dt, J ca. 17.2 and 8.5, CCHaHb),
2.39 (1H, br td, J ca. 9.6 and 3.9, CHCO2But), 1.95–1.80 (2H,
m, ring NCH2CH2), 1.61–1.40 (4H, 2 × m, NCHCH2Et and
COCHCH2Me), 1.40 (9H, s, OCMe3), 1.30–1.15 and 1.24 (6H,
overlapping m and t, J 7.1, remaining CH2 and OCH2CH3),
0.94 and 0.91 (6H, 2 × t, J 7.3 and 7.4, 2 × Me); dC (100 MHz;
(−)-tert-Butyl (2S,3R)-3-[(2E)-2-(benzyloxycarbonylmethy-
lene)pyrrolidin-1-yl]-2-ethylhexanoate 21b (174 mg, 81%) was
obtained from (−)-tert-butyl (2S,3R)-3-(2-thioxopyrrolidin-1-
yl)-2-ethylhexanoate 19b (157 mg, 0.52 mmol) and benzyl
bromoacetate (0.15 cm3, 217 mg, 0.95 mmol) stirred in MeCN
(3 cm3) for 18 h, followed by evaporation, dissolution in fresh
MeCN (3 cm3), and treatment with PPh3 (210 mg, 0.80 mmol)
=
=
CDCl3) 172.2 and 169.6 (2 × C O), 165.5 (NC CH), 80.7
=
(OCMe3), 79.3 (NC CH), 57.9 (OCH2Me), 55.9 (NCHPr), 53.0
t
(CHCO2Bu ), 45.7 (br, NCH2), 32.4 and 32.1 ( CCH2 and chain
and NEt3 (0.11 cm3, 80 mg, 0.79 mmol); yellow oil, Rf 0.58
=
22
NCHCH2Et), 27.7 (OCMe3), 23.1, 21.1 and 19.2 (remaining
CH2), 14.7 (OCH2CH3), 14.0 and 11.5 (2 × Me); m/z (EI) 353
(M+, 13%), 308 (20), 280 (18), 266 (19), 252 (19), 211 (44), 210
(100), 182 (27), 156 (69), 110 (23), 57 (18) and 55 (14) (found: M+,
353.2562. C20H35NO4 requires 353.2566).
(EtOAc–hexane, 3 : 7); [a]D
−38.5 (c 1.21 in ethanol);
mmax(film)/cm−1 3087 (w), 3065 (w), 3031 (w), 2964 (m), 2934
(m), 2874 (m), 1721, 1687 (s), 1580 (s), 1459 (m), 1422 (m), 1389
(m), 1367 (m), 1126 (m) and 1052 (m); dH (400 MHz; CDCl3;
Me4Si; assignments verified by HETCORR) 7.45–7.20 (5H, m,
=
(−)-tert-Butyl
(2S,3R)-3-[(2E)-(2-ethoxycarbonyl)methyl-
ArH), 5.09 (2H, s, PhCH2), 4.77 (1H, s, CH), 3.74 (1H, br t, J
enepyrrolidin-1-yl]-2-ethylhexanoate 20b (345 mg, 96%) was
obtained from (−)-tert-butyl (2S,3R)-3-(2-thioxopyrrolidin-
1-yl)-2-ethylhexanoate 19b (304 mg, 1.02 mmol) and ethyl
bromoacetate (0.19 cm3, 286 mg, 1.71 mmol) stirred in MeCN
(4 cm3) for 77 h, followed by evaporation, dissolution in
fresh MeCN (5 cm3), and treatment with PPh3 (391 mg,
1.49 mmol) and NEt3 (0.21 cm3, 152 mg, 1.50 mmol); yellow
ca. 9.4, NCHPr), 3.25–3.10 and 3.21 (4H, overlapping m and td,
t
=
J 7.7 and 1.4, NCH2 and CCH2), 2.31 (1H, br m, CHCOBu ),
1.90 (2H, quintet, J 7.3, ring NCH2CH2), 1.65–1.45 (2H, m,
COCHCHaHbMe and NCHCHaHbEt), 1.47 (9H, s, OCMe3),
1.40–1.30 (2H, m, COCHCHaHbMe and NCHCHaHbEt), 1.30–
1.10 (2H, m, NCHCH2CH2Me), 0.87 and 0.86 (6H, 2 × t, J 7.1
and 7.4, 2 × Me); dC (100 MHz; CDCl3; assignments verified by
23
=
=
oil, Rf 0.17 (EtOAc–hexane, 1 : 19); [a]D −35.52 (c 0.70,
HETCORR) 173.2 and 169.4 (2 × C O), 166.7 (br, NC CH),
EtOH); mmax(film)/cm−1 2970 (s), 2874 (s), 1725 (s), 1684 (s),
1590 (s), 1377 (m), 1267 (m), 1138 (m) and 1061 (m); dH
137.8 (ArC), 128.3, 127.9 and 127.4 (ArCH), 80.9 (OCMe3),
=
79.3 (NC CH), 64.3 (OCH2Ph), 55.7 (br, NCHPr), 52.0 (br,
CHCO2Bu ), 45.6 (br, NCH2), 32.7 (overlapping CCH2 and
t
=
=
(200 MHz; CDCl3; Me4Si) 4.70 (1H, s, CH), 4.08 (2H, q, J
7.1, OCH2Me), 3.75 (1H, br t, J ca. 10.4, NCHPr), 3.30–3.10
chain NCHCH2Et), 28.0 (OCMe3), 23.1 (COCHCH2Me), 21.1
(ring NCH2CH2), 19.3 (NCHCH2CH2Me), 13.8 and 11.5 (2 ×
Me); m/z (EI) 415 (M+, 13%), 342 (7), 314 (14), 308 (12), 273
(50), 272 (100), 266 (39), 252 (11), 244 (18), 218 (66), 210 (17), 138
(12), 110 (15), 91 (85), 83 (10), 57 (18) and 55 (13) (found: M+,
415.2720. C25H37NO4 requires 415.2723).
=
and 3.20 (4H, m and br t, J ca. 7.7, NCH2 and CCH2),
2.34 [1H, br m (t?), CHCO2But], 1.91 (2H, quintet, J 7.4,
ring NCH2CH2), 1.70–1.32 and 1.48 (12H, overlapping
m and s, NCHCH2Et, COCHCH2Me and OCMe3), 1.32–1.14
and 1.26 (6H, overlapping m and t, J 7.1, remaining CH2
and OCH2CH3), 0.88 and 0.87 (6H, 2 × t, J 7.1 and 7.4, 2 ×
(+)-tert-Butyl
(2R,3R)-2-ethyl-3-{(2E)-[2-(N-methoxy-N-
=
Me); dC (50 MHz; CDCl3) 173.2 and 169.8 (2 × C O), 166.8
methylaminocarbonyl)methylene]pyrrolidin-1-yl}hexanoate 22
(316 mg, 91%) was obtained from (+)-tert-butyl (2R,3R)-
3-(2-thioxopyrrolidin-1-yl)-2-ethylhexanoate 19a (282 mg,
0.94 mmol) and N-methoxy-N-methyl-2-bromoacetamide21
(343 mg, 1.88 mmol), stirred in MeCN (2 cm3) for 40 h, followed
by evaporation, dissolution in fresh MeCN (2 cm3), and
treatment with PPh3 (373 mg, 1.42 mmol) and NEt3 (0.17 cm3,
123 mg, 1.22 mmol); yellow oil, Rf 0.24 (EtOAc–hexane, 1 : 1);
=
=
(NC CH), 80.8 (OCMe3), 79.6 (NC CH), 58.2 (OCH2Me),
55.4 (br, NCHPr), 52.0 (CHCO2But), 45.4 (br, NCH2), 32.7
=
and 32.6 ( CCH2 and chain NCHCH2Et), 28.0 (OCMe3), 23.0,
21.1 and 19.2 (remaining CH2), 14.6 (OCH2CH3), 13.8 and 11.5
(2 × Me); m/z (EI) 353 (M+, 10%), 308 (15), 266 (17), 252 (16),
211 (34), 210 (100), 182 (19), 156 (72), 110 (23), 57 (24) and 55
(20) (found: M+, 353.2587. C20H35NO4 requires 353.2566).
(+)-tert-Butyl (2R,3R)-3-[(2E)-2-(benzyloxycarbonylmethy-
lene)pyrrolidin-1-yl]-2-ethylhexanoate 21a (195 mg, 90%) was
obtained from (+)-tert-butyl (2R,3R)-3-(2-thioxopyrrolidin-1-
yl)-2-ethylhexanoate 19a (157 mg, 0.52 mmol) and benzyl
bromoacetate (0.15 cm3, 217 mg, 0.95 mmol) stirred in MeCN
(2.6 cm3) for 18 h, followed by evaporation, dissolution in
fresh MeCN (2.6 cm3), and treatment with PPh3 (210 mg,
0.80 mmol) and NEt3 (0.11 cm3, 80 mg, 0.79 mmol); yellow
[a]D +148.6 (c 1.26, EtOH); mmax(film)/cm−1 2967 (m), 2875
19
(m), 1723 (s), 1637 (s), 1573 (s), 1455 (m), 1409 (m), 1370 (m),
1253 (m), 1159 (m) and 1099 (m); dH (400 MHz; CDCl3; Me4Si)
5.25 (1H, s, CH), 3.81 (1H, br td, J 10.6 and 3.0, NCHPr),
=
3.68 (3H, s, OMe), 3.40 (1H, ddd, J 9.3, 8.0 and 4.9, NCHaHb),
=
3.27 (1H, dddd, J 17.8, 8.8, 5.5 and 1.0, CCHaHb), 3.15, 3.14
and 3.10 [5H, overlapping br q? (J ca. 7.6?), s and br dd (J ca.
=
17.8 and 8.8), NCHaHb, NMe and, CCHaHb], 2.43 (1H, br
q, J ca. 8.2, CHCO2But), 1.95–1.75 (2H, m, ring NCH2CH2),
1.65–1.50 (4H, m, 2 × CH2), 1.38 (9H, s, OCMe3], 1.29–1.11
(2H, m, CH2), 0.93 and 0.91 (6H, 2 × t, J 7.4 and 7.3, 2 ×
22
oil, Rf 0.64 (EtOAc–hexane, 3 : 7); [a]D +56.7 (c 1.22, EtOH);
mmax(film)/cm−1 3065 (w), 3031 (w), 2965 (m), 2934 (m), 2874
(m), 1721 (s), 1687 (s), 1579 (s), 1457 (m), 1390 (m), 1367 (m),
1258 (m), 1125 (m) and 1052 (m); dH (300 MHz; CDCl3; Me4Si)
7.51–7.21 (5H, m, ArH), 5.15 and 5.02 (2 × 1H, AB system,
=
Me); dC (100 MHz; CDCl3) 172.5 and 172.1 (2 × C O), 165.1
=
=
(NC CH), 80.5 (OCMe3), 78.0 (NC CH), 60.7 (OCMe3), 55.9
(NCHPr), 52.5 (CHCO2But), 45.5 (br, NCH2), 33.0 (NCH3),
=
J 12.6, PhCH2), 4.77 (1H, s, CH), 3.73 (1H, br t, J ca. 10.6,
=
NCHPr), 3.40 (1H, ddd, J 9.3, 8.0 and 5.1, NCHaHb), 3.26–
32.5 and 31.9 ( CCH2 and chain NCHCH2), 27.8 (OCMe3),
=
3.10 (2H, m, NCHaHb and CCHaHb), 3.07 (2H, dt, J 17.8 and
23.0, 21.2 and 19.2 (remaining CH2), 13.9 and 11.6 (2 × Me);
m/z (EI) 368 (M+, absent), 309 (15), 308 (72), 295 (6), 253 (16),
252 (100), 225 (5), 182 (5), 164 (4), 136 (7), 110 (22), 57 (9)
and 55 (10) [found: M+ − N(OMe)Me, 308.2232. C18H30NO3
requires 308.2226. M+ − OCBut, 295.2019. C16H27N2O3 requires
295.2022].
t
=
8.7, CCHaHb), 2.45–2.28 [1H, br m (t?), CHCO2Bu ], 1.95–
1.82 (2H, m, ring NCHCH2), 1.65–1.40 (4H, m, CHCH2Et and
COCHCH2Me), 1.36 (9H, s, OCMe3), 1.19 (2H, sextet, J 7.7,
NCHCH2Me), 0.92 and 0.89 (6H, 2 × t, J 7.4 and 7.5, 2 ×
=
Me); dC (75 MHz; CDCl3) 172.3 and 169.4 (2 × C O), 166.0
=
(NC CH), 138.0 (ArC), 128.3, 127.9 and 127.4 (ArCH), 80.8
=
(OCMe3), 79.0 (NC CH), 64.2 (OCH2Ph), 56.2 (br, NCHPr),
(+)-Ethyl (5R,6R)-6-ethyl-7-oxo-5-propyl-1,2,3,5,6,7-
t
=
53.1 (CHCO2Bu ), ca 46.0 (br, NCH2), 32.6 and 32.2 ( CCH2
hexahydroindolizine-8-carboxylate 28a
and chain NCHCH2Et), 27.8 (OCMe3), 23.2, 21.1 and 19.2
(remaining CH2), 14.0 and 11.6 (2 × Me); m/z (EI) 415 (M+,
123%), 342 (9), 314 (12), 308 (8), 273 (49), 272 (77), 266 (28), 252
(a) A solution of (+)-tert-butyl (2R,3R)-3-[(2E)-(2-ethoxycar-
bonyl)methylenepyrrolidin-1-yl]amino-2-ethylhexanoate 20a
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 3 6 – 8 4 7
8 4 3

View Article Online
(478 mg, 1.35 mmol) in trifluoroacetic acid (2.70 cm3) was
stirred for 3 h at rt. Removal of the solvent in vacuo gave
crude (2R,3R)-3-[(2E)-(2-ethoxycarbonylmethylene)pyrrolidin-
1-yl]-2-ethylhexanoic acid 27a as an orange oil, Rf 0.16
(EtOAc–hexane, 3 : 7); dH (200 MHz; CDCl3; Me4Si) 6.6–6.2
J 7.2, ring NCH2CH2), 1.71–1.30 (4H, m, NCHCH2Et and
COCHCH2Me), 1.30–1.10 and 1.26 (5H, overlapping m and
t, J 7.1, CH2CH2Me and OCH2CH3), 0.91 and 0.88 (6H,
2 × t, J 7.1 and 7.3, 2 × CH3); dC (50 MHz; CDCl3) 179.0
=
=
(CO2H), 170.1 (CO2Et), 166.6 (NC CH), 79.0 (NC CH), 58.5
(OCH2CH3), 55.4 (NCHPr), 51.3 (CHCO2H), 45.7 (NCH2),
=
(1H, br s, CO2H), 4.66 (1H, s, CH), 4.04 [2H, overlapping q
=
(= incipient AB system, JAB ca. 3.7), J 7.1, OCH2CH3], 3.78
32.9 and 32.7 ( CCH2 and chain NCHCH2Et), 22.9, 21.2
(1H, br td, J 9.9 and 3.5, NCHPr), 3.40 (1H, ddd, J 9.2, 7.6
and 19.4 (remaining CH2), 14.7 (OCH2CH3), 13.8 and 11.7
(2 × Me); m/z (EI) 297 (M+, 10%), 252 (31), 211 (28), 210
(100), 182 (28), 156 (46), 136 (10), 110 (35) 102 (10) and 55 (23)
(found: M+, 297.1945. C16H27NO4 requires 297.1940).
=
and 5.5, NCHaHb), 3.20–2.90 (3H, m, CHaHbN and CCH2),
2.49 (1H, br dt, J ca. 8.5 and 7.7, CHCO2H), 1.95–1.80 (2H,
m, ring NCH2CH2), 1.80–1.40 (4H, m, NCHCH2Et and
COCHCH2Me), 1.32–1.00 and 1.23 (5H, overlapping m and t,
J 7.1, CH2CH2Me and OCH2CH3), 0.92 and 0.89 (6H, 2 × t, J
6.9 and 7.4, 2 × Me); dC (50 MHz; CDCl3) 177.9 (CO2H), 170.3
(b) The unpurified acid 27b was dissolved in MeCN (5.0 cm3)
containing K2CO3 (75 mg, 0.54 mmol, 2.0 equiv.) and acetic
anhydride (0.05 cm3, 54 mg, 0.53 mmol). The mixture was
stirred at 50 ◦C under N2 for 24 h, by which stage a thick
crystalline suspension had formed. A further portion of acetic
anhydride (0.05 cm3, 54 mg, 0.53 mmol) was added, and heating
was maintained for 12 h. The mixture was concentrated in
vacuo, then partitioned between H2O (5.0 cm3) and CH2Cl2. The
organic extracts were dried (MgSO4), filtered and evaporated
in vacuo. The resulting orange oil was purified by column
chromatography on silica gel with EtOAc as eluent. A mixture
of 28a and (+)-ethyl (5R,6S)-6-ethyl-7-oxo-5-propyl-1,2,3,5,6,7-
hexahydroindolizine-8-carboxylate 28b (39 mg, 52%; ca. 3 :
1) was isolated as yellow oil. Careful flash chromatography
afforded a small quantity of pure 28b for characterisation;
=
=
(CO2Et), 166.1 (NC CH), 78.7 (NC CH), 58.4 (OCH2CH3),
56.3 (NCHPr), 51.2 (CHCO2H), ca. 45 (missing or v br, NCH2),
=
32.7 and 31.9 ( CCH2 and chain NCHCH2Et), 22.7, 21.2 and
19.3 (remaining CH2), 14.6 (OCH2CH3), 13.9 and 11.8 (C-6)
(2 × Me).
(b) The unpurified acid 27a was dissolved in MeCN (7.0 cm3)
containing K2CO3 (564 mg, 4.08 mmol) and acetic anhydride
(0.51 cm3, 551 mg, 5.40 mmol). The solution was stirred at
rt under an atmosphere of N2 for 18 h, by which stage a
thick crystalline suspension had formed. The mixture was
heated under reflux for 3 h, then cooled to rt. The solids
were removed by filtration, and the filtrate was added to
a saturated aq. KHCO3 solution. Extraction with CH2Cl2,
drying (MgSO4), evaporation and chromatography on sil-
ica gel with EtOAc followed by MeOH–EtOAc (1 : 19)
yielded (+)-ethyl (5R,6R)-6-ethyl-7-oxo-5-propyl-1,2,3,5,6,7-
hexahydroindolizine-8-carboxylate 28a (321 mg, 85%); as a pale
19
Rf 0.53 (MeOH–EtOAc, 1 : 9); [a]D +38.1 (c 0.85, EtOH);
mmax(film)/cm−1 2962 (m), 2935 (m), 2876 (m), 1707 (m), 1647
(m), 1568 (s), 1462 (m), 1380 (m), 1307 (m), 1235 (m), 1154
(m) and 1103 (m); dH (400 MHz; CDCl3; Me4Si; assignments
confirmed by HETCORR) 4.20 [2H, overlapping q (= incipient
AB system), J 7.1, OCH2CH3], 3.75 (1H, dt, J 10.3 and 7.3,
3-Heq), 3.67–3.57 (2H, m, 3-Hax and 5-H), 3.37 (1H, dt, J 18.6
and 8.1, 1-Ha), 3.21 (1H, dt, J 18.6 and 7.6, 1-Hb), 2.48 (1H,
dt, J 7.1 and 5.8, 6-H), 2.10 (2H, quintet, J 7.5, 2-H), 1.93
[1H, ca. septet, J ca. 7.2, C(6)CHaHbMe], 1.71–1.57 [1H, m,
C(5)CHaHbEt], 1.56–1.42 [1H, m, C(5)CHaHbEt], 1.42–1.20
and 1.32 [6H, overlapping m and t, J 7.1, C(6)CHaHbMe,
C(5)CH2CH2Me and OCH2CH3], 0.96 and 0.91 (6H, 2 × t, J 7.5
and 7.2, 2 × Me); dC (100 MHz; CDCl3; assignments confirmed
by DEPT and HETCORR) 190.1 (C-7), 171.4 (C-8a), 166.4
19
yellow oil, Rf 0.46 (MeOH–EtOAc, 1 : 9); [a]D +50.5 (c 1.76,
EtOH); mmax(film)/cm−1 2961 (m), 2939 (m), 2876 (m), 1699
(m), 1653 (mO), 1559 (s), 1458 (m), 1381 (m), 1306 (m), 1236
(m), 1155 (m) and 1101 (m); dH (400 MHz; CDCl3; Me4Si;
assignments unambiguous by COSY, COLOC, NOESY and
HETCORR) 4.22 [2H, overlapping q (= incipient AB system),
J 7.1, OCH2CH3], 3.75 (1H, dt, J 10.3 and 7.8, 3-Heq), 3.51
(1H, ddd, J 10.3, 8.5 and 5.3, 3-Hax), 3.36 (1H, t, J 7.1, 5-H),
3.31 (1H, t?, J ca. 8.6, 1-Ha), 3.26 (1H, ddd, J 18.6, 8.4 and
5.9, 1-Hb), 2.20–2.04 (3H, m, 6-H and 2-H), 1.69–1.55 and 1.59
[3H, m and sextet?, J 7.6?, C(6)CHaHbMe and C(5)CH2Et],
1.48–1.35 [2H, m (= ca. septet, J ca. 7.5), C(6)CHaHbMe
and C(5)CH2CHaHbMe], 1.33–1.20 and 1.31 [4H, m and t,
J 7.1, C(5)CH2CHaHbMe and OCH2CH3], 0.96 [3H, t, J
7.5, C(6)CH2Me] and 0.90 [3H, t, J 7.3, C(5)CH2CH2Me];
dC (100 MHz; CDCl3; assignments unambiguous by COSY,
COLOC and HETCORR) 190.9 (C-7), 170.1 (C-8a), 166.4 (ester
=
=
(ester C O), 97.3 (C-8), 59.2 (OCH2CH3), 57.2 (C-5), 53.6 (C-
3), 48.8 (C-6), 34.6 (C-1), 29.0 [C(5)CH2Et], 21.0 (C-2), 19.5
[C(5)CH2CH2Me], 17.8 [C(6)CH2Me], 14.4 (OCH2CH3), 14.0
[C(5)CH2CH2Me] and 12.0 [C(6)CH2Me]; m/z (EI) 279 (M+,
8%), 248 (11), 234 (8), 222 (59), 208 (18), 204 (15), 196 (20), 140
(100) and 98 (16) (found: M+, 279.1835. C16H25NO3 requires
279.1834).
C
O), 95.8 (C-8), 59.3 (OCH2CH3), 58.2 (C-5), 53.8 (C-3),
50.9 (C-6), 34.8 (C-1), 31.8 [C(5)CH2Et], 24.6 [C(6)CH2Me],
21.1 (C-2), 18.7 [C(5)CH2CH2Me], 14.5 (OCH2CH3), 13.7
[C(5)CH2CH2Me] and 11.5 [C(6)CH2Me]; m/z (EI) 280 (MH+,
8%), 279 (M+, 41), 250 (6), 239 (10), 238 (69), 237 (8), 236 (23),
234 (49), 209 (13), 208 (100), 207 (10), 192 (11), 190 (52), 164 (36),
162 (26), 124 (23) and 55 (15) (found: M+, 279.1843. C16H25NO3
requires 279.1834).
(+)-Benzyl (5R,6R)-6-ethyl-7-oxo-5-propyl-1,2,3,5,6,7-
hexahydroindolizine-8-carboxylate 29a
A solution of (+)-tert-butyl (2R,3R)-3-[(2E)-(2-benzyloxy-
carbonyl)methylenepyrrolidin-1-yl]amino-2-ethylhexanoate 21a
(174 mg, 0.42 mmol) in trifluoroacetic acid (2 cm3) was stirred for
3 h at rt, followed by concentration in vacuo. The intermediate
carboxylic acid, obtained as an orange oil, was immediately
dissolved in MeCN (5 cm3), to which K2CO3 (173 mg,
1.25 mmol) was added, followed by acetic anhydride (0.16 cm3,
173 mg, 1.69 mmol). The mixture was heated under reflux
for 18 h in an atmosphere of N2, affording a thick crystalline
suspension. Work-up as described above followed by flash chro-
matography on silica gel (EtOAc, then MeOH–EtOAc, 1 : 19)
yielded (+)-benzyl (5R,6R)-6-ethyl-7-oxo-5-propyl-1,2,3,5,6,7-
hexahydroindolizine-8-carboxylate 29a (114 mg, 80%) as a pale
(+)-Ethyl (5R,6S)-6-ethyl-7-oxo-5-propyl-1,2,3,5,6,7-
hexahydroindolizine-8-carboxylate 28b
(a) A solution of (−)-tert-butyl (2S,3R)-3-[(2E)-(2-ethoxycar-
bonyl)methylenepyrrolidin-1-yl]amino-2-ethylhexanoate 20b
(96 mg, 0.27 mmol) in trifluoroacetic acid (0.45 cm3) was
stirred for 3 h at rt. Removal of the solvent in vacuo gave
crude (2S,3R)-3-[(2E)-(2-ethoxycarbonylmethylene)pyrrolidin-
1-yl]-2-ethylhexanoic acid 27b as an orange oil, Rf 0.20
(EtOAc–hexane, 3 : 7); dH (200 MHz; CDCl3; Me4Si) 8.5–7.5
22
yellow oil; Rf 0.38 (MeOH–EtOAc, 1 : 9); [a]D +25.8 (c 0.66,
EtOH); mmax(film)/cm−1 2960 (m), 2932 (m), 2874 (m), 1711
(m), 1676 (s), 1648 (s), 1566 (s), 1458 (m), 1384 (m), 1307
(m), 1232 (m), 1152 (m) and 1102 (m); dH (200 MHz; CDCl3;
Me4Si) 7.50–7.40 (2H, m, ArH), 7.35–7.20 (3H, m, ArH), 5.23
=
(1H, br s, CO2H), 4.74 (1H, s, CH), 4.09 (2H, q, OCH2CH3,
J 7.1), 3.84 (1H, br t, NCH, J 8.7), 3.35–3.00 (4H, br t, NCH2
=
and CCH2), 2.50 [1H, br m (t?), CHCO2H], 1.93 (2H, quintet,
8 4 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 3 6 – 8 4 7

View Article Online
(2H, s, OCH2Ph), 3.74 (1H, dt, J 10.4 and 7.9, 3-Heq), 3.49
(1H, ddd, J 10.5, 7.7 and 6.0, 3-Hax), 3.36 (1H, t, J 7.0, 5-
H), 3.28 (1H, ca. t, J ca. 8.5, 1-Ha), 3.25 [1H, m (= dd?, J ca.
8.4 and 6.9), 1-Hb], 2.25–2.00 [3H, m (including dt? J ca. 17.6
and 8.0?), 6-H and 2-H], 1.80–1.55 [3H, m (including sextet?,
J ca. 7.2), C(6)CHaHbMe and C(5)CH2Et], 1.55–1.20 (3H, m,
C(6)CHaHbMe and C(5)CH2CH2Me], 0.97 and 0.90 (6H, 2 ×
t, J ca. 7.0, 2 × Me); dC (50 MHz; CDCl3) 190.7 (C-7), 170.0
(96 mg, 83%) as a yellow oil; Rf 0.29 (MeOH–EtOAc, 1 : 9);
[a]D +103.1 (c 0.74, EtOH); mmax(film)/cm−1 2961 (m), 2934
18
(m), 2877 (m), 1724 (w), 1616 (s), 1576 (s), 1466 (m), 1385 (m),
1276 (m), 1081 (m) and 1014 (m); dH (200 MHz; CDCl3; Me4Si)
3.69 (3H, s, OMe), 3.69 (1H, dt, J 10.2 and 7.5, 3-Heq), 3.48
(1H, ddd, J 10.2, 7.4 and 6.0, 3-Hax), 3.38 (1H, br t, J 6.6,
5-H), 3.21 (3H, s, NMe), 3.10–2.90 (2H, m, 1-H), 2.21–2.00
(3H, m, 2-H and 6-H), 1.80–1.15 [6H, m, C(5)CH2CH2Me,
C(6)CH2Me], 0.98 [3H, t, J 7.4, C(6)CH2Me] and 0.92 [3H,
t, J 7.2, C(5)CH2CH2Me]; dC (50 MHz; CDCl3) 188.8 (C-7),
=
(C-8a), 165.8 (ester C O), 137.1 (ArC), 128.0, 127.3 and 127.1
(ArCH), 95.2 (C-8), 64.7 (OCH2Ph), 58.2 (C-5), 53.7 (C-3), 50.7
(C-6), 34.6 (C-1), 31.7 [C(5)CH2Et], 24.5 [C(6)CH2Me], 20.9
(C-2), 18.5 [C(5)CH2CH2Me], 13.5 [C(5)CH2CH2Me] and 11.3
[C(6)CH2Me]; m/z (EI) 341 (M+, 23%), 298 (6), 270 (31), 248
(11), 235 (19), 234 (90), 207 (36), 190 (15), 164 (23), 136 (17),
91 (100) and 55 (16) (found: M+, 341.2003. C21H27NO3 requires
341.1991).
=
166.1 (amide C O), 99.1 (C-8), 60.7 (OMe), 58.2 (C-5), 53.0
(C-3), 50.2 (C-6), 34.5 (br, NMe), 32.0 (C-1), 31.8 [C(5)CH2Et],
24.8 [C(6)CH2Me], 21.3 (C-2), 18.7 [C(5)CH2CH2Me], 13.8
[C(5)CH2CH2Me] and 11.5 [C(6)CH2Me], signal for C-8a
missing or obscured; m/z (EI) M+ absent, 279 (M+ − Me, 32%),
250 (4.6, M+ − CH3CH2), 236 (18), 234 (43), 222 (9), 209 (13),
208 (100), 207 (10), 191 (9), 190 (59), 164 (37), 162 (34), 136
(14), 109 (9) and 55 (17) [found: M+ − N(OMe)Me, 234.1493.
C14H20NO2 requires 234.1494].
Benzyl (5R,6S)-6-ethyl-7-oxo-5-propyl-1,2,3,5,6,7-
hexahydroindolizine-8-carboxylate 29b
A solution of (−)-tert-butyl (2S,3R)-3-[(2E)-(2-benzyloxycar-
bonyl)methylenepyrrolidin-1-yl]amino-2-ethylhexanoate (21b)
(308 mg, 0.74 mmol) in trifluoroacetic acid (2.5 cm3) was
stirred for 3 h at rt, followed by concentration in vacuo.
The intermediate carboxylic acid, obtained as an orange oil,
was immediately dissolved in MeCN (3.7 cm3), to which
K2CO3 (321 mg, 2.32 mmol) was added, followed by acetic
anhydride (0.28 cm3, 302 mg, 2.96 mmol). The mixture was
heated under reflux for 18 h in an atmosphere of N2. Work-
up as described above followed by flash chromatography
on silica gel (EtOAc, then MeOH–EtOAc, 1 : 19) yielded
three fractions: (+)-benzyl (5R,6R)-6-ethyl-7-oxo-5-propyl-
1,2,3,5,6,7-hexahydroindolizine-8-carboxylate 29a (81 mg, 32%)
as a pale yellow oil, Rf 0.38 (MeOH–EtOAc, 1 : 9); char-
acterisation as described above; a mixed fraction (22 mg,
9%); and benzyl (5R,6S)-6-ethyl-7-oxo-5-propyl-1,2,3,5,6,7-
hexahydroindolizine-8-carboxylate 29b (31 mg, 12%) as a pale
yellow oil; Rf 0.34 (MeOH–EtOAc, 1 : 9); mmax(film)/cm−1 2960
(m), 2933 (m), 2874 (m), 1710 (m), 1653 (m), 1647 (m), 1559 (s),
1458 (m), 1387 (m) and 1129 (m); dH (200 MHz; CDCl3; Me4Si)
7.45–7.10 (5H, m, ArH), 5.16 (2H, s, OCH2Ph), 3.66 (1H, dt,
J 10.2 and 7.4, 3-Heq), 3.60–3.45 (2H, m, 3-Hax and 5-H), 3.26
(1H, dt, J 18.7 and 8.2, 1-Ha), 3.11 (1H, dt, J 18.6 and 7.7, 1-Hb),
2.42 (1H, dt, J 7.2 and 5.6, 6-H), 1.99 (2H, quintet, J 7.6, 2-H),
1.84 [1H, ca. septet, J ca. 5.9, C(6)CHaHbMe], 1.70–1.00 (5H,
m, remaining CH2), 0.88 and 0.84 (6H, 2 × t, J 7.5 and 7.0,
2 × Me); dC (50 MHz; CDCl3) 190.2 (C-7), 171.7 (C-8a), 166.2
Ethyl (5R,6R,8S,8aS)-6-ethyl-7-oxo-5-propyloctahydroindo-
lizine-8-carboxylate 31 and its (5R,6R,8R,8aR) isomer 32
(a) LiAlH4 (49 mg, 1.29 mmol) was added to a solu-
tion of (+)-ethyl (5R,6R)-6-ethyl-7-oxo-5-propyl-1,2,3,5,6,7-
hexahydroindolizine-8-carboxylate 28a (199 mg, 0.71 mmol) in
dry THF (8.5 cm3) in a flame-dried flask under an atmosphere
of N2 at −78 ◦C. The mixture was stirred at this temperature
for 2.5 h, allowed to warm to room temperature, then treated
sequentially with water (50 ll), aqueous NaOH solution (15%;
50 ll) and water (150 ll). The granular precipitate was filtered
off through celite, the solids were washed with acetone, and the
filtrate was evaporated in vacuo. Column chromatography of the
crude product on silica gel with EtOAc–hexane (1 : 9) eluent
yielded an inseparable mixture of ethyl (5R,6R,8S,8aS)-6-ethyl-
7-oxo-5-propyloctahydroindolizine-8-carboxylate 31 and a mi-
nor isomer 32 with putative (5R,6R,8R,8aR)-stereochemistry
(158 mg, 79%; ratio 3 : 1 by NMR spectroscopy) as a yellow
oil; Rf 0.26 (EtOAc–hexane, 1 : 9); mmax(film)/cm−1 2961 (s), 2934
(s), 2876 (s), 2801 (m, Bohlmann band), 1744 (s), 1717 (s), 1566
(s), 1462 (m), 1378 (m), 1335 (m), 1303 (m), 1258 (m), 1204
(m), 1174 (m), 1151 (m), 1098 (m) and 1026 (m); m/z (EI) 281
(M+, 8%), 252 (17), 239 (14), 238 (100), 222 (27), 208 (32), 192
(17), 170 (13), 140 (12), 138 (27), 124 (38), 70 (15) and 55 (24)
(found: M+, 281.1953. C16H27NO3 requires 281.1991). Most of
the signals due to the individual isomers were distinguishable
by NMR spectroscopy. Major isomer 31: dH (400 MHz; CDCl3;
Me4Si) 4.22 [2H, overlapping q (= incipient AB system), J 7.2,
OCH2CH3], 3.31 (1H, d, J 11.0, 8-H), 3.15 (1H, td, J 8.7 and
2.8, 3-Heq), 2.73 (1H, ddd, J 11.0, 8.8 and 6.2, 8a-H), 2.35
(1H, br m, 5-H), 2.20 (1H, q?, J ca. 8.8, 6-H), 2.10–1.95 (1H,
m, 3-Hax), 1.95–1.70 (3H, m, 1-H and 2-Ha), 1.67–1.55 [4H,
m, 2-Hb, C(5)CH2Et and C(5)CH2CHaHbMe], 1.55–1.42 [2H,
m, C(5)CH2CHaHbMe and C(6)CHaHbMe], 1.42–1.25 and 1.28
[4H, overlapping m and t, J 7.2, C(6)CHaHbMe and OCH2CH3],
0.94 and 0.91 (6H, 2 × t, J 7.1 and 7.4, 2 × Me); dC (100 MHz;
=
(ester C O), 137.4 (ArC), 128.3, 127.6 and 127.3 (ArCH), 97.2
(C-8), 65.0 (OCH2Ph), 57.4 (C-5), 53.7 (C-3), 49.0 (C-6), 34.7 (C-
1), 29.2 [C(5)CH2Et], 21.1 (C-2), 19.6 [C(5)CH2CH2Me], 17.9
[C(6)CH2Me], 14.1 [C(5)CH2CH2Me] and 12.0 [C(6)CH2Me];
m/z (EI) 341 (M+, 19%), 339 (14), 284 (9), 270 (20), 249 (21),
248 (61), 235 (11), 234 (61), 231 (21), 207 (22), 164 (12), 140 (71),
136 (9), 91 (100) and 55 (15) (found: M+, 341.1998. C21H27NO3
requires 341.1991).
(+)-(5R,6R)-6-Ethyl-N-methoxy-N-methyl-7-oxo-5-propyl-
=
CDCl3) 205.7 (C-7), 168.6 (ester C O), 65.3 (C-8a), 64.0 (C-
1,2,3,5,6,7-hexahydroindolizine-8-carboxamide 30
5), 62.7 (C-8), 60.8 (OCH2CH3), 52.3 (C-6), 49.8 (C-3), 33.2
[C(5)CH2Et], 29.8 (C-1), 21.3 (C-2), 17.9 and 16.2 (remaining
CH2), 14.1 (OCH2CH3), 14.4 and 11.6 (2 × Me). Discernible
signals for minor isomer 32: dH (400 MHz; CDCl3; Me4Si) 3.29
(d, J 10.3, 8-H), 2.98 (br d, J ca. 11.0, 8a-H), 2.87 (td, J 8.4
and 3.7, 3-Heq), 1.28 (t, J 7.2, OCH2CH3) and 0.91 (t, J 7.6,
remaining Me); dC (100 MHz; CDCl3) 208.5 (C-7), 169.0 (ester
=
A solution of (+)-tert-butyl (2R,3R)-2-ethyl-3-{(2E)-[2-(N-
methoxy-N-methylaminocarbonyl)methylene]pyrrolidin-1-yl}-
hexanoate 22 (145 mg, 0.39 mmol) in trifluoroacetic acid
(1.0 cm3) was stirred for 3 h at rt, followed by concentration in
vacuo. The intermediate carboxylic acid, obtained as a brown oil,
was immediately dissolved in MeCN (2.0 cm3), to which K2CO3
(170 mg, 1.23 mmol) was added, followed by acetic anhydride
(0.15 cm3, 162 mg, 1.59 mmol). The mixture was heated under
reflux for 18 h in an atmosphere of N2. Work-up as described
above followed by chromatography on silica gel (MeOH–EtOAc,
1 : 9) yielded (+)-(5R,6R)-6-ethyl-N-methoxy-N-methyl-7-oxo-
C
O), 60.6 (OCH2CH3), 59.3, 57.6, 56.1, 48.6, 31.1, 27.7, 24.8,
22.3, 20.1, 14.0 and 12.1; two signals obscured by major isomer.
(b) When the above procedure was repeated with ethyl
(5R,6S)-6-ethyl-7-oxo-5-propyl-1,2,3,5,6,7-hexahydroindoli-
zine-8-carboxylate 28b (388 mg, 1.39 mmol) and LiAlH4 (91 mg,
2.40 mmol) in THF (15 cm3) under the conditions described
5-propyl-1,2,3,5,6,7-hexahydroindolizine-8-acetamide
30
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 3 6 – 8 4 7
8 4 5

View Article Online
above, the same mixture of isomers 31 and 32 (254 mg, 65%;
ratio 4 : 1 by NMR spectroscopy) was obtained as a yellow oil;
characterisation as described in (a).
J 7.1, C(5)CH2CHaHbMe and OCH2CH3], 0.94, 0.92 and 0.91
(9H, 3 × t, J 7.2, 7.5 and 7.4, 3 × Me); dC (100 MHz, CDCl3)
=
208.9 (C-7), 171.5 (ester C O), 68.5 (C-8a), 65.8 (C-8), 64.7 (C-
5), 60.6 (OCH2CH3), 51.1 (C-6), 49.9 (C-3), 33.0 [C(5)CH2Et],
24.2 (C-1), 21.6 (C-2), 20.9, 17.8 and 15.5 (remaining CH2), 14.1
(OCH2CH3), 14.5, 11.9 and 9.2 (3 × Me). Discernible signals for
minor isomer: dH 1.26 (t, J 7.1); dC 65.8, 60.4, 52.1, 51.5, 33.5,
25.0, 24.9, 22.3, 18.4, 15.6, 11.9 and 9.4.
Benzyl (5R,6R,8S,8aS)-6-ethyl-7-oxo-5-propyloctahydroindo-
lizine-8-carboxylate 33 and its (5R,6R,8R,8aR) isomer 34
When the above procedure was repeated with (+)-benzyl
(5R,6S)-6-ethyl-7-oxo-5-propyl-1,2,3,5,6,7-hexahydroindoli-
zine-8-carboxylate 29a (134 mg, 0.39 mmol) and LiAlH4 (22 mg,
0.58 mmol) in THF (3.9 cm3) under the conditions described
above, an inseparable mixture of benzyl (5R,6R,8S,8aS)-6-
ethyl-7-oxo-5-propyloctahydroindolizine-8-carboxylate 33 and
a minor isomer, probably (5R,6R,8R,8aR)-34 (99 mg, 73%;
ratio 3 : 1 by NMR spectroscopy) was obtained as a pale
yellow oil after purification by chromatography on silica gel
with EtOAc–hexane (1 : 9) as eluent; Rf 0.70 (MeOH–EtOAc,
1 : 9); mmax(film)/cm−1 3066 (w), 3033 (w), 2960 (m), 2934 (m),
2874 (m), 2801 (m, Bohlmann band), 1744 (s), 1713 (s), 1458
(m), 1382 (m), 1337 (m), 1302 (m), 1259 (m), 1146 (m), 749 (m)
and 697 (m); m/z (EI) 343 (M+, 7%), 301 (11), 300 (51), 234
(8), 222 (13), 192 (7), 140 (19), 124 (24), 91 (100) and 55 (13)
(found: M+, 343.2131. C21H29NO3 requires 343.2147). Most of
the signals due to the major isomer 33: were distinguishable by
NMR spectroscopy: dH (200 MHz; CDCl3; Me4Si) 7.40–7.20
(5H, m, aryl H), 5.20 (2H, distorted AB system, JAB ca. 12.4,
OCH2Ph), 3.38 (1H, d, J 11.1, 8-H), 3.13 (1H, td, J 8.3 and 3.2,
3-H-3eq), 2.75 (1H, ddd, J 11.1, 8.8 and 6.3, 8a-H), 2.30–2.40
(1H, br m, 5-H), 2.19 (1H, ca. q, J ca. 8.7, 6-H), 2.10–1.85 (1H,
m, 3-Hax), 1.85–1.70, 1.70–1.50 and 1.50–1.10 (3H + 6H +
1H, clusters of m, remaining CH2), 0.93 and 0.90 (6H, 2 × t,
7.1 and 7.4, 2 × Me); dC (50 MHz; CDCl3) 205.4 (C-7), 168.5
(+)-(5R,6R)-6-Ethyl-5-propyl-2,3,5,6-tetrahydroindolizin-
7(1H)-one 37
A suspension of (+)-ethyl (5R,6R)-6-ethyl-7-oxo-5-propyl-
1,2,3,5,6,7-hexahydroindolizine-8-carboxylate 28a (245 mg,
0.88 mmol) in aqueous NaOH solution (1 M, 5 cm3) was heated
under reflux for 1.5 h. The hot homogeneous solution was then
made acidic with conc. HCl, and heating was continued for
30 min. The solution was cooled to room temperature and
extracted with CH2Cl2. The extracts were dried (MgSO4), filtered
and evaporated in vacuo, and the resulting yellow oil was purified
by column chromatography on silica gel with EtOAc–hexane
(1 : 2) as eluent to give (+)-(5R,6R)-6-ethyl-5-propyl-2,3,5,6-
tetrahydroindolizin-7(1H)-one 37 (153 mg, 84%) as a pale yellow
22
oil, Rf 0.36 (EtOAc–hexane, 1 : 2); [a]D +210.01 (c 1.49, EtOH);
mmax(film)/cm−1 2960 (m), 2933 (m), 2873 (m), 1626 (m), 1576 (s),
11506 (w), 1472 (w), 1241 (w), 1186 (w), 1151 (w) and 1080 (w);
dH (200 MHz; CDCl3; Me4Si) 4.84 (1H, d, J 0.7, 8-H), 3.60 (1H,
dt, J 9.8 and 7.4, 3-Ha), 3.42 and 3.35 [2H, overlapping dt (J 9.8
and 6.5) and br td (J ca 5.1 and 1.4), 5-H and 3-Hb], 2.68 (2H,
br t, J ca. 7.5, 1-H), 2.07 and 2.06 (3H, ca. t and quintet, J ca.
7.6, 6-H and 2-H), 1.80–1.15 (6H, m, remaining CH2), 0.97 and
0.91 (6H, 2 × t, J 7.4 and 7.1, 2 × Me); dC (50 MHz, CDCl3)
193.8 (C-7), 165.0 (C-8a), 89.8 (C-8), 58.1 (C-5), 51.8 (C-3), 50.0
(C-6), 31.9 (C-1), 30.8 [C(5)CH2Et], 25.1 [C(6)CH2Me], 21.4
(C-2), 18.6 [C(5)CH2CH2Me], 13.8 [C(5)CH2CH2Me] and 11.4
[C(6)CH2Me]; m/z (EI) 207 (M+, 31%), 192 (5), 178 (7), 165
(12), 164 (53), 140 (9), 137 (10), 136 (100), 110 (22) and 55 (10)
(found: M+, 207.1630. C13H21NO requires 207.1623).
=
(ester C O), 135.7 (ArC), 128.4, 128.1 and 128.0 (ArCH), 66.6
(OCH2Ph), 65.3 (C-8a), 64.0 (C-5), 62.8 (C-8), 52.3 (C-6), 49.7
(C-3), 33.2 [C(5)CH2Et], 29.8 (C-1), 21.3 (C-2), 17.9 and 16.2
(remaining CH2), 14.4 and 11.6 (2 × Me). Discernible signals
for minor isomer 34: dH 3.36 (d, J 10.3); dC 63.7, 60.7, 59.4, 56.1,
48.6, 31.1, 30.8, 22.6, 20.1, 18.4, 14.0 and 12.1.
Ethyl 6,8-diethyl-7-oxo-5-propyloctahydroindolizine-8-
carboxylate isomers 35
Acknowledgements
NaH (19 mg, 0.79 mmol) was added in a single portion to
a solution of ethyl (5R,6R,8S,8aS)-6-ethyl-7-oxo-5-propylocta-
hydroindolizine-8-carboxylate 31 and its (5R,6R,8R,8aR) iso-
mer 32 (113 mg, 0.40 mmol) in THF (2.0 cm3) under an
atmosphere of N2 at 0 ◦C. The solution changed colour from
purple to deep green over 1.5 h. Iodoethane (0.04 cm3, 78 mg,
0.50 mmol) was then added, and the mixture was left to react
at rt for 7 d. After addition of saturated aqueous NH4Cl
(2.0 cm3) solution, the mixture was extracted with CH2Cl2.
The extracts were dried (Na2SO4), filtered and evaporated in
vacuo. Chromatography of the crude orange oil on silica gel
with EtOAc–hexane (1 : 19) as eluent yielded a mixture of
isomers of ethyl 6,8-diethyl-7-oxo-5-propyloctahydroindolizine-
8-carboxylate 35 (43 mg, 35%; 4 : 1 by NMR spectroscopy) as a
pale yellow oil; Rf 0.34 (EtOAc–hexane, 1 : 19); mmax(film)/cm−1
2961 (m), 2876 (m), 2796 (w, Bohlmann band), 1734 (s), 1711
(s), 1458 (m), 1374 (m), 1310 (w), 1239 (m), 1184 (w), 1125 (m)
and 1026 (w); m/z (EI) 309 (M+, 10), 294 (10), 267 (17), 266
(100), 236 (9), 166 (11), 140 (49), 125 (13), 124 (39), 97 (10),
70 (23), 69 (11), 57 (11) and 55 (21) (found: M+, 309.2307.
C18H31NO3 requires 309.2304). Discernible signals for major
isomer, tentatively assigned as (5R,6R,8R,8aS): dH (400 MHz;
CDCl3; Me4Si) 4.27–4.12 [2H, overlapping q (= incipient AB
system), J 7.1, OCH2CH3], 3.18 (1H,br td, J ca. 8.6 and 2.9,
3-Heq), 2.85 (1H, t, J 8.3, 8a-H), 2.31 (1H, ddd, J 10.6, 7.3 and
2.8, 6-H?), 2.24 and 2.17 [2H, br m and q?, J ca. 7.6, 5-H and
C(8)CHaHbCH3?], 2.07 [1H, br q, J ca. 8.8, 3-Hax?], 1.99 [1H,
ca. quintet, J ca. 7.2, C(8)CHaHbCH3?], 1.90–1.70 and 1.70–1.50
(9H, 2 × m, CH2), 1.35–1.20 and 1.27 [4H, overlapping m and t,
This work was supported by grants from the National Re-
search Foundation, Pretoria (grant number 2053652), and
the University of the Witwatersrand. We are grateful to Mrs
S. Heiss (University of the Witwatersrand) and Dr P. R. Boshoff
(formerly of the Cape Technikon) for recording NMR spectra
and mass spectra, respectively.
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O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 3 6 – 8 4 7
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