Hydrogenation of pyrrolizin-3-ones; New routes to pyrrolizidines

Article abstract of DOI:10.1039/b910199c

Pyrrolizin-3-ones (e.g.1) can be easily hydrogenated to their hexahydro (pyrrolizidin-3-one) derivatives in the presence of heterogeneous catalysts. Good diastereoselectivity (up to >97:3, depending on catalysts and solvent) can be achieved if the pyrroli

Full text of DOI:10.1039/b910199c

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Hydrogenation of pyrrolizin-3-ones; new routes to pyrrolizidines†
Xavier L. M. Despinoy and Hamish McNab*
Received 26th May 2009, Accepted 23rd July 2009
First published as an Advance Article on the web 26th August 2009
DOI: 10.1039/b910199c
Pyrrolizin-3-ones (e.g. 1) can be easily hydrogenated to their hexahydro (pyrrolizidin-3-one) derivatives
in the presence of heterogeneous catalysts. Good diastereoselectivity (up to >97:3, depending on
catalysts and solvent) can be achieved if the pyrrolizin-3-one is substituted at the 1- (or 7-) position(s),
but the selectivity is reduced if both positions are substituted. Subsequent deoxygenation of the
pyrrolizidin-3-ones provides concise, diastereoselective routes to the necine bases ( )-heliotridane 5,
( )-isoretronecanol 6 and ( )retronecanol 7.
Introduction
It has long been known that catalytic hydrogenation of
pyrrolizin-3-ones (e.g. 1) gives 1,2-dihydro-compounds 2 under
mild conditions.1–5 Isolated reports of further reduction to the
hexahydropyrrolizin-3-one (pyrrolizidin-3-one) system have also
appeared. For example, the 1,2-diphenylpyrrolizidinone(s) 3 were
obtained by hydrogenation of the corresponding pyrrolizinone
using Adam’s catalyst in acetic acid. Pyrrolizidin-3-one itself 4 can
Results and discussion
We have discovered that hydrogenation of pyrrolizin-3-one10 1 in
also be made by hydrogenation of 2 in ethanol at atmospheric pres-
sure in the presence of ca. 200%byweightof palladium/charcoal,6a
and other examples are known.6b Reduction under such mild
conditions is surprising because pyrroles in general require much
more forcing conditions.7 However, it is known that hydrogenation
of pyrroles bearing electron withdrawing groups on nitrogen
is facilitated by comparison with N-unsubstituted or N-alkyl
analogues.8
ethanol, using just 10% by weight of palladium/charcoal and an
H2 pressure of 45 psi, gives a 94% yield of the pyrrrolizidin-3-one
4 after 2 h at room temperature. Its NMR spectrum was almost
completely resolved at 600 MHz and the analysis is shown in the
ESI†.
Lithium aluminium hydride deoxygenation of pyrrolizidin-3-
ones to pyrrolizidines is well known14 and the parent compound
8 was isolated as the picrate salt in 51% yield by this procedure
(Scheme 1). (The low yield was due to the volatility of the free base.)
In contrast, direct catalytic hydrogenation of pyrrolizine 9 under
our conditions15 gave a mixture of 8, dihydropyrrolizine 10 and
2-propylpyrrole 11 in a 20:45:35 ratio (Scheme 1). These prelim-
inary results suggest that a pyrrolizinone route to pyrrolizidines
may be more efficient than a method involving pyrrolizines.
Here, we report the results of a systematic study of pyrrolizin-
3-one hydrogenation, including optimisation of the amount and
nature of the catalyst and the solvent. This method complements
the synthetic routes to pyrrolizidin-3-ones by ring synthesis,
which we reviewed in 2000.9 With the availability of a range
of substituted pyrrolizin-3-ones by various thermal strategies,10–12
the diastereoselectivity of hydrogenation of 1- and 7-substituted
pyrrolizinones was studied. The major use of pyrrolizidin-3-
ones9 is their reduction to the necine base components of the
important pyrrolizidine class of alkaloids,13 and this strategy
is applied here to ( )-heliotridane 5, ( )-isoretronecanol 6 and
( )-retronecanol 7.
Scheme 1 Reagents and conditions: (i) H2, Pd/C, 45 psi; (ii) LiAlH4,
Et2O/THF.
In order to develop a pyrrolizinone route to pyrrolizidines,
the diasteroselectivity of hydrogenation of 1-methylpyrrolizin-
3-one11 12 to the known16 pyrrolizidinones 14 and 15, and of
7-methylpyrrolizin-3-one11 16 to the known17 pyrrolizidinones 18
and 19 was studied (Scheme 2). The pairs of perhydro-compounds
were readily distinguished from the methyl signals in their
School of Chemistry, The University of Edinburgh, West Mains Road,
Edinburgh, EH9 3JJ, UK. E-mail: H.McNab@ed.ac.uk; Fax: +44 131 650
4743; Tel: +44 131 650 4718
† Electronic supplementary information (ESI) available: Experimental;
tables of diastereomeric ratios. See DOI: 10.1039/b910199c
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Table 1 Effect of catalysts and solvent on the diastereoselectivity of
hydrogenation of 12 (45 psi, 2 h) to 14 and 15
of the crude hydrogenation mixtures. Evans and Fandrick report
the formation of 14 and 15 in a 90:10 diastereomeric ratio, using
Rh/Al2O3 in ethanol, in agreement with our results.6b
Catalyst
Solvent
Ratio 14:15
As with pyrrolizine hydrogenation,15,18 control of further hydro-
genation of the dihydro-compound 13 depends on the steric effect
of the methyl group at the new asymmetric centre, which would
be expected to lie preferentially away from the catalyst surface,
leading to the cis-isomer 14. Indeed, 14 is the major product
under all but one of the hydrogenation conditions (Table 1)
with diastereomeric ratios (dr) ranging from 2.2 (Pd/C/acetic
acid) to 15.4 (Raney Ni/ethyl acetate). Both the nature of the
catalyst and the solvent affect the dr, with the former proving
to be the major influence. The highest selectivity was shown by
Raney nickel, but the catalyst activity was low, with the dihydro-
compound 13 the major product. 5% Rhodium/alumina (7% by
weightofsubstrate)inethanolwas thereforeusedfor apreparative-
scale hydrogenation, and gave a 90% yield of 14 and 15 in a
90:10 ratio.
Hydrogenation of the 7-methyl isomer 16 occurred with much
higher diastereoselectivity than that of the 1-methyl compound
12, with again the cis-isomer 18 being the major product (Table 2).
In this case, 5% rhodium/carbon (13% by weight) was used for
the preparative-scale reaction; 18 was obtained in 94% yield,
with a trace (ca. 3%) of the trans-isomer 19. The very high
diastereoselectivity observed in the hydrogenation of 16 (and other
7-substituted pyrrolizin-3-ones) is due to the cis-hydrogenation of
the pyrrole ring in 17 (and related compounds), which leads to the
hydrogen atoms at positions 7 and 7a to be cis to one another.
The synthesis of ( )heliotridane 5, a common alkaloid degra-
dation product,19 was completed by reduction of the lactam
using lithium aluminium hydride (cf. ref. 14). Heliotridane was
isolated as its picrate salt and freed from the minor diasteromer
by recrystallisation from ethanol to give 5 (70% from 14 + 15; 79%
from 18 + 19). The overall (unoptimised) yield of 5 in 3 steps from
2-acetylpyrrole via 12 is 36% and in 3 steps from 3-methylpyrrole-
2-carboxaldehyde via 16 is 53%.
5% Pd/C
5% Pd/C
5% Pd/C
5% Pd/C
5% Pd/C
5% Pd/C
5% Pd/CaCO3
5% Pd/CaCO3
Raney Ni
Raney Ni
Raney Ni
PtO2
Hexane
Ethyl acetate
Ethanol
82:18
74:26
76:24
Not formeda
74:26
69:31
89:11
87:13
93:7a
DMF
t-Butanol
Acetic acid
Hexane
Ethyl acetate
Hexane
Ethyl acetate
Ethanol
Hexane
Acetic acid
Hexane
Hexane
Acetic acid
Hexane
Ethyl acetate
Ethanol
94:6a
93:7a
85:15
78:22
85:15a
89:11
85:15
88:12
89:11
91:9
PtO2
Pt black
5% Rh/C
5% Rh/C
5% Rh/Al2O3
5% Rh/Al2O3
5% Rh/Al2O3
5% Rh/Al2O3
5% Rh/Al2O3
5% Ru/C
Ethanol
Acetic acid
Water
90:10b
90:10
33:67a
a Compound 13 present. b Hydrogenation at atmospheric pressure for 24 h.
Table 2 Effect of catalysts and solvent on the diastereoselectivity of
hydrogenation of 16 (45 psi, 2 h) to 18 and 19
Catalyst
Solvent
Ratio 18:19
5% Pd/C
5% Pd/C
Ethanol
Acetic acid
Hexane
Ethanol
Hexane
Hexane
Hexane
Ethyl acetate
Hexane
Acetic acid
84:16
86:14
92:8a
96:4a
93:7
5% Pd/CaCO3
Raney Ni
PtO2
5% Rh/C
5% Rh/C
5% Rh/C
5% Rh/Al2O3
5% Rh/Al2O3
98:2
98:2b
98:2
96:4
96:4
In order to approach the synthesis of the necine base
( )-isoretronecanol13,20 6, three pyrrolizinone precursors 20, 26 and
30 were studied (Scheme 3). 1-Methoxycarbonylpyrrolizin-3-one
20 is an unusual compound because it spontaneously dimerises
at the 1,2-double bond under normal conditions.12 However, it
was possible to isolate the stable 1,2-dihydro-compound 21 by
carrying out the hydrogenation at -20 ◦C at atmospheric pressure.
These conditions were not optimised and, unusually, some of the
2,5,6,7-tetrahydro compound21 23 was also isolated. This suggests
that the 5,6-double bond of 21 may be the first pyrrole bond to
be reduced, to provide the tetrahydro intermediate 22, then the
remaining double bond moves into conjugation. It is clear that
these steps must all take place on the catalyst surface since no
deuterium was incorporated into 23 when the hydrogenation was
carried out in [2H] methanol.
The known22 cis- and trans-hexahydro-1-methoxycarbonyl-
pyrrolizin-3-one 24 and 25 can be synthesised if the hydrogenation
of 20 (Pd/C in methanol) is carried out in two steps (viz.
atmospheric pressure H2, -20 ◦C, 2 h, followed by 55 psi H2,
20 ◦C, 24 h). The yield is 53% (for the two steps from the
pyrolysis precursor) and 24 and 25 are obtained in a ratio of
91:9. The intermediate formation of 23 may be beneficial stereo-
chemically, since its hydrogenation would be expected to provide
a Compound 17 present. b Hydrogenation at atmospheric pressure for 48 h.
Scheme 2 Reagents and conditions: (i) H2/catalyst, 45 psi, 20 ◦C. 2 h.
Best method for 14/15; 5% Rh/Al2O3, EtOH, yield 90%, dr 90:10. Best
method for 18/19; 5% Rh/C, hexane, yield 97%, dr 98:2. (For asymmetric
compounds, only one of the enantiomeric pairs is shown.)
1H NMR spectra (cis-isomer 14: dH 0.98, 3J 7.0 Hz; trans-isomer
3
3
15: dH 1.16, J 6.6 Hz16) and (cis-isomer 18: dH 0.81, J 7.3 Hz;
trans-isomer 19: dH 1.02, J 6.1 Hz17), and results are shown in
3
Tables 1 and 2. Ratios were measured from the 1H NMR spectra
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( )-Isoretronecanol 6 was obtained in each case by lithium
aluminium hydride reduction of the precursors 24 (+ 10% 25),
29 and 33 (+ 16% 18). The product was purified by bulb-to-bulb
distillation and/or by isolation and recrystallisation of the picrate
salt. In each case, the hydride performs the dual role of reducing
the lactam and the ester functions. As might be expected, the best
yield (83%) was obtained from the pure substrate 29, representing
an overall yield of 81% for the two steps from the pyrrolizinone
26. For comparison, a recent SmI2-mediated synthesis of
( )-isoretronecanol 6 required around 15 steps.20
Because many of the necine bases have alcohol groups at the
1(7)-position(s), preliminary studies were carried out to ascertain
if the diasteroselectivity of hydrogenation was likely to be affected
by oxygen-containing substituents at the these sites. Substrates
34 and 38 were prepared as previously described24 by sequential
hydrochlorination of pyrrrolizin-3-one 1 and quenching with
acetate and with water, respectively. The methoxy-compound 41
was prepared by the standard Meldrum’s acid pyrolysis route.11
Hydrogenation of the acetoxy-compound 34 provides the cis-
isomer 35 with significantly better selectivity than the correspond-
ing methyl derivative 12 (Scheme 4 and ESI†). The configuration
of the product was confirmed by transformation to the known25
1
pyrrolizidine 37. The pattern of the H NMR signal due to the
1-position was also characteristic of these compounds (cis-isomer
35, apparent triplet, 3J 5.0 Hz, due to equal coupling to H-7a and
one of the protons on H-2; trans-isomer 36, triplet of doublets J
8.2 and 4.9, due, respectively to equal coupling with both of the
protons H-2 and with H-7a – cf. data for 4 shown in Fig. S1 in
ESI†).
Scheme 3 Reagents and conditions: (i) H2/Pd/C, 15 psi, -20 ◦C, 2 h. (ii)
H2/catalyst, 45 psi, 20 ◦C. 2 h. Best method for 24/25; 5% Pd/C, MeOH,
yield 53%, dr 91:9. Best method for 29/30; 5% Rh/Al2O3, HOAc, yield
98%, dr >98:2. Best method for 33; 5% Rh/C, EtOH, yield 84% (remainder
18), dr >98:2. (For asymmetric compounds, only one of the enantiomeric
pairs is shown.)
the cis-isomer 24 by cis-hydrogenation of the C(7a)–C(1) double
bond.
7-Methoxycarbonylpyrrolizin-3-one11 26 proved more resistant
to complete hydrogenation, and only the dihydro-compound
27 was isolated under a variety of conditions. However, using
rhodium-on-alumina catalyst in acetic acid, and with extended
reaction times, the known23 cis-hexahydropyrrolizinone 29 was
obtained exclusively and in excellent yield; the trans-isomer 30
could not be detected. The high diastereoselectivity probably re-
sults from intermediate formation of the tetrahydro-intermediate
28, which was tentatively identified in one case (by comparison
with the 13C NMR spectrum of the known14 ethyl ester). Ring
opening occurs if the hydrogenation is carried out over PtO2 in
ethanol (see Experimental section); alcohol solvents should be
avoided when handling the ester 26.
Scheme 4 Reagents and conditions: (i) H2/catalyst, 45 psi, 20 ◦C. 2 h;
Best method for 35/36; 5% Pd/C, EtOH, yield 97%, dr 95:5. Best method
for 39/40; 5% Rh/Al2O3, EtOH, yield 93%, dr 90:10. Method for 43/44;
5% Pd/C, EtOH, dr 86:14 (not optimised). (ii) LiAlH4. (For asymmetric
compounds, only one of the enantiomeric pairs is shown.)
Hydrogenation of the acetoxy-compound24 31 also proved more
complex than anticipated (see ESI†). Although the dihydro-
compound 32 could be obtained, further reaction was complicated
by hydrogenolysis to give the 7-methyl compounds 18 and 19.
Hydrogenolysis was minimised (totalling 16% of the mixture)
when rhodium/carbon in ethanol was used as the catalyst. The
diastereoselectivity was again high, with only the cis-isomers 18
and 33 detected under these conditions.
The selectivity of hydrogenation of hydroxy-compounds may
be affected by coordination to the catalyst surface.26 In the case
of the 1,2-dihydro-1-hydroxypyrrolizinone 38, however, the major
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product was again the known27 cis isomer 39 (see ESI†). The
diastereoselectivity was relatively insensitive to the nature of the
catalyst and solvent (ratios of 39:40 vary from 83:17 using Pd/C in
ethanol, to 90:10 using Rh/Al2O3 in ethanol). The presence of the
7-methoxy substituent in compound 41 similarly had little effect
on the progress of the hydrogenation, with 43 and 44 obtained in
a 86:14 ratio under standard conditions (Pd/C, ethanol).
Lithium aluminium hydride reduction of the 86:14 mixture of
49 and 50 gave an 88% overall yield of retronecanol 7 and its
isomer 51, which provided pure retronecanol (as its picrate salt)
after recrystallisation of the picrate mixture from ethanol. The
characterisation of the picrate salt is secure (see Experimental
section) but our NMR spectra of retronecanol free base were not
consistent with the only literature data from a previous synthesis.28
Although retronecanol is most often obtained as an alkaloid
degradation product, its p-methoxybenzoyl ester has been isolated
from Ehretia aspera Willd.29
Some preliminary experiments were carried out to explore the
robustness of the hydrogenation method to other groups in the
7-position, but results were disappointing. Thus hydrogenation of
the ester 52 (see ESI) over Rh/alumina in glacial acetic acid gave
two major products, 53 and 54, in a 67:33 ratio. Stereochemistry
was assigned by analysis of the pattern of the H-1 proton, as
discussed above for 35/36 and 46/47. Hydrogenation of the
acetoxy-compound 55 (see ESI) was (as found for 31) complicated
by hydrogenolysis of the acetoxy group to provide 46 and 47, as
well as a mixture of acetoxy compounds 56.
With these results in place, the hydrogenation of the
1-substituted 7-methyl-1,2-dihydropyrrolizinones 45 and 48 was
studied (Scheme 5). The starting materials were made, as before,24
by sequential hydrochlorination and nucleophilic quenching of
the parent pyrrolizinone (see ESI). In these cases, three new
asymmetric centres are created in the hydrogenation, leading
to four possible enantiomeric pairs of products. In practice,
hydrogenation of 45 led to only two enantiomeric pairs 46 and 47,
but the selectivity relating these sets of isomers was poor, ranging
from 67:33 (5% Rh/C in ethanol) to 40:60 (5% Pd/CaCO3 in
ethanol) (see ESI). Assuming that the pyrrole ring is hydrogenated
in a cis manner (as observed for the other pyrrolizinones) the
assignment of 46 and 47 was confirmed by the NOE measurements
shown in Fig. S2† and the consistency of the coupling constants
with related examples as reported in the Experimental section.
(In particular cis-isomer 46, H-1 is an apparent triplet, 3J 4.0 Hz,
due to equal coupling to H-7a and one of the protons on H-2;
3
trans-isomer 47, H-1 is a triplet of doublets J 8.0 and 5.9, due,
respectively to equal coupling with both of the protons H-2 and
with H-7a.)
Conclusions
Hydrogenation of 1- or 7-substituted pyrolizin-3-ones to the
hexahydro-compound(s) can proceed in excellent yield in the
presence of small amounts (ca. 10%) of heterogeneous catalyst. By
appropriate choice of catalyst and solvent, the diastereoselectivity
can be optimised (and is often >90:10), with the major isomer
being formed by addition of all hydrogen atoms to the face of the
bicycle away from any sp3-hybridised substituent. Due to steric
hindrance on the inner face of the molecule, the diastereoselectivity
of hydrogenation of 1,7-disubstituted pyrrolizin-3-ones is lower
under similar conditions. These results have provided concise,
diasterocontrolled routes to the necine bases ( )-heliotridane 5,
( )-isoretronecanol 6 and ( )-retronecanol 7.
Scheme 5 Reagents and conditions: (i) H2/catalyst, 45 psi, 20 ◦C. 2 h; Best
method for 49/50; 5% Rh/C, EtOAc, yield 96%, dr 86:14. (ii) LiAlH4.
(Only one of the enantiomeric pairs is shown.)
Experimental
Conditions for more selective hydrogenation of the acetoxy-
compound 48 were discovered using 5% Rh/C in ethyl acetate,
which gave 49 and 50 in a 86:14 ratio (see ESI). This selectivity is
nevertheless considerably lower than for the model compound 34,
owing to the increased steric hindrance on the ‘inside’ face of the
pyrrolizidine. The structure of the two isomers was unequivocally
elucidated by NMR spectroscopy. The key NOE enhancements
which led to the assignment of stereochemistry are shown in the
ESI, in particular the correlation between the 1-proton and the
7-methyl group in 50.
1H and 13C NMR spectra were recorded at 200 (or 250) and 50
(or 63) MHz respectively for solutions in [2H]chloroform unless
otherwise stated. Coupling constants are quoted in Hz. Mass
spectra were recorded under electron impact conditions.
Hydrogenation of pyrrolizin-3-ones – general
The hydrogenations were performed at room temperature using
hydrogen pressures of 45 to 60 psi in a Parr hydrogenation
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apparatus. Preliminary hydrogenation experiments were carried
out on a small scale as follows; a solution of the substrate
(10–20 mg) in solvent (10–15 cm3) was hydrogenated with the
heterogeneous catalyst (ca. 5 mg) for the time stated. Filtration
through Celite and removal of the solvent under vacuum afforded
the hydrogenation products. Results are reported in Tables 1–2
and ESI†. Diastereomeric mixtures were generally not separated.
On larger scales, the amount of catalyst was progressively lowered
without further optimisation.
11 (7 mg), bp 65–70 ◦C (50 Torr) [lit.,34 111 ◦C (80 Torr)]; dH 7.87
(1H, br, NH), 6.66 (1H, m), 6.13 (1H, m), 5.91 (1H, m), 2.57
3
3
3
(2H, t, J 7.7), 1.66 (2H, tq, J 7.7 and 7.3) and 0.96 (3H, t, J
7.3); dC 132.57 (quat), 115.86, 108.14, 104.85, 29.71, 22.81 and
13.81. Hexahydropyrrolizine 8 was too volatile to be isolated; it
was identified by comparing the 1H and 13C NMR spectra of the
reaction mixture with those of the two isolated products; dH 3.56
(1H, quintet, J 6.8), 3.03–3.14 (2H, m) and 1.13–2.60 (10H, m); dC
64.19, 54.81, 32.23 and 25.75 (in agreement with literature data.35)
Hexahydropyrrolizin-3-one 4
Hydrogenation of 1-methylpyrrolizin-3-one 12
A solution of pyrrolizin-3-one10 1 (337 mg, 2.8 mmol) in ethanol
(20 cm3) was hydrogenated at 45 psi over 5% Pd/C (30 mg) for 2 h
at room temperature. After filtration through Celite, the solvent
was removed to yield hexahydropyrrolizin-3-one 4 (332 mg,◦94%)
(i) The diasteroselectivity of the hydrogenation was studied on a
small scale, varying the catalysts and solvents (Table 1).
(ii) A solution of 1-methylpyrrolizin-3-one11 12 (161 mg,
1.2 mmol) in ethanol (20 cm3) was hydrogenated over 5%
Rh/Al2O3 (11 mg) for 4 h at 45 psi. The usual work-up gave cis-
and trans-hexahydro-1-methylpyrrolizin-3-one (151 mg, 90%) in a
ratio of 90:10; cis-hexahydro-1-methylpyrrolizin-3-one 14; dH 3.91
(1H, td, 3J 9.6 and 6.4), 3.45 (1H, td, 3J 11.6 and 7.8), 3.02 (1H,
m), 2.84 (1H, ddt, 2J 16.3, 3J 8.0 and nJ 1.1), 2.49 (1H, m), 1.83–
◦
as a colourless liquid, bp 90–95 C (12 Torr) [lit.,30 88–94 C (8
Torr)]; dH (600 MHz) 3.80 (1H, m, H-7A), 3.43 (1H, ddd, 2J 11.6,
2
3J 7.8 and 7.8, H-5b), 2.95 (1H, dddd, J 11.6, 3J 9.1 and 3.8, 4J
1.4, H-5a), 2.64 (1H, dddt, 2J 16.6, 3J 11.2 and 8.9, nJ 1.1, H-2a),
2
2.35 (1H, ddd, 2J 16.6, 3J 9.4 and 1.9, H-2b), 2.20 (1H, dddd, J
12.6, 3J 8.9, 6.8 and 1.9, H-1a), 2.02 (1H, m, H-6b), 1.89–1.99 (2H,
m, H-6a and H-7a) 1.63 (1H, dddd, 2J 12.6, 3J 11.2, 9.4 and 7.8,
H-1b) and 1.23 (1H, m, H-7b); dC 174.49 (C3), 61.84 (C7A), 40.62
(C5), 35.07 (C2), 31.82 (C7), 26.83 (C1) and 26.67 (C6).
2
n
2.12 (2H, m; including 1H at 1.98 ppm, dd, J 16.3 and J 2.7),
1.42–1.73 (2H, m) and 0.91 (3H, d, 3J 7.2, Me); dC 174.12 (quat),
64.90, 42.95, 40.94, 29.44, 26.76, 24.86 and 15.74; m/z 139 (M+,
66%), 138 (14), 124 (6), 111 (60), 97 (24), 83 (9), 70 (100), 69 (56),
68 (31), 56 (14), 55 (15), 42 (33), 41 (56) and 39 (26) (in agreement
with literature data;16) trans-hexahydro-1-methylpyrrolizin-3-one
15; dH 1.09 (3H, d, 3J 6.5).
Pyrrolizidinium picrate 8
To an ice-cooled solution of hexahydropyrrolizin-3-one 4 (121 mg,
1.0 mmol) in dry ether (5 cm3) was added lithium aluminium
hydride (1 M in tetrahydrofuran, 3 cm3) and the mixture was
stirred at reflux for 1 h. Wet ether (10 cm3), water (5 cm3)
and a saturated aqueous solution of potassium sodium tartrate
(5 cm3) were added sequentially. After filtration through Celite,
the solution was extracted with ether (2 ¥ 20 cm3), dried (MgSO4)
and concentrated. Picric acid (1.0 g) dissolved in acetone (1 cm3)
was added to a solution of the concentrate in ether (1 cm3).
Crystallisation of the salt was completed by addition of ether
(10 cm3). The solid was filtered off and washed thoroughly with
ethe◦r to give pyrrolizidinium picrate 8 (167 mg,◦51%), mp 244–
261 C (slow decomp.) (from ethanol) (lit.,31 254 C); dH (picrate)
(iii) Hydrogenation on a small scale over 5% Pd/C in dimethyl
formamide afforded 1,2-dihydro-1-methylpyrrolizin-3-one 13, bp
50–55 ◦C (0.3 Torr) (Found: M+, 135.0690. C8H9NO requires M,
3
3
135.0684); dH 6.96 (1H, d, J 3.0), 6.42 (1H, t, J 3.0), 5.94 (1H,
3
2
3
d, J 3.3), 3.35 (1H, m), 3.22 (1H, dd, J 18.1 and J 8.0), 2.57
2
3
3
(1H, dd, J 18.1 and J 3.3) and 1.34 (3H, d, J 6.8, Me); dC
171.36 (quat), 145.28 (quat), 118.76, 110.44, 103.47, 43.31, 27.19
and 20.70; m/z 135 (M+, 100%), 120 (11), 107 (30), 106 (67), 94
(61), 80 (18), 66 (14), 53 (22) and 39 (18).
Hydrogenation of 7-methylpyrrolizin-3-one 16
(i) The diasteroselectivity of the hydrogenation was studied on a
small scale, varying the catalysts and solvents (Table 2).
3
11.39 (1H, br s), 8.85 (2H, s), 4.38 (1H, br q, J 7.0), 3.81 (2H,
3
br sextet, J 6.0), 2.98 (2H, s), 2.42–2.03 (6H, m) and 1.77 (2H,
(ii) A solution of 7-methylpyrrolizin-3-one11 16 (136 mg,
1.0 mmol) in hexane (40 cm3) was hydrogenated over 5% Rh/C
(18 mg) for 48 h at atmospheric pressure. The usual work-up gave
cis-hexahydro-7-methylpyrrolizin-3-one 18 (133 mg, 94%); dH 3.97
(1H, dt, 3J 5.3 and 7.4), 3.48 (1H, dt, 3J 11.4 and 7.6), 3.02 (1H,
s); dC (picrate) 162.21 (quat), 141.48 (quat), 127.85 (quat), 126.45,
68.03, 55.51, 30.95 and 25.02.
Hydrogenation of 3H-pyrrolizine 9
A solution of 3H-pyrrolizine32 9 (196 mg, 1.9 mmol) in ethanol
(20 cm3) was hydrogenated at 55 psi over 5% Pd/C (205 mg)
for 8 h at room temperature. After filtration through Celite, the
solvent was removed to yield an oil (200 mg) containing 1,2-
dihydro-3H-pyrrolizine, hexahydropyrrolizine and 2-propyl-1H-
pyrrole in the respective ratios 45:20:35. Dry flash chromatography
(using hexane and ethyl acetate as eluents) gave 1,2-dihydro-3H-
pyrrolizine 10 (16 mg); dH 6.63 (1H, dd, 3J 2.6, 4J 1.1), 6.25 (1H,
m), 2.68 (1H, dt, J 16.6 and J 9.7), 2.40 (1H, ddd, J 16.6,
2
3
2
3J 9.6 and 2.9), 1.66–2.24 (5H, m) and 0.81 (3H, d, J 7.3, Me)
3
(in agreement with the literature data17); dC 174.67 (quat), 64.25,
39.00, 34.64, 34.38, 32.63, 20.52 and 13.11; m/z 139 (M+, 67%),
138 (29), 137 (36), 97 (100), 84 (54), 69 (55) and 55 (42). A trace of
trans-hexahydro-7-methylpyrrolizin-3-one 19 was present (<3%);
dH 1.02 (3H, d, 3J 6.1, Me).
(iii) Hydrogenation (on a small scale) over Raney nickel in
ethanol for 2 h at 45 psi gave 1,2-dihydro-7-methylpyrrolizin-3-one
17 as white crystals, mp 78–80 ◦C (from hexane) (Found: C, 71.1;
H, 7.0; N, 10.4. C8H9NO requires C, 71.1; H, 6.65; N, 10.35%);
3
3
4
dd, J 3.3 and 2.6), 5.83 (1H, dd, J 3.3 and J 1.1), 3.96 (2H,
t, 3J 7.2), 2.86 (2H, t, 3J 7.2) and 2.59 (2H, quintet, 3J 7.2);
dC 137.03 (quat), 113.42, 111.93, 98.59, 45.94, 27.67 and 23.83
(consistent with literature data33) followed by 2-propyl-1H-pyrrole
3
3
dH 6.95 (1H, d, J 3.1), 6.27 (1H, d, J 3.1), 2.95–3.01 (2H, m),
4506 | Org. Biomol. Chem., 2009, 7, 4502–4511
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2.86–2.91 (2H, m) and 1.99 (3H, s); dC 171.79 (quat), 135.29 (quat),
121.08, 113.99 (quat), 110.48, 34.71, 18.09 and 10.22; m/z 135 (M+,
100%), 134 (63), 120 (46), 107 (74), 106 (97), 94 (87), 83 (57), 81
(56), 80 (61), 79 (58), 66 (55), 53 (77), 52 (72) and 51 (62).
(ii) No deuterium was incorporated into the tetrahydo
product 23 when the hydrogenation of 1,2-dihydro-1-methoxy-
carbonylpyrrolizin-◦3-one 21 was carried out in [2H]methanol over
5% Pd/C at ca. -20 C. Similarly, no resonance was observed by 2H
NMR spectroscopy when 1,2-dihydro- and 2,5,6,7-tetrahydro-1-
methoxycarbonylpyrrolizin-3-one were set aside in [2H4]methanol,
for 30 and 44 days respectively.
Heliotridane 5 – general LiAlH4 reduction method
The hexahydropyrrolizin-3-one (1 mmol) was reduced with an
excess of lithium aluminium hydride (LAH) in refluxing tetrahy-
drofuran (10 cm3) overnight (unless otherwise stated), under
anhydrous conditions. The mixture was then cooled in ice and wet
ether (10 cm3), water (5 cm3) and a saturated aqueous solution of
potassium sodium tartrate (5 cm3) were added sequentially. After
filtration through Celite the solution was extracted with ether (2 ¥
20 cm3), the organic phase was dried (MgSO4) and concentrated
to yield the products.
(iii) A solution of 1-methoxycarbonylpyrrolizin-3-one 20 [from
FVP of dimethyl pyrrol-2-ylbut-2-enedioate12 (174 mg, 0.8 mmol),
◦
700 ◦C, 90 C, 0.004 Torr, 40 min] in methanol (80 cm3) was
hydrogenated over 5% Pd/C (80 mg) for 2 h at atmospheric
pressure at ca. -20 ◦C, at which point the solution was colourless.
The hydrogen pressure was increased to 50 psi and the reaction
mixture was hydrogenated for a total time of 27 h at room tem-
perature. After filtration through Celite the solvent was removed
to yield cis- and trans-hexahydro-1-methoxycarbonylpyrrolizin-3-
one (81 mg, 53%) in a ratio 91:9 (by 13C NMR); cis-hexahydro-1-
(i) A 90:10 mixture of cis- to trans-hexahydro-1-methyl-
pyrrolizin-3-ones 14 and 15 (105 mg, 0.8 mmol) was reduced with
LAH (1 M in tetrahydrofuran, 3 cm3): treatment of the products
with picric acid followed by recrystallisation from ethanol gave
heliotridane 5 as its picrate (188 mg, 70%), mp 240–244 ◦C
(decomp.) (from ethanol) (lit.,36 240–243 ◦C); dH (picrate) 11.41
(1H, br s), 8.94 (2H, s), 4.28 (1H, m), 4.02 (1H, m), 3.67 (1H,
m), 3.12 (1H, m), 2.90–2.51 (2H, m), 2.27–1.95 (4H, m), 1.88–1.60
n
methoxycarbonylpyrrolizin-3-one 24; dH 4.09 (1H, ddd, J 10.1,
n
8.4 and 5.6), 3.70 (3H, s), 3.59 (1H, dt, J 11.5 and 8.0), 3.40
n
n
(1H, td, J 8.0 and 6.1), 3.04 (1H, ddd, J 11.8, 9.0 and 3.6),
2.80 (2H, m), 1.79–2.10 (3H, m) and 1.26 (1H, m); dC 173.95
(quat), 172.15 (quat), 62.58, 51.84, 41.57, 39.75, 35.98, 27.37 and
25.91 (in agreement with literature data22); trans-hexahydro-1-
methoxycarbonylpyrrolizin-3-one 25; dC (one quaternary signal
not apparent) 172.34, 63.64, 52.18, 45.66, 41.06, 38.35, 31.48 and
26.57 (in agreement with literature data22).
3
(2H, m) and 1.13 (3H, d, J 6.7, Me); dC (picrate) 160.05 (quat),
140.42 (quat), 130.29 (quat), 126.41, 70.92, 56.90, 54.58, 34.61,
30.44, 25.87, 25.70 and 13.32.
(iv) Hydrogenation (on a small scale) over 5% Rh/Al2O3 at
55 psi for 5 h, in either ethyl acetate or a mixture of ethyl
acetate and acetic acid (in a ratio of 94:6), gave a mixture of 1,2-
dihydro-, 2,5,6,7-tetrahydro- and the cis- and trans-hexahydro-
1-methoxycarbonylpyrrolizin-3-one 21 and 23–25, identified by
NMR spectroscopy. From the 13C NMR spectra the amount of
the trans-hexahydro 25 compound relative to its cis-isomer 24 was
barely detectable (≤5%).
(ii) A 98:2 mixture of cis- to trans-hexahydro-7-methyl-
pyrrolizin-3-ones 18 and 19 (86 mg, 0.6 mmol) was reduced with
LAH (1 M in tetrahydrofuran, 2.5 cm3). Treatment of the products
with picric acid gave heliotridane 5 as its picrate (173 mg, 79%),
◦
mp 242–245 C (decomp.) (after recrystallisation from ethanol);
the NMR data were the same as those reported above.
Hydrogenation of 1-methoxycarbonylpyrrolizin-3-one 20
Hydrogenation of 7-methoxycarbonylpyrrolizin-3-one 26
(i) A solution of 1-methoxycarbonylpyrrolizin-3-one 20 [from
FVP of dimethyl ◦pyrrol-2-ylbut-2-enedioate12 (131 mg, 0.6 mmol),
700 ◦C, 90-100 C, 0.004 Torr, 30 min] in methanol (60 cm3)
was hydrogenated over 5% Pd/C (80 mg) for 3 h at atmospheric
pressure at ca. -20 ◦C. After filtration through Celite the solvent
was removed under vacuum and the residue was purified by flash
chromatography (using hexane/ethyl acetate as eluents) to give
1,2-dihydro-1-methoxycarbo◦nylpyrrolizin-3-one 21 (37 mg, 33%
over two steps), bp 115–120 C (0.5 Torr) (Found: M+, 179.0585.
C9H9NO3 requires M, 179.0582); dH 7.04 (1H, d, 3J 3.0), 6.45 (1H,
t, 3J 3.0), 6.16 (1H, d, 3J 3.0), 4.19 (1H, dd, 3J 8.3 and 3.6), 3.77
(3H, s), 3.47 (1H, dd, 2J 18.7 and 3J 3.6) and 3.18 (1H, dd, 2J 18.7
and 3J 8.3); dC 170.40 (quat), 169.55 (quat), 135.80 (quat), 119.03,
111.90, 106.38, 52.85, 37.75 and 37.68; m/z 179 (M+, 67%), 151
(13), 125 (54), 121 (64), 120 (100), 94 (74), 93 (79), 92 (91) and 91
(51) followed by 1-methoxycarbonyl-2,5,6,7-tetrahydropyrrolizin-
3-one 23 (25 mg, 22%) as a light yellow solid mp 78–79 ◦C (from
(i) Small-scale hydrogenations of 7-methoxycarbonylpyrrolizin-3-
one11 26 at 45 psi for 3-4 h using a range of different catalysts
and solvents (5% Rh/C, ethyl acetate; 5% Rh/C, toluene; 5%
Rh/Al2O3, toluene; 5% Rh/Al2O3, hexane; 5% Rh/C, hex-
ane) gave 1,2-dihydro-7-methoxycarbonylpyrrolizin-3-one 27 as
colourless crystals, mp 85–86 ◦C (from hexane) (Found: C, 60.15;
H, 4.95; N, 7.65. C9H9NO3 requires C, 60.35; H, 5.05; N, 7.8%);
3
nmax (nujol) 1760 and 1706; dH 6.98 (1H, d, J 3.3), 6.76 (1H, d,
3J 3.3), 3.80 (3H, s), 3.20–3.26 (2H, m) and 3.00–3.06 (2H, m); dC
171.86 (quat), 164.17 (quat), 146.35 (quat), 118.08, 111.83 (quat),
111.63, 51.21, 33.70 and 20.62; m/z 179 (M+, 93%), 164 (10), 151
(36), 148 (33), 120 (100), 119 (26), 92 (28) and 65 (28).
(ii) A solution of 7-methoxycarbonylpyrrolizin-3-one 26 (69 mg,
0.4 mmol) in glacial acetic acid (13 cm3) was hydrogenated over
5% Rh/Al2O3 (39 mg) at 55 psi for 7 h. After filtration through
Celite, acetic acid was neutralised with a saturated solution of
sodium carbonate (60 cm3), extracted with dichloromethane (2 ¥
50 cm3) and washed with water (50 cm3). The combined organic
extracts were dried (MgSO4) and the solvent removed to give cis-
hexahydro-7-methoxycarbonylpyrrolizin-3-one 29 (70 mg, 98%);
◦
hexane/ethyl acetate) (lit.,21 80–81 C); dH (360 MHz) 3.69 (3H,
3
5
s), 3.54 (2H, t, J 7.1, H-5), 3.49 (2H, t, J 3.0, H-2), 2.89 (2H,
3
5
3
tt, J 7.7 and J 3.0, H-7) and 2.37 (2H, tt, J 7.7 and 7.1, H-6);
dC 172.76 (quat), 163.98 (quat), 161.57 (quat), 98.50 (quat), 50.90,
41.41, 41.05, 26.46 and 25.43; m/z 181 (M+, 81%), 150 (39), 123
(17), 122 (100), 95 (22), 94 (65) and 67 (25).
3
3
dH 4.13 (1H, apparent q, J 7.2), 3.77 (1H, dt, J 11.3 and 7.9),
3.65 (3H, s), 2.93–3.09 (2H, m), 2.61 (1H, m), 2.07–2.41 (4H, m)
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and 1.68 (1H, m); dC 175.29 (quat), 172.77 (quat), 62.96, 51.69,
45.14, 40.94, 33.74, 30.04 and 22.20 (in agreement with literature
data23); m/z 183 (M+, 36%), 168 (7), 155 (36), 152 (23), 97 (100),
69 (53), 58 (39), 55 (25), 43 (91) and 41 (33).
(typically 0.2 cm3 per mmol of LAH). The resulting mixture was
stirred for 5 h, then filtered. The filtrate was concentrated and
purified by bulb-to-bulb distillation.
(i) From
a 91:9 mixture of cis- to trans-hexahydro-1-
(iii) From the 13C NMR spectrum of the product obtained by
hydrogenation of 26 in ethanol over 5% Rh/Al2O3 (for 17 h at
45 psi), it was tentatively identified as 7-methoxycarbonyl-1,2,5,6-
tetrahydropyrrolizin-3-one 28; dC 172.00 (quat), 165.60 (quat),
160.05 (quat), 102.62 (quat), 50.94, 40.73, 33.56, 31.75 and 20.75
[by comparison with the data of the ethyl ester analogue previously
reported;14 dC 171.10 (quat), 164.35 (quat), 159.47 (quat), 101.33
(quat), 58.67, 40.02, 32.81, 31.12, 20.26 and 13.63].
methoxycarbonylpyrrolizin-3-ones 24 and 25 (81 mg, 0.5 mmol)
and LAH (60 mg, 1.6 mmol), cis- and trans-hexahydro-1-
hydroxymethylpyrrolizine (38 mg, 61%) were obtained in un-
changed ratio. One recrystallisation of the picrate gave the picrate
◦
salt of isoretronecanol 6, mp 186–188 C (from ethanol) (lit.,14
192–194 ◦C); dC (picrate) ([2H6]acetone) 160.99 (quat), 141.21
(quat), 125.72 (quat), 124.57, 69.13, 59.60, 55.34, 53.55, 42.02,
25.18, 24.93 and 24.47.
(iv) Hydrogenation of 26 (on a small scale) over PtO2 in
ethanol for 3 h at 45 psi gave ethyl (3-methoxycarbonyl)pyrrol-
2-ylpropanoate bp 110–115 ◦C (0.6 Torr) (Found: M+, 225.1001.
C11H15NO4 requires M, 225.1001); dH 9.14 (1H, br s), 6.55 (1H,
t, J 2.9), 6.50 (1H, t, J 2.9), 4.10 (2H, q, J 7.1), 3.77 (3H, s),
3.24 (2H, t, 3J 6.6), 2.66 (2H, t, 3J 6.6,) and 1.21 (3H, t, 3J 7.1); dC
174.41 (quat), 165.71 (quat), 137.90 (quat), 116.21, 111.00 (quat),
109.92, 60.66, 50.64, 33.46, 21.23 and 13.97; m/z 225 (M+, 23%),
193 (21), 180 (30), 165 (52), 151 (85), 150 (20), 138 (71), 124 (20),
120 (100), 108 (20), 106 (51), 94 (23), 93 (23) and 65 (20).
(ii) From cis-hexahydro-7-methoxycarbonylpyrrolizin-3-one 29
(69 mg, 0.4 mmol) and LAH (46 mg, 1.2 mmol), isoretronecanol 6
(46 mg, 83%) was obtained as a colourless oil, bp 110–120 ◦C◦(0.4
Torr), mp 188–189 ◦C (picrate) (from ethanol) (lit.,14 192–194 C).
The free base has the following spectroscopic data: dH 4.54 (1H,
br, OH), 3.62 (2H, dd, J 7.3 and 2.0), 3.43 (1H, td, J 6.9 and
9.9), 3.06 (1H, ddd, nJ 9.3, 6.5 and 3.5), 2.93 (1H, ddd, nJ 11.1, 9.2
and 6.4), 2.56 (1H, ddd, nJ 11.1, 7.7 and 3.4), 2.32–2.49 (2H, m)
and 1.22–1.84 (5H, m); dC 66.05, 62.88, 55.47, 53.87, 44.20, 27.00,
26.31 and 25.76; m/z 141 (M+, 26%), 140 (10), 124 (17), 110 (11),
97 (6), 84 (12), 83 (100), 82 (43), 70 (11) and 55 (32).
3
3
3
n
n
(iii) From
a 84:16 mixture of cis-7-acetoxymethylhexa-
Hydrogenation of 7-acetoxymethylpyrrolizin-3-one 31
hydropyrrolizin-3-one 33 to cis-hexahydro-7-methylpyrrolizin-
3one 18 (70 mg, 0.4 mmol) and LAH (64 mg, 1.7 mmol),
isoretronecanol 6 (30 mg, 56%) was obtained from the distillation
(spectra identical with those above). No trace of heliotridane was
observed in the 1H NMR spectrum.
(i) Hydrogenation (on a small scale) of 7-acetoxymethylpyrrolizin-
3-one24 31 in ethyl acetate at 45 psi for 2-3 h over either 5%
Pd/C, 5% Pd/CaCO3, or 5% Rh/C, gave 7-acetoxymethyl-1,2-
dihydropyrrolizin-3-one 32 as a brown oil, bp 140–145 ◦C (0.9
Torr) (Found: M+, 193.0744. C10H11NO3 requires M, 193.0739);
3
3
dH 6.96 (1H, d, J 3.1), 6.39 (1H, d, J 3.1), 4.87 (2H, s), 2.97
(4H, br s) and 1.99 (3H, s); dC (two quaternaries not apparent)
171.73 (quat), 170.84 (quat), 119.37, 111.30, 58.17, 34.21, 20.84
and 18.47; m/z 193 (M+, 32%), 179 (25), 173 (41), 145 (40), 138
(62), 134 (55), 133 (86), 120 (35), 106 (52), 105 (39), 97 (100), 79
(35), 69 (45) and 55 (53).
(ii) 7-Acetoxymethylpyrrolizin-3-one 31 (70 mg, 0.4 mmol)
was hydrogenated over 5% Rh/C (18 mg) in ethanol for 2.5 h
at 45 psi. The usual work-up gave a quantitative mixture
of cis-hexahydro-7-methylpyrrolizin-3-one 18 (16%) and cis-7-
acetoxymethylhexahydropyrrolizin-3-one 33 (84%); dH 3.95–4.12
(3H, m), 3.58 (1H, dt, J 11.7 and 7.6), 3.01 (1H, m), 2.66 (1H,
m), 2.32–2.46 (2H, m), 2.04 (3H, s) and 1.77–2.27 (4H, m); dC
174.59 (quat), 170.74 (quat), 63.25, 62.65, 40.09, 37.63, 34.43,
30.27, 21.31 and 20.76 (in agreement with literature data37); the
correct molecular ion was observed at m/z 197 (M+, 1%), but
breakdown peaks could not be assigned because the sample was
contaminated with 18.
Hydrogenation of 1-acetoxy-1,2-dihydropyrrolizin-3-one 34
A solution of 1-acetoxy-1,2-dihydropyrrolizin-3-one24 34 (505 mg,
2.8 mmol) in ethanol (50 cm3) was hydrogenated over 5% Pd/C
(59 mg) for 3 h at 45 psi. The usual work-up gave a mixture of
cis- and trans-1-acetoxyhexahydropyrrolizin-3-one (504 mg, 97%)
in a ratio of 95:5; cis-1-acetoxyhexahydropyrrolizin-3-one 35 is a
colourless liquid, bp 95–100 ◦C (0.3 Torr) (Found: M+, 183.0901.
3
C9H13NO3 requires M, 183.0895); dH 5.29 (1H, t, J 5.0, H-1),
4.07 (1H, ddd, 3J 8.7, 6.8 and 4.8, H-7A), 3.53 (1H, dt, 3J 11.2 and
7.7, H-5), 3.00 (1H, m, H-5), 2.97 (1H, ddt, 2J 17.2, 3J 5.6 and nJ
1.2, H-2), 2.40 (1H, d, 2J 17.2, H-2), 1.95–2.08 (2H, m), 2.01 (3H,
s) and 1.55–1.80 (2H, m); dC 171.75 (quat), 169.93 (quat), 69.79
(C1), 64.86 (C7A), 41.93 (C2), 41.06 (C5), 26.71, 24.07 and 20.54
(CH3); m/z 183 (M+, 4%), 140 (5), 125 (14), 123 (37), 112 (11), 97
(21), 95 (15), 86 (23), 84 (39) and 70 (100). The minor trans-isomer
36 has the following characteristic 1H NMR signal: dH 4.95 (1H,
td, J 8.2 and 4.9, H-1).
(iii) Cis- and trans-hexahydro-7-methylpyrrolizin-3-ones 18 and
19 were obtained from small-scale hydrogenations at 45 psi for
3 h under the following conditions; 5% Pd/C, ethanol; PtO2, ethyl
acetate; 5% Rh/Al2O3, acetic acid; 5% Rh/Al2O3, ethanol.
cis-Hexahydro-1-hydroxypyrrolizine 37
Using the general method outlined above for heliotridane, and
the work-up for isoretronecanol, a 95:5 mixture of cis- and
trans-1-acetoxyhexahydropyrrolizin-3-ones 35 and 36 (49 mg,
0.3 mmol) and LAH (40 mg, 1.0 mmol) gave cis-hexahydro-1-
hydroxypyrrolizine 37 (30 mg, 87%) as a colourless liquid, bp
80–90 ◦C (15 Torr); mp 241–243 ◦C (picrate) (from ethanol) (lit.,25
243–245 ◦C). The free base has the following spectroscopic data:
Isoretronecanol 6
Isoretronecanol 6 was obtained by LAH reduction of various
precursors (see below) using the general method outlined above for
heliotridane, but with the following workup method. The solution
was concentrated and ether (10 cm3) was added, followed by water
3
dH 4.20 (1H, dd, J 7.0 and 4.4), 3.39–3.67 (3H, m), 2.91–3.10
4508 | Org. Biomol. Chem., 2009, 7, 4502–4511
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(2H, m), 2.43–2.68 (2H, m) and 0.70–2.04 (5H, m); dC 71.38,
68.78, 55.35, 51.93, 36.78, 27.53 and 24.09.
isomers were overlapping; a range of chemical shifts has been
given in those cases: cis-7,7A-cis-7A,1-hexahydro-1-hydroxy-7-
methylpyrrolizin-3-one 46 dH (360 MHz) 4.53 (1H, td, 3J 4.0 and
nJ 1.3, H-1), 3.77–3.85 (2H, m), 2.65–2.93 (2H, m), 2.30–2.43 (1H,
Hydrogenation of 1,2-dihydro-1-hydroxypyrrolizin-3-one 38
2
m), 2.23 (1H, d, J 16.8, H-2), 1.91 (1H, m), 1.60–1.69 (1H, m)
A solution of 1,2-dihydro-1-hydroxypyrrolizin-3-one24 38 (882 mg,
6.4 mmol) in ethanol (55 cm3) was hydrogenated over 5%
Rh/Al2O3 (76 mg) for 6 h at 45 psi. The usual work-up gave
a mixture of cis- and trans-hexahydro-1-hydroxypyrrolizin-3-one,
which were partially separated by dry flash chromatography (using
ethyl acetate as eluent). A first fraction gave a mixture of the
two isomers (171 mg, 19%). The second fraction afforded cis-
hexahydro-1-hydroxypyrrolizin-3-one 39 (671 mg, 74%) as a light
yellow solid, mp 97–99 ◦C (from ethyl acetate); dH 4.33 (1H, t, 3J
4.5, H-1), 3.92 (1H, m), 3.48 (1H, dt, 3J 11.7 and 7.1), 2.97 (1H,
and 1.25 (3H, d, 3J 7.1, Me); dC 172.40 (quat), 71.74, 67.46, 44.41,
39.88, 34.49, 31.93 and 13.86; cis-7,7A-trans-7A,1-hexahydro-1-
hydroxy-7-methylpyrrolizin-3-one 47; dH (360 MHz) 4.35 (1H, td,
3J 8.0 and 5.9, H-1), 3.77–3.85 (1H, m), 3.51 (1H, dt, 3J 11.6 and
7.9), 3.02 (1H, m), 2.65–2.93 (2H, m), 2.30–2.43 (1H, m), 2.15
(1H, m), 1.60–1.69 (1H, m) and 0.90 (3H, d, 3J 7.1, Me); dC 175.86
(quat), 71.34, 67.63, 45.15, 43.03, 34.79, 34.69 and 13.37.
(ii) Using ethanol as the solvent, the two products 46 and 47 were
formed after hydrogenation for 5 h at 55 psi, in the ratios 64:36
using 5% Rh/Al2O3 and 40:60 using 5% Pd/CaCO3 catalysts.
In some reaction mixtures a third isomer was observed: dH 0.80
(3H, 3J 7.1, Me).
2
3
n
2
m), 2.88 (1H, ddt, J 16.7, J 4.9, J 1.2, H-2), 2.34 (1H, d, J
16.7, H-2), 1.94–2.12 (3H, m) and 1.71 (1H, m); dC 173.39 (quat),
67.77, 67.02, 45.46, 41.33, 27.04 and 22.79 (in agreement with the
literature data27); m/z 141 (M+, 82%), 113 (36), 112 (85), 70 (100),
69 (27) and 41 (28). Trans-hexahydro-1-hydroxypyrrolizin-3-one
40 has the following NMR data: dH 2.71 (1H, apparent d, 3J 8.3,
H-2); dC (one quaternary not apparent) 72.91, 69.13, 44.18, 41.37,
29.59 and 26.44 (in agreement with literature data27).
Hydrogenation of 1-acetoxy-1,2-dihydro-7-methylpyrrolizin-3-
one 48
(i) A solution of 1-acetoxy-1,2-dihydro-7-methylpyrrolizin-3-one
48 (106 mg, 0.5 mmol) (see ESI†) in ethyl acetate (25 cm3) was
hydrogenated at 55 psi over 5% Rh/C (21 mg) for 4 h, at which
point only 40% of the starting material had been converted. The
mixture was rehydrogenated under the same conditions, but with
a higher loading of catalyst (50 mg) for a total time of 15 h.
The usual work-up gave a mixture of the 1-acetoxyhexahydro-7-
methylpyrrolizin-3-one isomers 49 and 50 (104 mg, 96%) in a 86:14
ratio, which were not separated. (Found: M+, 197.1050. C10H15NO3
requires M, 197.1051); m/z 197 (M+, 5%), 139 (62), 138 (36), 137
(84), 126 (21), 109 (35), 97 (100), 95 (33), 84 (96), 83 (24), 69 (58),
68 (30), 56 (36), 55 (52), 43 (91) and 41 (59). Cis-7,7A-cis-7A,1-
1-acetoxyhexahydro-7-methylpyrrolizin-3-one 49; dH (360 MHz)
5.40 (1H, ddd, 3J 5.8, 5.0 and 2.5, H-1a), 4.00 (1H, dd, 3J 7.4 and
5.0, H-7Aa), 3.82 (1H, ddd, 3J 11.4, 7.6 and 4.6, H-5b), 2.96 (1H,
m, H-5a), 2.91 (1H, dd, 2J 17.2 and 3J 5.8, H-2a), 2.38 (1H, dd, 2J
17.2 and 3J 2.5, H-2b), 2.35 (1H, m, H-7a), 2.05 (3H, s, OCOMe),
Hydrogenation of 7-methoxypyrrolizin-3-one 41
(i) Hydrogenation (on a small scale) of 7-methoxypyrrolizin-3-
one11 41 over 5% Rh/C in hexane/ethyl acetate for 2.5 h at 45 psi
gave 1,2-dihydro-7-methoxypyrrolizin-3-one 42 bp 50–55 ◦C (0.4
Torr) (Found: M+, 151.0632. C8H9NO2 requires M, 151.0633); dH
6.88 (1H, d, 3J 3.4), 6.22 (1H, d, 3J 3.4), 3.81 (3H, s), 3.06–3.14 (2H,
m) and 2.93–3.00 (2H, m); dC 171.29 (quat), 142.19 (quat), 118.35,
110.95, 109.09, 58.39, 34.26 and 30.76 (1 quat not assigned); m/z
151 (M+, 59%), 120 (100), 92 (42), 80 (45), 79 (33), 65 (25) and
52 (14).
(ii) Hydrogenation (on a small scale) of 7-methoxypyrrolizin-
3-one 41 over 5% Pd/C in ethanol for 3 h at 45 psi gave a
mixture of cis- and trans-hexahydro-7-methoxypyrrolizin-3-one in
a 86:14 ratio; cis-isomer 43, bp 95–100 ◦C (0.8 Torr) (Found: M+,
155.0942. C8H13NO2 requires M, 155.0946); dH 3.87 (1H, m, H-
7A), 3.48–3.60 (2H, m, H-7 and H-5), 3.28 (3H, s, OMe), 3.06 (1H,
br t, nJ 10.1, H-5), 2.62 (1H, m), 2.12–2.48 (2H, m) and 1.89–2.05
(3H, m); dC (one quaternary not apparent) 68.93, 66.40, 56.27,
39.18, 35.75, 34.29 and 17.80; m/z 155 (M+, 37%), 97 (100), 86
(28), 84 (60), 69 (67), 55 (34) and 41 (50). Trans-isomer 44; dH 3.34
(3H, s, OMe).
3
2.02 (1H, m, H-6a), 1.63 (1H, dq, J 12.3 and 7.6, H-6b) and
3
1.04 (3H, d, J 7.1, Me); dC 174.24 (quat), 170.05 (quat), 71.76,
65.89, 42.35, 41.37, 34.71, 34.34, 21.05 and 13.52. The cis-7,7A-
trans-7A,1-isomer 50 was identified by comparison with the data
obtained from the Pd/C reduction (see below).
(ii) Small-scale hydrogenations of 48 were carried out at 55 psi
for 4–6 h. The catalysts, solvents and ratios of 49:50 are indicated;
5% Rh/C, ethyl acetate, 83:17; 5% Rh/Al2O3, ethyl acetate,
72:28; 5% Rh/C, ethanol, 79:21; 5% Pd/C, ethanol, 40:60. These
latter conditions allowed the NMR characterisations, from the
reaction mixture, of the following isomer: cis-7,7A-trans-7A,1-
1-acetoxyhexahydro-7-methylpyrrolizin-3-one 50; dH (360 MHz)
Hydrogenation of 1,2-dihydro-1-hydroxy-7-methylpyrrolizin-3-
one 45
(i) Hydrogenation (on a small scale) of 45 (ESI†) in ethanol at
45 psi for 6 h over 5% Rh/C gave the hexahydro-1-hydroxy-
7-methylpyrrolizin-3-one isomers 46 and 47 in a 67:33 ratio.
(Found: M+, 155.0948. C8H13NO2 requires M, 155.0946); m/z
155 (M+, 69%), 126 (100), 97 (62), 84 (100), 83 (31), 82 (41),
71 (43), 69 (32), 56 (80), 55 (39) and 41 (84). The two isomers
were not separated; their NMR data were obtained by compar-
ison of the spectra of the above reaction mixture and that of
the 5% Pd/CaCO3 reduction in which the major product was
reversed (see below). Some of the proton signals of the two
3
3
5.10 (1H, ddd, J 8.7, 6.9 and 4.8, H-1b), 3.82 (1H, t, J 4.8, H-
3
7Aa), 3.50 (1H, dt, J 11.7 and 8.5, H-5b), 3.07 (1H, m, H-5a),
2.87 (1H, dd, 2J 17.3 and 3J 8.7, H-2b), 2.77 (1H, dddd, 2J 17.3,
3J 6.9, J 1.4 and 1.0, H-2a), 2.33 (1H, m, H-7a), 2.15 (1H, m,
n
H-6a), 2.07 (3H, s, O(CO)Me), 1.73 (1H, m, H-6b) and 0.88 (3H,
d, 3J 7.1, Me); dC 171.88 (quat), 170.50 (quat), 70.43, 68.38, 40.99,
39.47, 33.98, 32.37, 20.75 and 13.68.
In some reaction mixtures a third, minor, isomer was observed:
dH 0.82 (3H, 3J 7.4, Me).
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Retronecanol 7
small scale) over 5% Rh/C for 3 h at 45 psi. A complex
mixture of 4 major perhydro products was obtained; cis-
7,7A-cis-7A,1- and cis-7,7A-trans-7A,1-hexahydro-1-hydroxy-7-
methylpyrrolizin-3-one 46 and 47 were identified from their 13C
NMR resonances. The other two compounds were assigned as
isomers of hexahydro-1-hydroxy-7-acetoxymethylpyrrolizin-3-one
56 from the 13C NMR spectrum of the mixture; dC (one carbon
signal not apparent) 175.33 (quat), 172.10 (quat), 170.87 (quat),
170.71 (quat), 69.72, 67.86, 65.99, 64.01 (CH2), 63.36 (CH2), 45.13,
43.61, 42.77, 40.70, 39.94, 37.10, 30.55, 30.07, 20.84 and 20.77.
A 86:14 mixture of 1-acetoxyhexahydro-7-methylpyrrolizin-3-
ones 49 and 50 (104 mg, 0.5 mmol)] was reduced by LAH
(75 mg, 2.0 mmol) using the general method outlined above for
heliotridane, and the workup method for isoretronecanol. The
products were distilled at 100–110 ◦C (0.6 Torr) to give a mixture
of the hexahydro-1-hydroxy-7-methyl-3H-pyrrolizines 7 and 51
(66 mg, 88%) in a 86:14 ratio; cis-7,7A-cis-7A,1-hexahydro-1-
hydroxy-7-methyl-(3H)-pyrrolizine (retronecanol)7 dH (360 MHz)
3
4.29 (1H, m, H-1), 3.50 (1H, m), 3.40 (1H, dd, J 7.8 and 3.3,
3
3
H-7A), 3.25 (1H, td, J 7.0 and 4.0), 2.92 (1H, td, J 10.9 and
6.8), 2.80 (1H, td, nJ 10.0 and 1.6), 2.34 (1H, m), 1.84–2.02
Acknowledgements
3
(3H, m), 1.75 (1H, m) and 1.26 (3H, d, J 7.0, Me); dC 72.80,
We are grateful to The University of Edinburgh for support and
to Dr. I. H. Sadler for recording the 600 MHz spectra.
72.58, 56.15, 54.35, 37.27, 35.48, 32.85 and 13.87 (13C and H
1
NMR data disagree with values claimed in the literature,28 but
characterisation of the picrate salt is secure–see below); m/z
141 (M+, 14%), 97 (58), 83 (21), 82 (100), 69 (19), 55 (26) and
41 (41); cis-7,7A-trans-7A,1-hexahydro-1-hydroxy-7-methyl-3H-
pyrrolizine 51 showed characteristic signals at dH 4.53 (1H, m)
and 1.08 (3H, d, 3J 7.1, Me); dC 73.97, 71.56, 54.02, 53.23, 34.98,
32.57, 31.76 and 14.41. Purification of the mixture was achieved by
synthesis of the picrates and recrystallisation from ethanol to give
the picrate salt of retronecanol 7, mp 208–211 ◦C (from ethanol)
(lit.,38 210 ◦C); dH ([2H6]acetone) (picrate) 10.57 (1H, br), 8.77 (2H,
s), 4.59 (1H, br s), 4.01–4.19 (2H, m), 3.76 (1H, m), 3.31–3.57 (2H,
m), 2.65 (1H, m), 2.02–2.41 (3H, m) and 1.39 (3H, d, 3J 6.9, Me); dC
([2H6]acetone) (picrate) 159.94 (quat), 140.68 (quat), 127.28 (quat),
124.61, 73.70, 70.31, 54.79, 54.22, 35.48, 33.97, 31.17 and 10.91.
The picrate of the minor isomer 51 has the following characteristic
NMR signals; dH ([2H6]acetone) (picrate) 1.26 (3H, d, 3J 7.0, Me);
dC ([2H6]acetone) (non-picrate signals) 74.12, 68.76, 53.65, 52.70,
33.48, 32.97, 30.22 and 11.57.
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1
69 (100), 68 (73), 67 (55) and 55 (88). The following H NMR
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7-methoxycarbonylpyrrolizin-3-one 53; dH 5.45 (1H, td, nJ 5.0
n
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