Synthesis of the necine base (-)-supinidine from (S)-glutamic acid

Article abstract of DOI:10.1039/b005516f

A report on the synthesis of the necine base (-)-supinidine from (S)-glutamic acid was presented. An approach using a Witting reaction to effect ring closure on to the carbonyl group of a succinimide derivative was reported. Melting points were obtained o

Full text of DOI:10.1039/b005516f

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Synthesis of the necine base (؊)-supinidine from (S)-glutamic acid
Carole M. Boynton, Alan T. Hewson* and Douglas Mitchell
Division of Chemistry and Biomedical Research Centre, Sheffield Hallam University,
Pond Street, Sheffield, UK S1 1WB
1
Received (in Cambridge, UK) 10th July 2000, Accepted 4th September 2000
First published as an Advance Article on the web 19th October 2000
A route is described towards the pyrrolizidine† nucleus from derivatives of 5-acetylpyrrolidin-2-one using
an intramolecular Wittig reaction with vinylphosphonium salts. The acetoxy ketone 15, derived from
(S)-N-benzyloxycarbonylpyroglutamic acid,‡ affords 16, a known precursor of (Ϫ)-supinidine.
Introduction
The pyrrolizidine alkaloids such as retrorsine 1 are usually
composed of two moieties, namely a necine base (a pyrrol-
izidine alcohol, exemplified by retronecine 2 and supinidine 3)
Fig. 1 Numbering system for pyrrolizidine nucleus.
and a necic acid (usually a hydroxy carboxylic acid).1 They have
attracted much synthetic interest over recent years, partly
because of their interesting range of biological activities, but
also because they provide challenging targets for testing new
synthetic methods. In particular, a range of methods has been
reported towards the necine bases, resulting in both racemic
and optically pure products.1a–d Many approaches to these
pyrrolizidine alcohols build a second five-membered ring on
to a preformed, functionalised pyrrolidine, though the final
bond formed in the synthesis can be N–C3, C7a–C1 or C1–C2
(Fig. 1). Amongst many elegant approaches, those involving
radicals,2 acyliminium ions3 and dipolar cycloadditions4 are
noteworthy.
chemistry present in the reacting carbonyl compound is
retained in the process (Scheme 2). We therefore hoped that
Scheme 2
necine bases should be obtainable by a related process (C1–C2
bond formation) using an appropriately functionalised
pyrrolidin-2-one (Scheme 3), and we describe here the outcome
of studies towards that end.
Scheme 3
Early development was directed towards ( )-supinidine
3, and the procedure was then modified to provide the same
compound in enantiomerically pure form.
An approach using a Wittig reaction to effect ring closure
(C7a–C1 bond formation) on to the carbonyl group of a
succinimide derivative has also been reported (Scheme 1).5
Results and discussion
Treatment of (S)-glutamic acid with acetic anhydride–tri-
ethylamine–4-dimethylaminopyridine (Dakin–West reaction)8
produced 1,5-diacetylpyrrolidin-2-one 4 which underwent base
hydrolysis to give 5-acetylpyrrolidin-2-one 5.9 Unfortunately
the Dakin–West reaction racemises the original α-amino acid
so inevitably any alkaloid produced from 5 will be racemic, but
it provides a readily available precursor to test the concept
of the synthesis. Treatment of 5 with sodium hydride and
the appropriate vinylphosphonium salt 6 or 7 gave the corre-
sponding pyrrolizidine 8 (40%) or 9 (68%). In the latter case
there was some difficulty in purification since the product co-
chromatographed with triphenylphosphine oxide. This problem
could be circumvented by using vinylphosphine oxide 1010
which afforded 9 (84%), in this case the phosphorus containing
Scheme 1
We have previously described the use of the intramolecular
Wittig reaction to form a range of carbocyclic6 and hetero-
cyclic compounds,7 including a demonstration that the stereo-
† The IUPAC name for pyrrolizidine is hexahydro-1H-pyrrolizine.
‡ The IUPAC name for pyroglutamic acid is 5-oxopyrrolidine-2-
carboxylic acid.
DOI: 10.1039/b005516f
J. Chem. Soc., Perkin Trans. 1, 2000, 3599–3602
This journal is © The Royal Society of Chemistry 2000
3599

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by-products being water soluble. The phenylthio group could be
removed from 9 by treatment with Raney nickel (acetone–H2O),
giving 8 (47%), although this method was somewhat capricious
and over reduction was often observed. The same trans-
formation could be achieved less erratically by oxidation to the
sulfone 11 which was reduced with sodium dithionite§11 to
hydrolysed to the corresponding alcohol 18 (77%) which was
converted to the Mosher’s ester 19. Analysis of the 1H and 13
NMR spectra of 19 showed that it was >95% a single diastereo-
isomer and hence that there is little or no racemisation in the
cyclisation reactions leading to 15 and 16. Since 16 has been
reduced12,14 to supinidine, our route constitutes a new approach
to the natural enantiomer of this necine base.
C
1
provide 8 (40% from 9). The H NMR spectrum of 8 was in
agreement with that described by Hart and co-workers,12 who
have previously converted to it to ( )-supinidine 3 by allylic
acetoxylation followed by LiAlH4 reduction.
Experimental
General methods
Melting points were obtained on an Electrothermal melting
point apparatus and are uncorrected. Specific rotations were
determined using a Perkin-Elmer 241 polarimeter and are given
in units of 10Ϫ1 deg cm2 gϪ1. IR spectra were obtained on an
ATI Mattson Genesis Series FTIR spectrophotometer. NMR
spectra were obtained on a Bruker 250AC spectrometer.
J values are quoted in Hz. Mass spectra and high resolution
mass spectra were obtained on a VG Micromass 70/70F
mass spectrometer fitted with a MSS data system. TLC was
performed on Merck 555 Alufolien Kieselgel 60F254 plates,
and flash chromatography was performed on Sorbsil C-60H
(40–60 µm) silica gel. Light petroleum refers to the fraction
boiling between 40 and 60 ЊC. Solvents were dried and distilled
prior to use.
5,6,7,7a-Tetrahydro-1-methyl-2-phenylthiopyrrolizin-5(3H)-one
9
5-Acetylpyrrolidin-2-one 5 (1.51 g, 11.9 mmol) was dissolved
in a mixture of THF (10 cm3) and acetonitrile (40 cm3) and
sodium hydride (60% dispersion, 0.48 g, 12 mmol) was added.
The mixture was stirred for 0.5 h and then diphenyl(1-phenyl-
thiovinyl)phosphine oxide 10 (2.00 g, 6.0 mmol) was added
and the stirring was continued overnight. After removal of the
solvents, the residue was purified by flash chromatography with
ethyl acetate–light petroleum (1:1) to give the product 9 as an
oil (2.46 g, 84%) (Found Mϩ 245.0852. C14H15NOS requires
245.0874); νmax (film)/cmϪ1 3100, 1690, 1580; δH (250 MHz;
CDCl3) 1.83 (3H, s, CH3), 1.90–2.95 (4H, m, CH2CH2), 3.55
(1H, m, NCH), 4.05–4.76 (2H, m, NCH2), 7.15 (5H, br s, ArH);
m/z 245(Mϩ), 230, 189, 136, 121, 55.
The method was then extended to provide (Ϫ)-supinidine
in the following way. The readily available (S)-N-benzyl-
oxycarbonylpyroglutamic acid 1213 was converted to its acid
chloride and then, by treatment with diazomethane, to the
diazoketone 13 (84%) which was heated with acetic acid to
provide the acetoxy ketone 14 (78%). The Cbz group was then
removed from 14 by hydrogenolysis to give the pyrrolidin-2-one
15 which was cyclised with the vinylphosphonium salts 6
and 7 to provide the pyrrolizidines 16 (58%) and 17 (62%)
respectively. In the latter case there was no advantage in using
1
the vinylphosphine oxide 10. The H NMR spectrum of 16
was in total agreement with that previously described.12
5,6,7,7a-Tetrahydro-1-methylpyrrolizin-5(3H)-one 8
(a) Prepared as described above for 9 but using vinyltriphenyl-
phosphonium bromide. Oil (40%) (Found Mϩ 137.0857.
C8H11NO requires 137.0841); νmax (film)/cmϪ1 1710, 1650;
δH (250 MHz; CDCl3) 1.70 (3H, s, CH3), 1.90–2.95 (4H, m,
CH2CH2), 3.50 (1H, m, NCH), 4.05–4.60 (2H, m, NCH2), 5.26
(1H, br s, C᎐CH); m/z 137(Mϩ), 122, 81. (b) 5,6,7,7a-Tetra-
᎐
hydro-1-methyl-2-phenylthiopyrrolizin-5(3H)-one 9 (0.64 g, 2.6
mmol) was dissolved in methanol (50 cm3) and a solution
of Oxone (6.2 g, 13.5 mmol) in water (50 cm3) was added.
The mixture was stirred overnight at room temperature, the
methanol was removed on the rotary evaporator and the
residue was diluted with water (50 cm3) and extracted with ethyl
acetate (3 × 25 cm3). The organic extracts were dried (MgSO4)
and evaporated to give the crude sulfone 11. This was dissolved
in DMF (50 cm3) and a solution of sodium hydrogen carbonate
(1.1 g, 13 mmol) and sodium dithionite§ (1.1 g, 7 mmol) in
water (50 cm3) was added. The mixture was refluxed for 4 h,
cooled and partitioned between 2 M aq. HCl (50 cm3) and
DCM (50 cm3). The aqueous layer was extracted with DCM
(2 × 20 cm3) and the combined organic layers were washed
with 2 M aq. HCl (2 × 20 cm3), dried (MgSO4) and evaporated
to provide the crude product which was purified by flash
chromatography with ethyl acetate–light petroleum (1:1)
to give 8 as an oil (0.14 g, 40%) identical with that from (a)
above.
Under the basic conditions of the cyclisation there is the
possibility of 15 being racemised. In order to investigate the
optical purity of the pyrrolizidine products, the ester 17 was
§ The IUPAC name for sodium dithionite is sodium hydrosulfite.
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J. Chem. Soc., Perkin Trans. 1, 2000, 3599–3602

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(S)-N-Benzyloxycarbonyl-5-diazoacetylpyrrolidin-2-one 13
J 16.0, NCH), 4.40 (1H, br d, J 16.0, NCH), 4.65 (1H, m,
NCH), 4.69 (2H, s, CH OCO), 5.81 (1H, s, C᎐CH); δ (62.5
᎐
2
C
(S)-N-Benzyloxycarbonylpyroglutamic acid (6 g, 23 mmol)
was dissolved in dry THF (50 cm3) and cooled to 0 ЊC. Oxalyl
chloride (6.43 g, 101 mmol) was added slowly with stirring.
The mixture was then stirred at room temperature for 3 h and
evaporated to leave the crude acid chloride. This was dissolved
in dry THF (100 cm3) and into it was distilled an ethereal
solution of diazomethane obtained from diazald¶ (38 g) and
potassium hydroxide (10.25 g). The reaction mixture was left to
stand overnight and then concentrated under reduced pressure
to give the product 13 as a pale yellow solid (8.68 g, 84%);
mp 121–123 ЊC (MeOH) (Found: C, 58.3; H, 4.35; N, 14.35.
C14H13N3O4 requires C, 58.52; H, 4.56; N, 14.63%); [α]D22 Ϫ27.2
(c 2.10 in CHCl3); νmax (KBr)/cmϪ1 3010, 2930, 2100, 1780,
1720, 1630; δH (250 MHz; CDCl3) 2.03 (1H, m), 2.28 (1H, m),
2.50 (1H, m), 2.69 (1H, m), 4.57 (1H, m, NCH), 5.26 (3H, m,
CHN2 ϩ OCH2Ph), 7.34 (5H, m, ArH); m/z 287(Mϩ), 197, 115,
107, 91, 83, 55, 41.
MHz; CDCl3) 21.0, 29.7, 33.7, 49.9, 60.1, 68.1, 123.5, 136.5,
170.8, 177.6; m/z 195(Mϩ), 135, 134, 122, 106, 93, 80, 79, 68, 55,
53, 52, 43.
(S)-5,6,7,7a-Tetrahydro-1-acetoxymethyl-2-phenylthio-
pyrrolizin-5(3H)-one 17
(S)-5-Acetoxyacetylpyrrolidin-2-one 15 (0.28 g, 1.51 mmol)
was dissolved in a mixture of THF (5 cm3) and acetonitrile
(20 cm3) and sodium hydride (60% dispersion, 0.07 g, 1.75
mmol) was added. The mixture was stirred for 0.5 h and then
1-(phenylthiovinyl)triphenylphosphonium iodide 7 (0.95 g,
1.8 mmol) was added and the stirring was continued over-
night. After removal of the solvents the residue was purified
by flash chromatography with ethyl acetate to give the product
17 as an oil (0.24 g, 62%) (Found Mϩ 303.0920. C16H17NO3S
requires 303.0929); [α]D22 Ϫ10.7 (c 1.10 in CHCl3); νmax (film)/
cmϪ1 3080, 3000–2900, 2880, 1740, 1700, 1585; δH (250 MHz;
CDCl3) 1.81–2.02 (1H, m), 2.08 (3H, s, CH3), 2.25–2.44 (2H,
m), 2.60–2.78 (1H, m), 3.56 (1H, dd, J 14.7, 2.2, NCH), 4.27
(1H, br d, J 15.0, NCH), 4.72 (1H, m, NCH), 4.89 (2H, br s,
CH2OCO), 7.28 (5H, m, ArH); δC (62.5 MHz; CDCl3) 21.0,
29.4, 33.5, 52.5, 58.5, 69.2, 127.6, 128.8, 129.7, 130.9, 132.8,
136.4, 170.9, 177.6; m/z 303(Mϩ), 277, 245, 244, 230, 210, 188,
186, 149, 134, 121, 109, 91, 77, 71, 55, 43.
(S)-5-Acetoxyacetyl-N-benzyloxycarbonylpyrrolidin-2-one 14
(S)-N-Benzyloxycarbonyl-5-diazoacetylpyrrolidin-2-one
13
(6.46 g, 23 mmol) was added to acetic acid (65 cm3) and the
mixture was refluxed for 1 h. The excess acetic acid was
removed in vacuo to give the crude product which was purified
by flash chromatography with ethyl acetate to give the product
14 as a white solid (5.6 g, 78%); mp 62–64 ЊC (Found: C, 66.6;
H, 5.85; N, 4.65. C16H17NO6 requires C, 66.89; H, 5.96;
N, 4.88%); [α]D22 Ϫ38.4 (c 2.25 in CHCl3); νmax (KBr)/cmϪ1
3100, 2940, 1730, 1680; δH (250 MHz; CDCl3) 2.13 (3H, s, CH3),
2.01–2.63 (4H, m, 2 × CH2), 4.57 (1H, d, J 17.0, OCH), 4.78
(1H, dd, J 9.5, 3, NCH), 4.83 (1H, d, J 17.0, OCH), 5.21 (2H, s,
OCH2Ph), 7.34 (5H, m, ArH); δC (62.5 MHz; CDCl3) 20.6, 20.7,
31.2, 61.2, 66.4, 68.9, 128.4, 128.9, 129.0, 127.9, 131.3, 135.1,
151.3, 170.5, 173.2 and 201.3; m/z 319(Mϩ), 295, 218, 174, 107,
91, 85, 64, 43.
(S)-5,6,7,7a-Tetrahydro-1-hydroxymethyl-2-phenylthio-
pyrrolizin-5(3H)-one 18
(S)-5,6,7,7a-Tetrahydro-1-acetoxymethyl-2-phenylthiopyrrol-
izin-5(3H)-one 17 (0.3 g, 1.15 mmol) was dissolved in methanol
(5 cm3), 2 M aq NaOH (20 cm3), was added and the solution
was stirred for 5 h. After removal of the methanol the residue
was extracted with DCM (3 × 20 cm3) and the combined organic
extracts were dried (MgSO4) and evaporated. Flash chroma-
tography of the residue with ethyl acetate gave the product 18 as
an oil (0.2 g, 77%) (Found Mϩ 261.0839. C14H15NO2S requires
261.0824); [α]D22 Ϫ12.9 (c 1.10 in CHCl3); νmax (film)/cmϪ1 3400,
3100, 2960–2900, 1680, 1630; δH (250 MHz; CDCl3) 1.92–2.95
(5H, m), 3.5 (1H, br s), 4.25 (2H, t, J 2, CH2O), 4.45 (1H, m),
4.80 (1H, m), 7.1 (5H, m, ArH); δC (62.5 MHz; CDCl3) 29.5,
33.3, 52.4, 58.5, 62.5, 127.4, 128.6, 129.7, 130.7, 132.9, 136.1,
177.6.
(S)-5-Acetoxyacetylpyrrolidin-2-one 15
(S)-5-Acetoxyacetyl-N-benzyloxycarbonylpyrrolidin-2-one 14
(3.0 g, 9.4 mmol) was dissolved in methanol (40 cm3),
10% palladium on charcoal (0.5 g) was added and the mixture
was stirred under hydrogen for 6 h. The catalyst was filtered
off and the filtrate evaporated to give the product 15 as a white
solid (1.51 g, 87%); mp 35–36 ЊC (Found: C, 51.7; H, 5.8;
N, 7.75. C8H11NO4 requires C, 51.89; H, 5.99; N, 7.56%);
[α]D23 Ϫ24.1 (c 1.54 in CHCl3); νmax (KBr)/cmϪ1 3400–3300, 2940,
1740, 1700; δH (250 MHz; CDCl3) 2.08 (3H, s, CH3), 2.01–2.53
(4H, m, 2 × CH2), 4.33 (1H, m, NCH), 4.76 (2H, s, CH2), 7.66
(1H, s, NH); δC (62.5 MHz; CDCl3) 20.6, 24.1, 29.6, 60.1, 66.2,
170.6, 179.9 and 203.0; m/z 185(Mϩ), 154, 84, 41.
Mosher’s ester 19
(S)-5,6,7,7a-Tetrahydro-1-hydroxymethyl-2-phenylthiopyrrol-
izin-5(3H)-one 18 (0.10 g, 0.35 mmol) was dissolved in
DCM (10 cm3) and (2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-
propanoic acid (0.088 g, 0.38 mmol), DCC (0.083 g, 0.4 mmol)
and DMAP (0.01 g) were added. The mixture was stirred
at room temperature for 8 h, after which the consumption
of 18 was complete, and filtered. The filtrate was washed with
2 M aq. HCl (10 cm3), 2 M aq. NaOH (10 cm3), and water (10
cm3), dried (MgSO4) and evaporated to give the crude product
which was purified by flash chromatography with ethyl acetate–
light petroleum (1:1) to give the product 19 as a colourless oil
(0.14 g, 77%) (Found Mϩ 478.1288. C24H23 F3NO4S requires
478.1300); δH (250 MHz; CDCl3) 1.7–1.9 (1H, m ), 2.15–2.4
(2H, m,), 2.6 (1H, ddd, J 16.2, 12.7, 8.3 Hz), 3.6 (4H, m ϩ s),
4.25 (1H, dd, J 15.6, 3.6 ), 4.6 (1H, m), 5.1 (2H, s), 7.3–7.5
(10H, m); δC (62.5 MHz; CDCl3) 28.6, 33.1, 52.4, 55.5, 59.8,
68.7, 121.3, 125.8, 127.4, 128.6, 128.8, 129.6, 129.8, 130.4,
132.1, 132.7, 134.5, 136.0, 166.5, 177.3.
(S)-5,6,7,7a-Tetrahydro-1-acetoxymethylpyrrolizin-5(3H)-one
16
(S)-5-Acetoxyacetylpyrrolidin-2-one 15 (0.23 g, 1.24 mmol)
was dissolved in a mixture of THF (5 cm3) and acetonitrile
(20 cm3) and sodium hydride (60% dispersion, 0.06 g, 1.5 mmol)
was added. The mixture was stirred for 0.5 h and then vinyl-
triphenylphosphonium bromide (0.55 g, 1.5 mmol) was added
and the stirring was continued overnight. After removal of
the solvents the residue was purified by flash chromatography
with ethyl acetate to give the product 16 as a pale yellow solid
(0.14 g, 58%); mp 89–91 ЊC (Found: C, 61.3; H, 6.55; N, 6.95.
C10H13NO3 requires C, 61.53; H, 6.71; N, 7.17%); [α]D22 Ϫ19.8
(c 1.24 in CHCl3); νmax (KBr)/cmϪ1 3000–2880, 1740, 1700,
1650; δH (250 MHz; CDCl3) 1.84–2.03 (1H, m), 2.09 (3H,
s, CH3), 2.29–2.46 (2H, m), 2.64–2.79 (1H, m), 3.72 (1H, br d,
Acknowledgements
We thank EPSRC (formerly SERC) for financial support (to
C. M. B. and D. M.) for this work. We wish to acknowledge the
use of the EPSRC’s Chemical Database Service at Daresbury.15
¶ The IUPAC name for diazald is N-methyl-N-nitrosotoluene-p-
sulfonamide.
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