Investigation of a route to ibotenic acid analogues via a reduced pyroglutamate template

Article abstract of DOI:10.1039/b600195e

Two alternative "ring switch" based syntheses have been shown to give access to the reduced protected homochiral analogues, 27, 28 and 36, of the CNS active compound ibotenic acid. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b600195e

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Investigation of a route to ibotenic acid analogues via a reduced
pyroglutamate template
Omar Ahmed, Peter B. Hitchcock and Douglas W. Young*
Received 6th January 2006, Accepted 16th February 2006
First published as an Advance Article on the web 14th March 2006
DOI: 10.1039/b600195e
Two alternative “ring switch” based syntheses have been shown to give access to the reduced protected
homochiral analogues, 27, 28 and 36, of the CNS active compound ibotenic acid.
Introduction
(2S)-Glutamic acid is an excitatory neurotransmitter which in-
teracts with a variety of ionotropic (ion channel controlling)
and metabotropic (G-protein linked) receptors.1 Analogues of
glutamic acid have been shown to be specific in their action by
interacting with one or more of these receptors to give selective
physiological effects. Thus, while the natural product ibotenic acid
1, an active constituent of the psychotropic fly agaric mushroom
Amanita muscaria, acts at both ionotropic and metabotropic
glutamate receptor sub-types,1 analogues such as (R)-2-amino-2-
(3-hydroxy-5-methylisoxazol-4-yl)-acetic acid [(R)-AMAA] 2 and
DL-tetrazolylglycine 3 act specifically at the ionotropic N-methyl-
D-aspartate (NMDA) receptor sub-type.1 These compounds con-
We have discovered a versatile and economical synthesis for a
sist of a heterocyclic ring system fused to a glycine moiety.
The homologue (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazoyl)-
propionic acid (AMPA) 4 and many analogues which have a
heterocyclic ring fused to the b-carbon of L-alanine are active
at a different ionotropic glutamate receptor sub-type, the AMPA
site.1 Glutamate receptors are involved in memory and learning
processes and antagonists have been identified as potential drugs
for variety of neurodegenerative diseases,2 including Alzheimer’s
disease,2 epilepsy2,3 and ischaemia.2,4
large variety of homochiral compounds in which a heterocyclic
ring system is fused to the b-carbon atom of L-alanine or the c -
carbon atom of ethylglycine. These compounds were designed to
have potential for activity at individual receptors5–9 and some have
shown interesting CNS activity. The synthesis, shown in Scheme 1,
involved reaction of aldehydes 5 of protected pyroglutamic acid
(n = 1)5–8 and of protected 6-oxopipecolic acid (n = 2),9 with
bisnucleophiles and involved a minimum of steps. We have
christened this powerful synthetic tool a “ring switching” reaction5
and recently extended it to the use of b-lactam aldehydes 12 from
which a plethora of analogues of ibotenic acid could be obtained10
(Scheme 2).
Department of Chemistry, University of Sussex, Falmer, Brighton, UK BN1
9QJ
Scheme 1
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Scheme 2
An alternative way of obtaining analogues of ibotenic acid
might be to react the pyroglutamate-3-aldehyde 19 with bisnucleo-
philes and indeed reaction with a substituted hydrazine, as in
Scheme 3, might yield isomers 20 of the ibotenate analogues 15,
obtained by the b-lactam route.10 Further, reaction of an enone 21
with substituted hydrazines, as in Scheme 4, might yield the com-
pounds 22, reduced isomers of the ibotenate analogue 14, which
was obtained by the b-lactam route.10 Unfortunately, synthesis
of 3-substituted pyroglutamate derivatives such as the aldehydes
19 would best be approached via enones such as 21, and we have
Scheme 3
Scheme 4
Scheme 5 Reagents and conditions: (i) ref. 13; (ii) (a) O3, CH2Cl2, −78 ◦C, 15 min (b) Ph3P, rt, 1 h (96%); (iii) (a) O3, CH2Cl2, −78 ◦C, 15 min, (b) Zn,
HOAc, rt, 1 h (18%); (iv) H2NNH2, MeOH, rt, 18 h (41% 27); (v) MeNHNH2, MeOH, rt, 18 h (65% 28); (vi) TBAF, THF, 0 ◦C, then rt, 25 min (96%);
(vii) RuO2·H2O, NaIO4, H2O, CCl4–CH3CN, rt, 18 h (35%).
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1
shown11 that such compounds are extremely prone to racemisation
and dimerisation under very mild conditions. We therefore decided
to test the route using the reduced compounds 23 and 25.
doublet was present at d 4.86 ppm in the H NMR spectrum of
product 27 and at d 4.74 ppm in the 1H NMR spectrum of product
28.
The “ring switch” reactions had, therefore, succeeded but,
to prepare the desired ibotenic acid analogues 20, it was now
necessary to deprotect the products to the corresponding alcohols
and then oxidise these to the acids. The N-methylpyridazine 28 was
therefore treated with tetrabutylammonium fluoride in tetrahydro-
furan to afford the alcohol 29 in 96% yield. When this was oxidised
using ruthenium oxide monohydrate and sodium periodate, no
reaction was observed after 18 h at room temperature although,
when 2.2 mol% of catalyst and 4.1 equivalents of sodium periodate
were used, a new, less polar product was obtained in 34% yield.
This was evidently not the desired acid and the spectroscopic data
suggested that it might be the cyclic imino ether 30. This, and the
relative stereochemistry was confirmed by X-ray structure deter-
mination (Fig. 2). An attempt to oxidise the primary alcohol 29
using ruthenium trichloride and periodate which had proved
successful in our hands12 for oxidation of other protected amino
alcohols was unsuccessful, as was the use of oxygen and a
platinum catalyst.
Results and discussion
The aldehyde 25 was prepared as shown in Scheme 5 by a similar
route to one we have previously used.12 The 4-vinyl substituted
compound 24 was prepared from the enone 23 by the method of
Herdeis and Hubmann.13 Ozonolysis followed by a triphenylphos-
phine work-up then gave the aldehyde 25. In an earlier ozonolysis
reaction where zinc and acetic acid were used followed by methanol
in the work-up, the hemiacetal 26 was obtained. The structure of
this compound was assigned on the basis of the spectral data
and confirmed by X-ray crystallography. The crystal structure is
shown in Fig. 1, confirming the relative stereochemistry of two of
the centres, the hydroxyl group being disordered over two locations
in the crystal, indicating a mixture of epimers.
Fig. 1 X-Ray structure determination of (4S,5S)-N-tert-butoxycarbonyl-
5-tert-butyldiphenylsiloxymethyl-4-hydroxymethoxymethylpyrrolidin-2-
one 26.
Fig. 2 X-Ray structure determination of (4aS,5S)-5-tert-butoxycarbo-
nylamino-2-methyl-3-oxo-2,3,4,4a,5,6-hexahydrofuro[2,3-c]pyridazine 30.
Having prepared the desired aldehyde 25, we were now in a
position to attempt the “ring-switching” reaction. We therefore
reacted the aldehyde separately with hydrazine and with methyl-
hydrazine and obtained the “ring-switched” products 27 and 28
in 41 and 65% yields, respectively. The urethane–lactam band at
ca. 1770 cm−1 was no longer present in the infra-red spectra of these
compounds and the imine proton, H-6, appeared at d 7.03 ppm in
the 1H NMR spectrum of product 27 and at d 7.06 ppm in 1H NMR
spectrum of product 28. A characteristic exchangeable NHBoc
The alternative “ring switching” reaction method of Scheme 4
has already been carried out successfully on the reduced analogue
3114 but when we reacted the TBDPS derivative 23 with hydrazine
hydrate or with methylhydrazine no reaction ensued. We therefore
deprotected the TBDPS derivative 23 using tetrabutylammonium
fluoride and acetic acid in tetrahydrofuran to obtain the alcohol 32
in quantitative yield as shown in Scheme 6. This was reacted with
tert-butyldimethylsilyl triflate and lutidine in dichloromethane at
Scheme 6 Reagents and conditions: (i) TBAF, HOAc, THF, 0 ◦C then rt, 18 h (quant.); (ii) TBDMSOTf, 2,6-lutidine, CH2Cl2, −78 ◦C, then 0 ◦C,
30 min, then rt, 30 min (43% 31 + 43% 33); (iii) TBDMSOTf, pyridine, CH2Cl2, −78 ◦C, 30 min, then −10 ◦C, 30 min then rt, 30 min (76% 31);
(iv) MeNHNH2, MeOH, H2O, rt, 18 h (80%); (v) aq. NaOH, MeOH, reflux, 18 h (48%); (vi) TBAF, HOAc, THF, 0 ◦C, then rt, 18 h (61%).
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−78 ◦C to give the required TBDMS ether 31 in 43% yield. This
was the only product in small scale reactions but the pyrrole 33
was obtained in yields of up to 46% in larger scale reactions. When
pyridine was used as base in this reaction, the compound 31 was
obtained in 76% yield. We were now able to react the enone 31
with methylhydrazine in water and methanol to obtain the product
34 in yields of up to 80%. The singlet N-methyl and the NH2
signals in the 1H NMR-spectrum confirmed the regiochemistry of
nucleophilic attack. When the adduct 34 was heated at reflux for
18 h in aqueous methanolic sodium hydroxide the desired “ring
switched” product 35 was obtained in 48% yield. The difference in
reactivity between the TBDPS and TBDMS derivatives 23 and 31
respectively may be ascribed to steric considerations.
(4S,5S)-N-tert-Butoxycarbonyl-5-tert-butyldiphenylsiloxymethyl-
4-formylpyrrolidin-2-one (25)
A solution of (4R,5S)-N-tert-butoxycarbonyl-5-tert-butyldiphen-
ylsiloxymethyl-4-vinylpyrrolidin-2-one (24)13 (250 mg, 0.52 mmol)
in dichloromethane (10 ml) was cooled to −78 ◦C under nitrogen.
Nitrogen was displaced by bubbling oxygen through the solution
for 15 min. Ozone was passed through the solution until a
blue colouration was observed. Oxygen was passed for 5 min,
followed by nitrogen for 5 min and triphenylphosphine (149 mg,
0.57 mmol) was added. The mixture was allowed to warm to
room temperature and was stirred for a further 1 h. The solvent
was removed in vacuo and the residue was purified by flash
column chromatography on silica gel using petroleum ether–ethyl
acetate (3 : 2) with 1% triethylamine as the mobile phase to
give (4S,5S)-N-tert-butoxycarbonyl-5-tert-butyldiphenylsiloxy-
methyl-4-formylpyrrolidin-2-one (25) as a clear colourless oil
(240 mg, 96%); [a]D26 +1.3 (c 0.8, CHCl3) (lit.12 [a]2D0 +1.5 (c 1.0,
CHCl3)); m/z [ES+ (NH4)] Found 499.2628, [C27H35NO5Si +
NH4]+ requires 499.2628; m/z [EI+] 424 ([M-tBu]+); dH (300 MHz,
C2HCl3) 9.70 (1H, s, CHO), 7.68–7.58 (4H, m, ArH), 7.46–7.37
(6H, m, ArH), 4.57 (1H, m, H-5), 3.98 (1H, dd, J6A,6B 10.5, J6A,5
3.9, H-6A), 3.81 (1H, dd, J6B,6A 10.5, J6B,5 2.6, H-6B), 3.19 (1H,
m, H-3A), 2.97–2.90 (2H, m, H-3B, H-4), 1.43 (9H, s, C(CH3)3)
Treatment of the “ring switched” product with TBAF and acetic
acid in tetrahydrofuran gave the alcohol 36 in 61% yield but, again,
all attempts to oxidise this to the acid proved fruitless.
Conclusions
We have shown that a further two alternative modes of “ring
switching” reactions are viable. However for the first time it
had proved necessary to use protected amino alcohols rather
than protected amino acids in the synthesis. To obtain CNS
active ibotenic acid analogues, however, subsequent oxidation
was necessary. This did not prove possible using the heterocyclic
products of the “ring switching” reactions and so it would appear
that oxidation after addition to the double bond in 23 has removed
the danger of dimerisation or racemisation would have to precede
the “ring switching” process for the method to be completely
successful. Oxidation of such pyroglutaminols has been achieved
by a variety of methods.15
2
and 1.05 (9H, s, SiC(CH3)3); dC (75.5 MHz, C6 H6) 197.7 (C-7),
170.3 (lactam), 150.6 (urethane), 135.9, 133.2 and 130.2 (Ar), 82.6
(OC(CH3)3), 64.9 (C-6), 57.7 (C-5), 45.6 (C-4), 32.2 (C-3), 28.1
(OC(CH3)3), 26.9 (SiC(CH3)3) and 19.3 (SiC(CH3)3).
(4S,5S)-N-tert-Butoxycarbonyl-5-tert-butyldiphenylsiloxymethyl-
4-hydroxymethoxymethylpyrrolidin-2-one (26)
A solution of (4S,5S)-N-tert-butoxycarbonyl-5-tert-butyldiphen-
ylsiloxymethyl-4-vinylpyrrolidin-2-one (24) (381 mg, 0.79 mmol)
in dichloromethane (9 ml) was cooled to −78 C under nitrogen
Experimental
◦
MeltingpointsweredeterminedusingaKofler hot-stageapparatus
and are uncorrected. Optical rotation measurements (in units
of 10−1 deg cm2 g−1) were obtained on a Perkin Elmer PE241
polarimeter using a 1 dm pathlength cell. IR spectra were recorded
with stirring. The nitrogen was displaced by bubbling oxygen
through the solution for 15 min. Ozone was passed through
the solution until a blue coloration was observed. Oxygen was
passed for 5 min, followed by nitrogen for 5 min and acetic acid
(0.45 ml, 7.9 mmol) and zinc dust (519 mg, 7.9 mmol) were
added. The mixture was allowed to warm to room temperature
and was stirred for a further 1 h. The mixture was filtered and
the residue was rinsed with methanol. The solvent was removed
from the filtrate in vacuo to give an oil which was purified by
flash column chromatography on silica gel using petroleum ether–
ethyl acetate (1 : 1) containing 1% triethylamine as the mobile
phase. (4S,5S)-N-tert-Butoxycarbonyl-5-tert-butyldiphenylsiloxy-
methyl-4-hydroxymethoxymethylpyrrolidin-2-one (26) was ob-
tained◦ as a white crystalline solid (74 mg, 18%); mp 112.4–
113.8 C; [a]2D2 −36.5 (c 0.16, CHCl3); (Found: C, 65.3; H, 7.7;
N, 2.7. C28H39NO6Si requires C, 65.5; H, 7.65; N, 2.7%); m/z
[+ve FAB (3-NBA)] 536 ([M + Na]+); mmax (film)/cm−1 3479 (OH)
and 1771 (urethane); dH (300 MHz, C2H3O2H) 7.62–7.51 (4H, m,
ArH), 7.38–7.31 (6H, m, ArH), 4.81 (3H, s, OCH3), 4.45 (1H, d,
J7,4 4.3, H-7), 4.13 (1H, m, H-5), 3.92 (1H, dd, J6A,6B 10.7, J6A,5
2.8, H-6A), 3.60 (1H, dd, J6B,6A 10.7, J6B,5 1.8, H-6B), 2.81 (1H,
m, H-4), 2.48–2.32 (2H, m, H-3), 1.28 (9H, s, C(CH3)3) and 0.92
(9H, s, SiC(CH3)3); dC (75.5 MHz, C2H3O2H) 177.7 (lactam), 151.4
(urethane), 137.0, 134.4, 134.2 and 129.4 (Ar), 100.4 (C-7), 84.5
1
using a Perkin Elmer 1710 Fourier transform spectrometer. H
NMR spectra were recorded using a Bruker DPX 300 (300 MHz)
Fourier transform instrument. 13C NMR spectra (1H decoupled)
were recorded using a Bruker DPX 300 (75.5 MHz) Fourier
transform instrument. DEPT, H COSY and H–13C COSY ex-
periments were used to help assign NMR spectra where necessary.
Homonuclear decoupling and NOE experiments were used to
help determine stereochemistry where necessary. d are given in
ppm and J in Hz. Residual undeuteriated solvent peaks and
tetramethysilane (TMS) were used as internal references. All NMR
spectra were recorded at 25 ◦C unless otherwise stated. Low-
resolution mass spectra were recorded by Dr A. Abdul-Sada
using Kratos MS 80RF (FAB), VG Autospec (EI) or Bruker
BioApex III (ESI) double focusing spectrometers. High-resolution
spectra were recorded by Dr A. Abdul-Sada using a 4.7 FT-ICR
(Bruker BioApex III) spectrometer or obtained from the EPSRC
Central Mass Spectrometry Service at Swansea. Microanalyses
were performed by Medac Ltd., Egham, Surrey. Column chro-
1
1
R
matography was performed using Davisilꢀ Silica 60A, 35–70 mesh
silica gel. Petroleum ether refers to that fraction of hexanes of
boiling point 60–80 ◦C.
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(OC(CH3)3), 66.9 (C-6), 62.3 (C-5), 41.3 (C-4), 36.1 (C-3), 28.6
(OC(CH3)3), 27.7 (SiC(CH3)3), 20.4 (SiC(CH3)3) and 9.6 (OCH3).
Crystal data for (4S,5S)-N-tert-butoxycarbonyl-5-tert-butyl-
diphenylsiloxymethyl-4-hydroxymethoxymethylpyrrolidin-2-one
(26),† C28H39NO6Si, M = 513.69, monoclinic, space group P21
acetate (3 : 2) as eluent to afford (5S)-2-methyl-5-[(1S)-1-tert-
butoxycarbonylamino-2-tert-butyldiphenylsilanyloxyethyl]-3-oxo-
2,3,4,5-tetrahydropyridazine 28 as a clear colourless oil (298 mg,
65%); [a]2D0 +91.38 (c 1.0, CHCl3); m/z [ES+] Found 510.2799,
[C28H39N3O4Si + H]+ requires 510.2788; m/z [+ve FAB (3-NBA)]
532 ([M + Na]+); mmax (film)/cm−1 3326 (NH), 1712 (urethane)
and 1662 (amide); dH (300 MHz, C2HCl3) 7.63–7.58 (4H, m,
ArH), 7.48–7.36 (6H, m, ArH), 7.06 (1H, s, H-6), 4.74 (1H, br
˚
(No. 4), a = 7.6412(4), b = 11.8424(9), c = 15.8245(7) A, b =
◦
3
102.434(3) , V = 1398.37(14) A , Z = 2, Dcalc 1.22 mg m−3, l(Mo
˚
Ka) = 0.13 mm−1, T = 173(2) K, 3805 independent reflections
(Rint = 0.044). The final R values were R1 = 0.042 (for 3372
reflections with I > 2r(I)) and wR2 = 0.095 (for all reflections). The
hydroxy group was disordered over two positions. Data collection
was carried out using a Kappa CCD diffractometer, structure
analysis using program package WinGX, and refinement using
SHELXL-97. The atomic coordinates are available on request
from The Director, Cambridge Crystallography Data Centre,
University Chemical Laboratory, Lensfield Road, Cambridge,
CB2 1EW.
d, JNH,1 8.8, NH), 3.95 (1H, m, H-1ꢀ), 3.70 (2H, m, H-2ꢀ), 3.30
ꢀ
(3H, s, NCH3), 2.92 (1H, m, H-5), 2.50 (1H, dd, J4A,4B 16.7, J4A,5
7.5, H-4A), 2.26 (1H, dd, J4B,4A 16.7, J4B,5 12.6, H-4B), 1.43 (9H, s,
C(CH3)3) and 1.06 (9H, s, SiC(CH3)3); dC (75.5 MHz, C2HCl3)
165.2 (amide), 155.3 (urethane), 146.0 (C-6), 135.5, 132.4, 130.1
and 127.9 (Ar), 80.0 (OC(CH3)3), 63.3 (C-2ꢀ), 51.6 (C-1ꢀ), 36.1
(NCH3 and C-5), 28.5 (C-4), 28.2 (OC(CH3)3), 26.9 (SiC(CH3)3)
and 19.2 (SiC(CH3)3).
(5S)-2-Methyl-5-[(1S)-1-tert-butoxycarbonylamino-2-
hydroxyethyl]-3-oxo-2,3,4,5-tetrahydropyridazine (29)
(5S)-5-[(1S)-1-tert-Butoxycarbonylamino-2-tert-
butyldiphenylsilanyloxyethyl]-3-oxo-2,3,4,5-
tetrahydropyridazine (27)
A solution of (5S)-2-methyl-5-[(1S)-1-tert-butoxycarbonylamino-
2-tert-butyldiphenylsilanyloxy]-3-oxo-2,3,4,5-tetrahydropyrida-
zine (28) (100 mg, 0.19 mmol) in tetrahydrofuran (5 ml) was cooled
to 0 ◦C with stirring. Tetrabutylammonium fluoride (TBAF, 1.0 M
solution in THF containing 5%wt water, 0.235 ml, 0.235 mmol)
was slowly added and the mixture was allowed to warm to room
temperature with stirring over a further 25 min. Ethyl acetate
(10 ml) was added and the solution was washed with saturated
aqueous ammonium chloride (2 × 10 ml). The organic layer was
dried (MgSO4) and filtered, and the solvent was removed in vacuo
to give a pale yellow clear oil. The crude product was purified
by column chromatography on silica gel initially using ethyl
acetate (100%) and then ethyl acetate–methanol (96 : 4) as elu-
ent to afford (5S)-2-methyl-5-[(1S)-1-tert-butoxycarbonylamino-
2-hydroxyethyl]-3-oxo-2,3,4,5-tetrahydropyridazine (29) as a clear
colourless oil (51 mg, 96%); [a]2D7 +133.8 (c 0.25, CHCl3); m/z
[ES+] Found 272.1606, [C12H22N3O4 + H]+ requires 272.1610; m/z
[+ve FAB (3-NBA)] 294 ([M + Na]+) and 272 ([M + H]+); mmax
(film)/cm−1 3400 (OH, NH), 1690 (urethane) and 1649 (amide);
A solution of (4S,5S)-N-tert-butoxycarbonyl-5-tert-butyldiphen-
ylsiloxymethyl-4-formylpyrrolidin-2-one (25) (207 mg, 0.43 mmol)
in methanol (15 ml) was stirred at room temperature. Hydrazine
monohydrate (31.4 ll, 0.6 mmol) was added and the reaction
was stirred for 18 h at room temperature. The solvent was
removed in vacuo and the crude pale yellow foam was purified
by column chromatography on silica gel using petroleum
ether–ethyl acetate (3 : 2) containing triethylamine (1%) as
eluent to afford (5S)-5-[(1S)-1-tert-butoxycarbonylamino-2-tert-
butyldiphenylsilanyloxyethyl]-3-oxo-2,3,4,5-tetrahydropyridazine
27 as a white foam (87 mg, 41%); [a]2D3 +47.2 (c 0.6, CHCl3); m/z
[ES+] Found 496.2620, [C27H37N3O4Si + H]+ requires 496.2632;
m/z [+ve FAB (3-NBA)] 518 ([M + Na]+); mmax (film)/cm−1 3278
(NH) and 1694 (urethane, amide); dH (300 MHz, C2HCl3) 8.63
2
(1H, br s, exch. H2O, NH) 7.65–7.58 (4H, m, ArH), 7.45–7.37
ꢀ
(6H, m, ArH), 7.03 (1H, s, H-6), 4.86 (1H, br, d, JNH,1 8.2, NH),
3.95 (1H, m, H-1ꢀ), 3.70 (2H, m, H-2ꢀ), 2.96 (1H, m, H-5), 2.54
(1H, dd, J4A,4B 17.1, J4A,5 7.3, H-4A), 2.28 (1H, dd, J4B,4A 17.1, J4B,5
12.0, H-4B), 1.45 (9H, s, C(CH3)3) and 1.08 (9H, s, SiC(CH3)3);
dC (75.5 MHz, C2HCl3) 167.4 (amide), 155.7 (urethane), 146.5
(C-6), 135.9, 132.8, 130.5 and 128.4 (Ar), 80.5 (OC(CH3)3), 63.7
(C-2ꢀ), 52.0 (C-1ꢀ), 36.1 (C-5), 28.7 (OC(CH3)3), 28.3 (C-4), 27.3
(SiC(CH3)3) and 19.6 (SiC(CH3)3).
dH (300 MHz, C2HCl3) 7.20 (1H, s, H-6), 5.35 (1H, br d, JNH,1 8.1,
ꢀ
NH), 3.92 (1H, m, H-1ꢀ), 3.71 (2H, br, H-2ꢀ), 3.34 (3H, s, NCH3),
2.97 (1H, m, H-5), 2.61 (1H, dd, J4A,4B 16.8, J4A,5 6.9, H-4A), 2.41
(1H, dd, J4B,4A 16.8, J4B,5 11.3, H-4B) and 1.45 (9H, s, C(CH3)3); dC
(75.5 MHz, C2HCl3) 165.3 (amide), 155.3 (urethane), 146.2 (C-6),
80.3 (OC(CH3)3), 62.9 (C-2ꢀ), 51.6 (C-1ꢀ), 36.2 and 36.0 (NCH3
and C-5), 28.7 (C-4) and 28.2 (OC(CH3)3)
(5S)-2-Methyl-5-[(1S)-1-tert-butoxycarbonylamino-2-tert-
butyldiphenylsilanyloxyethyl]-3-oxo-2,3,4,5-
tetrahydropyridazine (28)
(4aS,5S)-5-tert-Butoxycarbonylamino-2-methyl-3-oxo-
2,3,4,4a,5,6-hexahydrofuro[2,3-c]pyridazine (30)
A solution of (4S,5S) - N - tert - butoxycarbonyl - 5 - tert - butyl -
diphenylsiloxymethyl-4-formylpyrrolidin-2-one (25) (436 mg,
0.906 mmol) in methanol (25 ml) was stirred at room temperature.
Methylhydrazine (72.3 ll, 1.36 mmol) was added and the reaction
was stirred for a further 18 h at room temperature. The solvent
was removed in vacuo and the crude yellow foam was purified by
column chromatography on silica gel using petroleum ether–ethyl
Sodium periodate (160 mg, 0.75 mmol) was added to a flask of
vigorously stirred water (0.6 ml) at room temperature. Ruthenium
oxide monohydrate (0.5 mg, 0.00376 mmol) was added and
stirring was continued for 10 min as the solution turned orange.
A solution of (5S)-2-methyl-5-[(1S)-1-tert-butoxycarbonylamino-
2-hydroxyethyl]-3-oxo-2,3,4,5-tetrahydropyridazine (29) (50 mg,
0.18 mmol) in carbon tetrachloride (0.35 ml) and acetonitrile
(0.35 ml) was added and a black colouration was instantly
observed in both phases. Vigorous stirring was continued for 18 h
† CCDC reference number 294595. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b600195e
1600 | Org. Biomol. Chem., 2006, 4, 1596–1603
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©

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at room temperature and isopropyl alcohol (4 drops) was added.
The mixture was stirred for 30 min and filtered through a pad
(C-3), 127.7 (C-3), 83.9 (OC(CH3)3), 65.0 (C-5), 62.5 (C-6) and
28.4 (OC(CH3)3).
R
of Celiteꢀ. The aqueous layer was extracted with ethyl acetate
(5S)-N-tert-Butoxycarbonyl-5-tert-butyldimethylsiloxymethyl-
1,5-dihydro-2H-pyrrol-2-one (31) and N-tert-
butoxycarbonyl-2-tert-butyldimethylsiloxy-5-tert-
butyldimethylsiloxymethylpyrrole (33)
(3 × 1 ml). The organic layers were combined and dried (MgSO4),
and the solvent was removed in vacuo to give a clear colourless
oil. Purification by column chromatography on silica gel using
ethyl acetate as eluent gave (4aS,5S)-5-tert-butoxycarbonylamino-
2-methyl-3-oxo-2,3,4,4a,5,6-hexahydrofuro[2,3-c]pyridazine 30 as
a clear colourless residue which crystallised on standing to give a
white solid (17 mg, 35%); m/z [+ve FAB (3-NBA)] 270 ([M + H]+);
mmax (film)/cm−1 3303 (NH), 1712 (urethane) and 1644 (amide); dH
(300 MHz, C2HCl3) 4.89 (1H, br d, JNH,5 7.5, NH), 4.59 (1H, t,
J6A,5 7.9, H-6A), 4.20 (1H, m, H-5), 3.90 (1H, t, J6B,5 9.0, H-6B),
3.15 (3H, s, NCH3), 2.95–2.84 (2H, m, H-4a, H-4A), 2.41 (1H, br,
H-4B) and 1.37 (9H, s, C(CH3)3); dC (75.5 MHz, C2HCl3) 162.4
and 162.0 (amide, C-8), 154.0 (urethane), 79.8 (OC(CH3)3), 72.2
(C-6), 54.5 (C-5), 37.8 (C-4a), 35.2 (NCH3), 31.8 (C-4) and 27.2
(OC(CH3)3). A second compound (146 mg, 28%) was also isolated
as a clear colourless oil with spectroscopic data identical to those
of the starting material 29.
Method A: Using 2,6-lutidine as the hindered base. tert-Butyl-
dimethylsilyltrifluoromethanesulfonate (TBDMSOTf, 3.17 ml,
13.8 mmol) was added dropwise to a solution of (5S)-N-tert-
butoxycarbonyl-5-hydroxymethyl-1,5-dihydro-2H-pyrrol-2-one
(32) (1.960 g, 9.2 mmol) and 2,6-lutidine (2.14 ml, 18.4 mmol) in
dichloromethane (110 ml) at −78 ◦C under nitrogen. The solution
was allowed to warm to 0 ◦C for 30 min and to room temper-
ature for a further 30 min. Saturated aqueous sodium hydrogen
carbonate (80 ml) was added and the layers were separated. The
aqueous phase was extracted with dichloromethane (3 × 60 ml),
the combined organic layers were dried (MgSO4) and the solvent
was removed in vacuo. The crude pungent oil was purified by
column chromatography on silica gel using petroleum ether–ethyl
acetate (10 : 1) as eluent to afford (5S)-N-tert-butoxycarbonyl-5-
tert-butyldimethylsiloxymethyl-1,5-dihydro-2H-pyrrol-2-one (31)
as a clear colourless oil which crystallised on standing to give a
Crystal data for (4aS,5S)-5-tert-butoxycarbonylamino-2-
methyl-3-oxo-2,3,4,4a,5,6-hexahydrofuro[2,3-c]pyridazine (30)‡,
C12H19N3O4, M = 269.30, orthorhombic, space group P212121
˚
(No. 19), a = 5.6733(2), b = 11.5380(9), c = 21.3149(16) A, V =
◦
white solid (1.288 g, 43%); mp 57.3–58.4 C; [a]2D6 −174.2 (c 0.5,
1395.24(16) A , Z = 4, Dcalc 1.28 mg m−3, l(Mo Ka) = 0.10 mm−1,
3
˚
CH2Cl2) (lit16 mp 64–65 ◦C, [a]D25 −176 (c 1.0, CHCl3)); m/z [ES+]
Found 677.3613, [2 × C16H29NO4Si + Na]+ requires 677.3623;
mmax (film)/cm−1 1782 (urethane), 1745 and 1713 (lactam); dH
(300 MHz, C2HCl3) 7.24 (1H, dd, J4,3 1.8, J4,5 6.0, H-4), 6.06 (1H,
d, J3,4 1.8, H-3), 4.55 (1H, br, J5,6A 3.7, J5,6B 3.0, H-5), 4.10 (1H,
dd, J6A,6B 9.6, J6A,5 3.7, H-6A), 3.66 (1H, dd, J6B,6A 9.6, J6B,5 3.0,
H-6B), 1.53 (9H, s, OC(CH3)3), 0.84 (9H, s, SiC(CH3)3) and 0.03
(6H, s, Si(CH3)2); dC (75.5 MHz, C2HCl3) 169.7 (lactam), 150.1
(C-4), 149.8 (urethane), 127.4 (C-3), 83.3 (OC(CH3)3), 63.9 (C-5),
62.8 (C-6), 28.5 (OC(CH3)3), 26.0 (SiC(CH3)3), 18.5 (SiC(CH3)3)
and −5.1 (SiCH3).
T = 173(2) K, 1449 independent reflections (Rint = 0.056). The
final R values were R1 = 0.045 (for 1208 reflections with I > 2r(I))
and wR2 = 0.107 (for all reflections). Data collection was carried
out using a Kappa CCD diffractometer, structure analysis using
program package WinGX, and refinement using SHELXL-97.
The atomic coordinates are available on request from The Director,
Cambridge Crystallography Data Centre, University Chemical
Laboratory, Lensfield Road, Cambridge, CB2 1EW.
(5S)-N-tert-Butoxycarbonyl-5-hydroxymethyl-1,5-dihydro-2H-
pyrrol-2-one (32)
The above procedure was followed using (5S)-N-tert-butoxy-
carbonyl-5-hydroxymethyl-1,5-dihydro-2H -pyrrol-2-one (32)
(705 mg, 3.31 mmol) and 2,6-lutidine (0.77 ml, 6.62 mmol) in
dichloromethane (40 ml). After work up, the crude oil was purified
by column chromatography on silica gel using petroleum ether–
ethyl acetate (15 : 1) as eluent to afford N-tert-butoxycarbonyl-2-
tert-butyldimethylsiloxy-5-tert-butyldimethylsiloxymethylpyrrole
(33) as a clear colourless oil (371 mg, 25%); m/z [ES+] Found
442.2780, [C22H43NO4Si2 + H]+ requires 442.2803; mmax (film)/cm−1
1756 (urethane); dH (300 MHz, C2HCl3) 5.82 (1H, d, J4,3 3.4, H-4),
5.13 (1H, d, J3,4 3.4, H-3), 4.67 (2H, s, H-6), 1.55 (9H, s, OC(CH3)3),
0.96 (9H, s, SiC(CH3)3), 0.87 (9H, s, SiC(CH3)3), 0.22 (6H, s,
Si(CH3)2) and 0.00 (6H, s, Si(CH3)2); dC (75.5 MHz, C2HCl3) 147.6
(urethane), 142.9 (C-2), 124.4 (C-5), 89.2 (C-3), 81.9 (OC(CH3)3),
59.0 (C-6), 26.8 (OC(CH3)3), 24.9 (SiC(CH3)3), 24.7 (SiC(CH3)3),
17.7 (SiC(CH3)3) and −4.1 (SiCH3). (5S)-N-tert-Butoxycarbonyl-
5-tert-butyldimethylsiloxymethyl-1,5-dihydro-2H-pyrrol-2-one
(31) (325 mg, 30%) was also eluted with spectroscopic data
identical to those of the sample of 31 prepared above.
Acetic acid (1.14 ml, 19.94 mmol) was added to a solution
of (5S)-N-tert-butoxycarbonyl-5-tert-butyldiphenylsiloxymethyl-
1,5-dihydro-2H-pyrrol-2-one (23) (4.50 g, 9.97 mmol) in tetrahy-
drofuran (60 ml) and the mixture was cooled to 0 ◦C. Tetrabuty-
lammonium fluoride (TBAF, 1.0 M solution in THF containing
5wt% water, 11.9 ml, 11.9 mmol) was slowly added and the mixture
was allowed to warm to room temperature. After stirring for 18 h
at room temperature, the solvent was removed in vacuo and the
pale brown solid residue was purified by column chromatography
on silica gel using ethyl acetate–petroleum ether (3 : 2) as eluent to
afford (5S)-N-tert-butoxycarbonyl-5-hydroxymethyl-1,5-dihydro-
2H-pyrrol-2-one (32) as a clear pale yellow oil (2.121 g, quant.);
m/z [ES+] Found236.0881, [C10H15NO4 + Na]+ requires 236.0893;
m/z [+ve FAB (3-NBA)] 449 ([2M + Na]+), 236 ([M + Na]+) and
214 ([M + H]+); mmax (film)/cm−1 3425 (OH), 1765 (urethane) and
1716 (lactam); dH (300 MHz, C2HCl3) 7.25 (1H, dd, J4,3 1.7, J4,5 3.7,
H-4), 6.13 (1H, d, J3,4 1.7, H-3), 4.73–4.68 (1H, m, H-5), 4.02–3.95
(2H, m, H-6), 3.38 (1H, br, s, OH) and 1.55 (9H, s, OC(CH3)3);
dC (75.5 MHz, C2HCl3) 170.1 (lactam), 150.4 (urethane), 149.4
Method B: Using pyridine as the base. tert-Butyldimethylsilyl-
trifluoromethanesulfonate (TBDMSOTf, 161.7 ll, 0.704 mmol)
was slowly added to a solution of (5S)-N-tert-butoxycarbonyl-
5-hydroxymethyl-1,5-dihydro-2H-pyrrol-2-one (32) (100 mg,
‡ CCDC reference number 294596. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b600195e
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The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 1596–1603 | 1601
©

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0.469 mmol) and pyridine (163.0 ll, 2.01 mmol) in dichloro-
methane (4 ml) at −78 ◦C under nitrogen. After 30 min the
solution was allowed to warm to −10 ◦C for 30 min and to
room temperature for a further 30 min. Saturated aqueous sodium
hydrogen carbonate (3 ml) was added and the layers were sepa-
rated. The aqueous phase was extracted with dichloromethane
(3 × 4 ml), the combined organic layers were dried (Na2SO4)
and the solvent was removed in vacuo using a vacuum pump
with heating. The viscous, pale brown crude oil was purified by
column chromatography on silica gel using petroleum ether–ethyl
acetate (13 : 1) as eluent to afford (5S)-N-tert-butoxycarbonyl-5-
tert-butyldimethylsiloxymethyl-1,5-dihydro-2H-pyrrol-2-one (31)
as a clear colourless oil which crystallised on standing to give a
white solid (117 mg, 76%) with identical spectra to those of the
sample prepared by method A.
The above procedure was followed using (5S)-N-tert-butoxy-
carbonyl-5-hydroxymethyl-1,5-dihydro-2H -pyrrol-2-one (32)
(1.844 g, 8.657 mmol) and pyridine (3.0 ml, 37.1 mmol) in
dichloromethane (45 ml). After work up the crude oil was purified
by column chromatography on silica gel using petroleum ether–
ethyl acetate (12 : 1) as eluent to afford N-tert-butoxycarbonyl-2-
tert-butyldimethylsiloxy-5-tert-butyldimethylsiloxymethylpyrrole
(33) (690 mg, 18%) with spectroscopic data identical to those of
the sample prepared using method A.
column chromatography on silica gel using petroleum ether–ethyl
acetate (3 : 2, 1 : 1 and 2 : 3) as eluent to afford (5S)-5-[(1S)-
1-tert-butoxycarbonylamino-2-tert-butyldimethylsiloxyethyl]-
1-methylpyrazolidin-3-one (35) as a pale yellow oil which
◦
crystallised on standing (512 mg, 48%); mp 131–132.5 C; [a]D20
+14.0 (c 2.0, MeOH) [lit14 [a]2D0 +12.2 (c 1.7, MeOH)]; m/z [ES+]
Found 769.4735 [2M + Na]+, [C34H70N6O8Si2 + Na]+ requires
769.4685; mmax (film)/cm−1 3275 (NH) and 1693 (amide); dH
(300 MHz, C2H3O2H) 3.73 (1H, dd, J2 A,2 B 10.1, J2 A,1 4.5, H-2ꢀA),
ꢀ
ꢀ
ꢀ
ꢀ
3.62 (1H, dd, J2 B,2 A 10.1, J2 B,1 3.3, H-2ꢀB), 3.44 (1H, m, H-1ꢀ),
3.12 (1H, m, H-5), 2.81 (1H, dd, J4A,4B 17.3, J4A,5 8.8, H-4A),
2.50 (3H, s, NCH3), 2.18 (1H, dd, J4B,4A 17.3, J4B,5 3.3, H-4B),
1.35 (9H, s, OC(CH3)3), 0.85 (9H, s, SiC(CH3)3) and 0.03 (6H, s,
Si(CH3)2); dC (75.5 MHz, C2HCl3) 174.4 (C-3), 156.0 (urethane),
80.0 (OC(CH3)3), 64.7 (C-5), 62.3 (C-2ꢀ), 53.5 (C-1ꢀ), 48.0 (NCH3),
31.6 (C-4), 28.7 (OC(CH3)3), 26.2 (SiC(CH3)3), 18.6 (SiC(CH3)3)
and −5.1 (2 × SiCH3).
ꢀ
ꢀ
ꢀ
ꢀ
(5S)-5-[(1S)-1-tert-Butoxycarbonylamino-2-hydroxyethyl]-1-
methylpyrazolidin-3-one (36)
Acetic acid (23.5 ll, 0.410 mmol) was added to a solution of
(5S)-5-[(1S)-1-tert-butoxycarbonylamino-2-tert-butyldimethylsil-
oxyethyl]-1-methylpyrazolidin-3-one (35) (139 mg, 0.373 mmol)
in tetrahydrofuran (5 ml) at 0 ◦C. Tetrabutylammonium fluoride
(TBAF, 1.0 M solution in THF, containing 5% wt. water,
0.485 ml, 0.485 mmol) was slowly added and the solution was
allowed to warm to room temperature. After stirring at room
temperature for 3 h, further TBAF (1.0 M solution in THF,
containing 5wt% water, 0.186 ml, 0.186 mmol) was added and the
mixture was stirred for 15 h at room temperature. The solvent was
removed in vacuo and the pale brown oil was purified by column
chromatography on silica gel using chloroform–methanol (95 : 5)
as eluent to afford (5S)-5-[(1S)-1-tert-butoxycarbonylamino-2-
hydroxyethyl]-1-methylpyrazolidin-3-one (36) as a clear colourless
oil which crystallised on standing to give a white solid (59 mg,
61%); mp 189.5–190.5 ◦C; [a]2D1 +27.2 (c 1.5, MeOH); m/z [ES+]
Found 260.1611, [C11H21N3O4 + H]+ requires 260.1604; mmax
(film)/cm−1 3278 (NH, OH) and 1686 (br, lactam, urethane); dH
(300 MHz, C2H3O2H) 3.76–3.54 (3H, m, H-1ꢀ and H-2ꢀ), 3.24
(1H, m, H-5), 2.93 (1H, dd, J4A,4B 17.3, J4A,5 8.8, H-4A), 2.63
(3H, s, NCH3), 2.27 (1H, dd, J4B,4A 17.3, J4B,5 3.3, H-4B) and 1.46
(9H, s, OC(CH3)3); dC (75.5 MHz, C2H3O2H) 176.9 (amide), 158.8
(urethane), 80.7 (OC(CH3)3), 66.3 (C-5), 62.9 (C-2ꢀ), 55.4 (C-1ꢀ),
47.7 (NCH3), 32.8 (C-4) and 29.1 (OC(CH3)3).
(4S,5S)-N-tert-Butoxycarbonyl-5-tert-butyldimethylsiloxymethyl-
3 - N - methylhydrazinopyrrolidin - 2 - one (34). Methylhydrazine
(0.29 ml, 5.413 mmol) was slowly added to a solution of (5S)-
N -tert-butoxycarbonyl-5-tert-butyldimethylsiloxymethyl-1,5-
dihydro-2H-pyrrol-2-one (31) (1.180 g, 3.609 mmol) in methanol
(40 ml) and water (1 ml) at room temperature. The solution was
stirred for 18 h at room temperature and the solvent was removed
in vacuo. The residual oil was purified by gradient column
chromatography on silica gel using petroleum ether–ethyl acetate
(4 : 1) followed by ethyl acetate (100%) as eluent to afford (4S,5S)-
N -tert-butoxycarbonyl-5-tert-butyldimethylsiloxymethyl-3-N -
methylhydrazinopyrrolidin-2-one (34) as
a clear colourless
oil (1.081 g, 80%); [a]D22 −39.5 (c 2.0, MeOH) (lit14 [a]2D0 − 37.3
(c 2.2, MeOH)); m/z [ES+] Found 374.2457, [C17H35N3O4Si + H]+
requires 374.2469; mmax (film)/cm−1 3344 (NH), 1784 (urethane)
and 1712 (lactam); dH (300 MHz, C2HCl3) 4.24 (1H, m, H-5),
3.88 (1H, dd, J6A,6B 10.4, J6A,5 3.7, H-6A), 3.68 (1H, dd, J6B,6A
10.4, J6B,5 2.2, H-6B), 3.05 (1H, m, H-4), 2.86 (2H, br s, exch.
C2H3O2H, NH2), 2.70 (1H, dd, J3A,3B 18.0, J3A,4 8.1, H-3A), 2.53
(1H, dd, J3B,3A 18.0, J3B,4 1.1, H-3B), 2.47 (3H, s, NCH3), 1.51
(9H, s, OC(CH3)3), 0.87 (9H, s, SiC(CH3)3), 0.03 (3H, s, SiCH3)
and 0.01 (3H, s, SiCH3); dC (75.5 MHz, C2HCl3) 174.1 (lactam),
150.4 (urethane), 83.1 (OC(CH3)3), 63.9 (C-6), 62.1 and 61.9
(C-4 and C-5), 47.5 (NCH3), 36.4 (C-3), 28.5 (OC(CH3)3), 26.2
(SiC(CH3)3), 18.5 (SiC(CH3)3), −5.1 (SiCH3) and −5.2 (SiCH3).
Acknowledgements
One of us (O. A.) thanks the EPSRC for a studentship.
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Org. Biomol. Chem., 2006, 4, 1596–1603 | 1603
©