Synthesis and reactions of polymer-bound Ph3P=C=C=O: A quick route to tenuazonic acid and other optically pure 5-substituted tetramates

Article abstract of DOI:10.1039/b412779j

Polystyrene-bound cumulated ylide Ph₃PCCO was prepared on a large scale in two steps. It reacts with Grignard compounds, amines and alcohols to give immobilized acyl, amide and ester ylides, respectively. Their Wittig reactions lead to alkenes

Full text of DOI:10.1039/b412779j

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A R T I C L E
= = =
Synthesis and reactions of polymer-bound Ph3P C C O: a quick
route to tenuazonic acid and other optically pure 5-substituted
tetramates
Rainer Schobert,* Carsten Jagusch, Claire Melanophy and Gillian Mullen
Organic Chemistry Laboratory, University of Bayreuth, D-95440, Bayreuth, Germany.
E-mail: Rainer.Schobert@uni-bayreuth.de; Fax: +49 (0)921 552671
Received 18th August 2004, Accepted 30th September 2004
First published as an Advance Article on the web 5th November 2004
Polystyrene-bound cumulated ylide Ph3PCCO was prepared on a large scale in two steps. It reacts with Grignard
compounds, amines and alcohols to give immobilized acyl, amide and ester ylides, respectively. Their Wittig reactions
lead to alkenes free of phosphane oxide. Optically pure 5-substituted tetramates were obtained from reactions of
resin-bound Ph3PCCO with a-ammonium esters in one step. The mycotoxin (−)-tenuazonic acid was accordingly
prepared in just three steps.
contaminated with a little (<10%) immobilized phosphane oxide
Introduction
which does not interfere with the reactions of the cumulated
Polymer-supported reagents offer numerous procedural and
ylide. From the yields of these reactions, from the spectra, and
conceptual advantages over their soluble congeners, first and
from the weight increase during its synthesis, an effective loading
of >85% available for reactions was gauged for representative
samples of 3.
foremost the suitability for automation and parallelization.1
Hence almost every useful class of reagents has been made
available in an immobilized form. This includes various types of
phosphorus ylides,2 such as alkylides,3–5 benzylides,4–6 allylides,7,8
methylide,4,5 methoxycarbonylmethylide,6 cyanomethylide,5,9
and a-iodoalkylides.5 However, cumulated P-ylides have not
= = =
yet been attached to a solid support. Ph3P C C O, for
instance, offers a multi-faceted chemistry of its own,10 serving
as a versatile C2-building block for heterocycles in domino
and multicomponent reactions with functionalized carbonyl
compounds.11 Through addition of alcohols,12 amines,13 and
Grignard compounds14 it also renders accessible the families
of stabilized ester, amide, and acyl ylides. The employment of an
immobilized variant of this ylide combines these features with
the intrinsic advantages of solid-phase organic synthesis. This is
demonstrated for the synthesis of 5-substituted tetramates from
a-ammonium esters where the typical problems of base-induced
racemization at C-5 and incomplete separation from byproduct
Ph3PO are overcome by the use of polystyrene-bound Ph3PCCO.
Scheme 1 Two-step synthesis of polystyrene-supported (triphenyl-
phosphoranylidene)ketene 3.
Synthesis of a,b-unsaturated esters, amides and ketones
Immobilized ylide 3 underwent the same reactions as Ph3PCCO
in solution under almost identical conditions with the bonus of
ease of product purification, in particular the straightforward
removal of resin-bound phosphane oxide as formed in Wittig
alkenations. For example, the three-component reaction of 3
with an aldehyde (e.g. piperonal) and an alcohol (e.g. hexanol) or
amine (e.g. piperidine) produced the E-a,b-unsaturated esters or
amides 5, respectively, as products of a domino addition–Wittig
alkenation process. The intermediate ester or amide ylides 4 can
be obtained in the absence of an aldehyde and may be used
separately for olefinations or other ylide reactions. Immobilized
acyl ylides 7 were readily accessible by Grignard reaction14 of 3.
The ylide can be simply added in one portion to the Grignard
solution. Wittig alkenation of 7 with aldehydes furnished the
corresponding pure E-enones 8 (Scheme 2).
Results and discussion
Synthesis of polystyrene-bound Ph3PCCO
The preparation of the polystyrene-bound cumulated ylide 3
(Scheme 1) had to be modified when compared with that of
10a
free Ph3PCCO, mainly due to problems related to swelling of
the resin and removability of byproduct alkoxides. The most
important alteration was the quantitative alkylation of the
polystyrene-bound triphenylphosphane 1 (1.41 mmol g−1) with
benzyl bromoacetate instead of methyl bromoacetate to give the
immobilized benzoxycarbonylmethylphosphonium bromide 2.
Salt 2 was then washed with dry benzene and finally converted to
3 by shaking with an excess of lithium bis(trimethylsilyl)amide in
THF–benzene at room temperature for 24 h.15 Unlike sodium or
lithium methoxide which pertinaciously adhere to the resin, the
byproduct lithium benzoxide, together with lithium bromide and
hexamethyldisilazane, can be completely removed by filtration
and repeated rinsing with THF, benzene and toluene. 3 was
Synthesis of nonracemic 5-substituted tetramates
Ph3PCCO is also known11,17 to add and Wittig alkenate primary
a-amino esters in a tandem fashion to give the corresponding
tetramates, a class of compounds that has attracted consider-
able interest due to their often distinct biological activity.18–20
However, in solution the reaction with Ph3PCCO proceeds only
slowly and N-substituted derivatives sometimes fail to react
obtained as a yellow, pH-neutral, fairly air-stable resin. The
31
16a
16b
P MAS TOSS NMR (d 4.97 ppm) and ATR-IR (m =
2092 cm−1) (Fig. 1) spectra of 3 clearly proved the absence both
of starting salt 2 and its corresponding ester ylide which is an
intermediate en route from 2 to 3. Batches of 3 were occasionally
3 5 2 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 5 2 4 – 3 5 2 9
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
©

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Fig. 1 IR spectrum of pulverized polystyrene-bound Ph3PCCO 3.
alkoxides formed as byproducts in the generation of Ph3PCCO
from ester ylides.
Scheme 2 Acyl ylides 4 and 7 from 3 and consecutive Wittig alkenation
reactions to give E-a,b-unsaturated esters, amides, or ketones.
Scheme 3 Consecutive addition and Wittig alkenation of a-ammonium
esters 9 with 3 to give tetramates 12.
altogether. Hence it was gratifying to find both primary and
secondary a-amino esters as well as their ammonium salts react
with immobilized ylide 3 to give tetramates in decent yields and
not contaminated with otherwise difficult to remove phosphane
oxide. Ammonium salts, which are the customary form of
storage of a-amino esters, generally reacted faster and their use
also allowed a stepwise procedure with optional isolation and
washing of the intermediates. For instance, ammonium tosylates
9 readily added onto 3, either under thermal (THF, 60 ◦C, 14 h)
or microwave (THF, max. 300 W, 90 ◦C, 30 min) conditions,
quantitatively furnishing easy to purify phosphonium salts 10
(Scheme 3). Deprotonation of 10 with DBU at room temperature
gave the conjugate amide ylides 11 which after rinsing were
submitted to a thermal or microwave induced intramolecular
Wittig alkenation to leave pure tetramates 12 in 50–60%
overall yields. Optically pure chiral a-ammonium esters were
converted with retention to enantiopure (>94% ee) tetramates
(HPLC: CD-b-PM, Macherey-Nagel; comparison with baseline
separated authentic racemic samples). This is a major advantage
over reactions with Ph3PCCO in solution which were frequently
found to give racemic products due to adhering traces of
With 3 being so readily available now, an excess of it can
be used as the base in lieu of DBU, thus immobilizing both
by-products (phosphane oxide and the counter anion of the
ammonium salt) and yielding pure tetramates in a one-pot
variant. This was demonstrated for the hydrogen chlorides or
tosylates 9 which furnished optically pure tetramates 12 in
yields ranging from 40% to 93% (Scheme 4). No 5-epimers were
detectable by NMR, GC and HPLC, respectively. It is worthy of
note that even relatively acidic hydroxy groups such as the one
in tyrosine allyl ester tosylate 9e need not be protected.
The twofold action of 3 as a base was not anticipated in
the first place. The deprotonation of intermediate phosphonium
salts of type 10 is slow and requires them to get in contact
with another ylide group attached to the same resin which is
only possible for sufficiently packed, coiled-up, or backfolded
polymer strands. When THF was replaced by the less polar
solvent benzene the yields of the respective product tetramates
dropped sharply, e.g. from 52% to 5% for 12c. Apparently,
the solvent is crucial to the shape of the swollen resin and
thus to the spatial distribution of the immobilized functional
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 5 2 4 – 3 5 2 9
3 5 2 5

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charcoal in dry methanol quantitatively furnished 5-s-butyl-
pyrrolidine-2,4-dione (5S,6S)-13 with properties identical to
those reported earlier.28 As anticipated, the enol tautomer of 13,
the 4-hydroxy-5-s-butyl-pyrrol-2(5H)-one, was not detectable
in the NMR spectra. Acylation of (−)-13 with an excess of
acetyl chloride and boron trifluoride–diethyl etherate23 and care-
ful hydrolytic work-up24 gave tenuazonic acid, (−)-(5S,6S)-3-
acetyl-5-s-butylpyrrolidine-2,4-dione, 14 as a mixture of various
tautomers34 in 60% yield.
In conclusion we have established a large-scale synthesis of 3,
the first immobilized cumulated phosphorus ylide. It can be used
as a precursor to resin-bound stabilized acyl, ester and amide
ylides and as a C2-building block in the stereoselective synthesis
of heterocycles, e.g. of tetramates from a-ammonium esters. This
approach complements the inverse protocol employing resin-
bound amino- and hydroxy-substituted carbonyl derivatives
with Ph3PCCO in solution, as described previously.35
Scheme 4 One-pot synthesis of tetramates 12 from a-ammonium esters
9 and two equivalents of 3.
groups. This interaction of individual ylide groups on the resin
somewhat dashed our hopes to generate highly reactive spatially
Experimental
+
= =
sequestered ketenylium cations PS-Ph3P -CH C O by treat-
Microwave irradiations were carried out in sealed vials inside
a CEM DiscoverTM single-mode synthesizer (300 W). Melting
points were recorded using a Gallenkamp apparatus and are
uncorrected. Optical rotations were recorded at 589 nm using
a Perkin-Elmer polarimeter 241 and 5 mL cuvettes (10 cm); [a]
values are given in 10−1 deg cm2 g−1. IR spectra were recorded
of solids or neat films on a Perkin-Elmer Spectrum One FT-
IR spectrophotometer equipped with an ATR sampling unit.
Nuclear magnetic resonance (NMR) spectra were recorded
under conditions as indicated using a Bruker Avance 300
spectrometer. Chemical shifts are given in parts per million (d)
ing 3 with HBF4 or other acids with non-nucleophilic counter
anions. In solution and in the absence of a suitably nucleophilic
+
= =
anion, the cation Ph3P -CH C O reacts rapidly with a second
molecule of the starting ylide to give a preparatively useless
protonated “dimer” with cyclobutane-1,3-dione structure.
Synthesis of tenuazonic acid
The above one-pot process is applicable to the synthesis of
3-unsubstituted tetramates. Tetramic acids (pyrrolidine-2,4-
diones) bearing 3-allyl residues are also readily accessible from
the corresponding allyl esters (9: R2 = allyl) via a sequence
extended by a terminal Claisen rearrangement step.21 3-Acyl
residues which are so common in naturally occurring tetramates
must be introduced by downstream acylation of tetramic
acids with the appropriate acid chloride in the presence of
boron trifluoride–diethyl etherate.22,23 This is no less economical
than the alternative Lacey–Dieckmann condensation of N-(b-
ketoacyl)-a-amino esters which requires an initial N-acylation
of the respective a-amino esters.24–27 In addition, racemization
still poses a problem when the cyclization is carried out under
basic conditions.28
1
downfield from tetramethylsilane as internal standard for H
and 13C nuclei and H3PO4 as external standard for 31P; coupling
constants (J) are given in Hz. Mass spectra were recorded using
a Varian MAT 311A (EI). Analytical HPLC was performed on a
Beckman system with programmable solvent module 126 and a
diode array detector 168 equipped with a Nucleodex CD-b-PM
column from Macherey-Nagel. Analytical GC was conducted
using a Lipodex-E column (25 m, 0.25 mm) from Macherey-
Nagel. Microanalyses were carried out with a Perkin-Elmer 2400
CHN elemental analyser. Flash chromatography was effected
using Merck silica gel 60 (230–400 mesh). a-Ammonium ester
chlorides and tosylates were prepared from the respective a-
amino acids according to the method by Muramatsu and Arai,36
triphenylphosphane polystyrene 1 (100–200 mesh, 1% divinyl-
benzene) was purchased from Rapp Polymere GmbH, Tu¨bingen
(Germany), all other starting compounds were purchased from
Aldrich and used as such without further purification.
Scheme 5 depicts a straightforward three-step synthesis of
optically pure tenuazonic acid (−)-14, a mycotoxin exhibiting
a broad spectrum of biological activity.29,30 It was first isolated
in 1957 from the culture filtrates of Alternaria tenuis and later
on also from other Alternaria and Pyricularia species.31,32 L-
Isoleucine benzyl ester chloride 9g33 was reacted with a twofold
excess of ylide 3 in THF at 60 ◦C to give tetramate (−)-12g.
The purity and in particular the absence of the (5R,6S)-epimer
1
Immobilized (triphenylphosphoranylidene)ketene 3
1
of 12g was ascertained by GC and H NMR [(5S,6S)-12g: d
Triphenylphosphane polystyrene 1 (10.0 g, 1.4 mmol g−1,
14.1 mmol) in a fritted solid-phase reaction flask was treated
with dry THF (40 mL) and shaken at room temperature for 1 h.
A solution of benzyl bromoacetate (12.9 g, 56.4 mmol, 4 equiv.)
in THF (40 mL) was added under argon and the mixture was
shaken for 16 h. The resin was filtered and washed carefully
with dry THF (3 × 30 mL), diethyl ether (2 × 30 mL), CH2Cl2
(3 × 30 mL) and benzene (2 × 30 mL). The light yellow resin
2 was dried under reduced pressure; conversion: 99% as to the
weight increase; mmax(ATR)/cm−1 1721 and 1110. An aliquot
of the obtained carbobenzyloxymethyltriphenylphosphonium
bromide resin 2 (10.6 g, 10 mmol) was washed with dry benzene
(100 mL) under exclusion of air and moisture and then treated
first with THF–benzene (1 : 1, 40 mL) and then with lithium
hexamethyldisilazanide (6.7 g, 40 mmol, 4 equiv.). The mixture
was shaken at room temperature for 24 h and the yellow resin
was finally filtered and washed with dry THF (3 × 250 mL),
benzene (3 × 250 mL) and toluene (2 × 250 mL) and dried
under reduced pressure to leave 8.2 g of bright yellow resin 3
0.95 (6-CH3), 4.08 (5-H); (5R,6S)-12g: d 0.73 (6-CH3), 4.15 (5-
H)]. Debenzylation of 12g by hydrogenolysis with 5% Pd on
Scheme 5 Three-step synthesis of tenuazonic acid.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 5 2 4 – 3 5 2 9
3 5 2 6

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(98%); mmax(ATR)/cm−1 2092 and 1108; dP (TOSS; 203 MHz;
CDCl3; H3PO4 ext) 4.97 ppm.
synthesizer and irradiated at 90 ◦C and 3.5 bar for 30 min.
The resin-bound salt 10 was washed three times with 10 mL
each of THF, toluene, CH2Cl2 and then dried under reduced
pressure. It was resuspended in CH2Cl2 (4 mL) and treated with
DBU (0.15 mL, 1.0 mmol). The resulting mixture was shaken for
60 min at rt. Washing of the resin with 2× 10 mL each of CH2Cl2,
THF, toluene and drying left polymer-bound ylide 11. This was
suspended in THF (4 mL) and irradiated with microwaves as
described above. After filtration of the reaction mixture and
washing of the resin with THF (20 mL), pure tetramates 12 were
obtained upon concentration of the combined organic phases.
2
General procedure for the synthesis of (E)-a,b-unsaturated
esters and amides 5
3 (830 mg, 1.0 mmol) was suspended in THF (6 mL) and
treated with piperonal (75 mg, 0.5 mmol) and 0.5 mmol of
the appropriate alcohol or amine, respectively. The mixture was
shaken at 60 ◦C for 24 h with the exclusion of air and moisture.
The resin was filtered and washed twice with THF (10 mL). The
combined filtrates were concentrated under reduced pressure
and the residue thus obtained was purified by preparative TLC
or column chromatography (silica gel).
(5S)-4-Methoxy-5-methylpyrrolin-2-one 12a. Colourless solid
(70 mg, 54%) from L-alanine methyl ester tosylate 9a (◦275 mg),
◦
Rf 0.21 (ethyl acetate), mp 115 C (lit.,39 112.5–117.3 C), [a]2D5
Hexyl (E)-3ꢀ,4ꢀ-(methylenedioxy)cinnamate 5a. Yellow oil
(82 mg, 60%) from hexanol (50 mg). Rf 0.48 (ethyl acetate–n-
hexane, 1 : 12, v/v) (Found: C, 69.3; H, 7.5. C16H20O4 requires
C, 69.5; H, 7.3%); dH (270 MHz; CDCl3) 0.87 (3 H, t, J 7.0,
Me), 1.20–1.34 (8 H, m, CH2), 4.11 (2 H, t, J 6.6, CO2CH2), 5.93
+4.0 (c 0.5, MeOH) (lit.,39 +4.5), mmax(ATR)/cm−1 3199 (br),
1658, 1615; dH (300 MHz; CDCl3) 1.29 (3 H, d, J 6.7, 5-Me),
3.76 (3 H, s, OMe), 4.05 (1 H, q, J 6.7, 5-H), 4.96 (1 H, s, 3-H),
6.31 (1 H, br s, NH); dC (75 MHz; CDCl3) 17.8 (5-Me), 53.7
(C-5), 58.3 (OMe), 92.8 (C-3), 174.2 (C-2), 179.4 (C-4).
=
(2 H, s, OCH2O), 6.20 (1 H, d, J 16.1, CHCO), 6.81–7.01 (3
=
H, m, ArH), 7.52 (1 H, d, J 16.1, HC CHCO); dC (75 MHz;
(5S)-4-Allyloxy-5-i-butylpyrrolin-2-one 12b. Colourless solid
(117 mg, 60%) from L-leucine allyl ester tosylate 9b (315 mg),
CDCl3) 14.1 (Me), 22.6, 25.7, 28.8, 31.5 (CH2), 77.6 (CO2CH2),
101.6 (OCH2O), 106.6, 108.6 (ArC), 116.3 (CCO2), 124.4, 128.9
◦
Rf 0.21 (ethyl acetate), mp 86 C, [a]2D5 −20.4 (c 0.25, MeOH)
=
(ArC), 144.3 (C CCO2), 148.4, 149.6 (ArC), 167.3 (CO2).
(Found: C, 67.8; H, 8.9; N, 7.3. C11H17NO2 requires C, 67.7;
H, 8.8; N, 7.2%); mmax(ATR)/cm−1 3189 (br), 1666, 1610; dH
(300 MHz; CDCl3) 0.95 (6 H, d, J 6.4, CMe2), 1.36–1.44 (1 H,
m, CHMe2), 1.67–1.75 (2 H, m, CH2), 4.12 (1 H, dd, J 9.6, 3.5,
5-H), 4.48 (2 H, d, J 5.5, OCH2), 5.05 (1 H, s, 3-H), 5.26 (1 H,
(E)-1-[3ꢀ,4ꢀ-(Methylenedioxy)cinnamoyl]piperidine 5b. White
◦
solid (84 mg, 64%)◦from piperidine (42 mg), mp 84 C (lit.,37
◦
85–87 C; lit.,13 83 C). dH (300 MHz; CDCl3) 1.59–1.72 (6 H,
m), 3.74 (4 H, m), 5.98 (2 H, s), 6.74 (1 H, d, J 15.5), 6.77–7.03
(3 H, m), 7.56 (1 H, d, J 15.5).
=
=
dd, J 10.1, 1.4, H2C ), 5.32 (1 H, dd, J 17.1, 1.4, H2C ), 5.88–
5.99 (1 H, m, CH), 6.57 (1 H, br s, NH); dC (75 MHz; CDCl3)
=
21.9 (Me), 22.8 (Me), 25.5 (CMe2), 42.7 (CH2), 56.9 (C-5), 72.2
(OCH2), 93.2 (C-3), 119.7 ( CH2), 130.8 (C CH2), 174.6 (C-2),
3
General procedure for the synthesis of (E)-enones 8
=
=
3 (830 mg, 1.0 mmol) was added to a solution of butylmagnesium
bromide (1.5 mmol) in THF (5 mL), freshly prepared from 1-
bromobutane (210 mg) and magnesium turnings (40 mg). The
mixture was shaken at 60 ◦C for 16 h or alternatively heated at
90 ◦C for 30 min in a microwave reactor. The resin was filtered,
washed with THF and resuspended in THF (4 mL). Saturated
aqueous NH4Cl solution (4 mL) was added and the mixture was
shaken at rt for 5 min. The resin of 7 thus obtained was washed
with 2 × 10 mL each of H2O, Et2O, THF, CH2Cl2, and toluene,
then dried on an oil pump and resuspended in THF (3 mL). The
respective aldehyde (1 mmol) was added, the resulting mixture
was shaken for 16 h while gently refluxing and finally filtered.
Concentration of the filtrate and prep. TLC (silica gel) of the
residue gave pure (E)-enone 8.
178.4 (C-4).
5
General procedure for the one-pot synthesis of tetramates 12
3 (1.66 g, 2.0 mmol) was suspended in THF (10 mL) and after
10 min swelling treated with the appropriate a-ammonium ester
◦
salt 9 (1.0 mmol). The mixture was either shaken at 60 C for
14 h or irradiated in the microwave synthesizer at 90 ◦C for
30 min. After filtration and washing of the resin with 2 × 10 mL
each of THF, CH2Cl2, and MeOH, the combined filtrates were
evaporated under reduced pressure and the crude products were
purified by column chromatography (silica gel).
(5S)-5-Benzyl-4-benzyloxypyrrolin-2-one12c. Colourless vis-
cous oil (145 mg, 52%) from L-phenylalanine benzyl ester
tosylate 9c (420 mg), Rf 0.35 (ethyl acetate), [a]2D5 −13.2 (c 0.7,
MeOH) (Found: C, 77.3; H, 6.0; N, 4.9. C18H17NO2 requires C,
77.4; H, 6.1; N, 5.0%); mmax(ATR)/cm−1 3222 (br), 1681, 1617;
dH (300 MHz; CDCl3) 2.60 (1 H, dd, J 13.45, 8.9, CH2), 3.14 (1
H, dd, J 13.45, 3.0, CH2), 4.21 (1 H, m, 5-H), 4.89 (2 H, d, J
4.4, OCH2), 4.98 (1 H, s, 3-H), 5.84 (1 H, br s, NH) 7.09–7.38
(10 H, m, ArH); dC (75 MHz; CDCl3) 38.5 (CH2), 58.7 (C-5),
73.2 (OCH2), 95.1 (C-3), 126.9, 127.8, 128.6, 128.7 128.8, 129.1
(ArC), 134.6 (C-ipso), 136.4 (C-ipso), 172.5 (C-2), 176.0 (C-4).
(E)-1-Phenylhept-1-en-3-one 8a38. Colourless oil (100 mg,
55%) from benzaldehyde (105 mg), Rf 0.75 (diethyl ether–n-
hexane, 1 : 1, v/v); mmax(ATR)/cm−1 3029, 2958, 1690, 1608; dH
(300 MHz; CDCl3) 0.86 (3 H, t, J 7.3, Me), 1.30 (2 H, tq, J 7.5,
7.3, CH2CH3), 1.58 (2 H, tt, J 7.5, 7.3, CH2Et), 2.58 (2 H, t, J
=
7.3, CH2CO), 6.66 (1 H, d, J 16.2, CHCO), 7.28–7.50 (5 H,
m, ArH), 7.46 (1 H, d, J 16.2, HC CCO); dC (75 MHz; CDCl3)
=
13.8 (Me), 20.9, 22.4, 40.6 (CH2), 126.2 (CCO), 128.8, 129.6,
130.3, 134.5 (ArC), 142.2 (C CCO), 203.5 (CO).
=
(E)-Undec-6-en-5-one 8b14. Yellowish oil (110 mg, 66%)
from pentanal (85 mg), Rf 0.76 (ethyl acetate–n-hexane, 1 : 4,
v/v); mmax(ATR)/cm−1 2958, 1676, 1630; dH (300 MHz; CDCl3)
0.85 (6 H, t, J 7.3, 2 × Me), 1.20–1.60 [8 H, m, 2 × (CH2)2], 2.10–
(5S,6S)-5-s-Butyl-4-methoxy-1-methylpyrrolin-2-one 12d.
Colourless oil (102 mg, 62%) from N-methyl-L-isoleucine methyl
ester hydrogen chloride 9d (195 mg), Rf 0.18 (ethyl acetate), [a]D25
+10.5 (c 1.0, CHCl3) (Found: C, 65.3; H, 9.2; N, 7.4. C10H17NO2
requires C, 65.5; H, 9.35; N, 7.6%); mmax(ATR)/cm−1 1683, 1621;
dH (300 MHz; CDCl3) 0.67 (3 H, d, J 6.9, CHCH3), 0.89 (3 H,
t, J 7.4, CH2CH3), 1.27–1.52 (2 H, m, CH2), 1.76–1.85 (1 H,
m, CHMe), 2.79 (3 H, s, NCH3), 3.67 (3 H, s, OCH3), 3.76 (1
H, d, J 2.8, 5-H), 4.98 (1 H, s, 3-H); dC (75 MHz; CDCl3) 12.3
(CH3CH2), 12.9 (CH3CH), 25.2 (MeCH2), 26.7 (NCH3), 35.0
(MeCH), 57.7 (OCH3), 65.7 (C-5), 94.8 (C-3), 171.9 (C-4), 175.3
(C-2); m/z (EI, 70 eV) 183 (M+, 20%), 152 (M+ − OCH3, 5%),
126 (100%).
=
2.22 (2 H, m, CH2C ), 2.45 (2 H, t, J 7.0, CH2CO), 6.00 (1 H, dt,
=
=
J 15.85, 1.5, CHCO), 6.75 (1 H, dt, J 15.85, 7.0, HC CCO);
dC (75 MHz; CDCl3) 13.9 (Me), 14.2 (Me), 22.2, 22.4, 26.4, 30.2,
=
32.1, 39.8 (CH2), 130.3 (CCO), 147.2 (C CCO), 201.0 (CO).
4
General procedure for the three-step synthesis of
tetramates 12
A sealed vial charged with 3 (830 mg, 1.0 mmol), THF (4 mL)
and 9 (1.0 mmol) was placed in a CEM DiscoverTM microwave
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 5 2 4 – 3 5 2 9
3 5 2 7

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(5S)-4-Allyloxy-5-(p-hydroxybenzyl)pyrrolin-2-one 12e.
Colourless oil (95 mg, 40%) from tyrosine allyl ester tosylate
9e (410 mg), Rf 0.18 (ethyl acetate), [a]2D5 +2.4 (c 0.35, MeOH)
(Found: C, 68.8; H, 6.45; N, 5.6. C14H15NO3 requires C, 68.6;
H, 6.2; N, 5.7%); mmax(ATR)/cm−1 3149 (br), 1651, 1610, 1592,
1516; dH (300 MHz; CDCl3) 2.89 (1 H, dd, J 10.8, 2.9, 5-CH2),
3.08 (1 H, dd, J 10.8, 2.9, 5-CH2), 4.22 (1 H, m, 5-H), 4.40–4.50
(2 H, m, OCH2), 4.94 (1 H, s, 3-H), 5.32 (1 H, dd, J 12.7,
gel; MeOH–CHCl3, 1 : 5) and then by “recrystallization” from
petroleum ether (bp range 40–60 ◦C) to give beige gummy 14
(120 mg, 60%), [a]D20 −128 (c 1.0, MeOH) {lit.,31 [a]2D0 −132 (c 0.5,
CHCl3)}; mmax(film)/cm−1 3296, 1769, 1696, 1628; dH (300 MHz;
CD3OD) 0.90 (3 H, t, J 7, CH3CH2), 1.00 (3 H, d, J 7, CH3CH),
1.20–1.45 (2 H, m, MeCH2), 1.86 (1 H, m, MeCH), 2.43 (3
=
H, s, CH3C ), 3.84 (1 H, d, J 3, 5-H); dC (75 MHz; CD3OD)
=
12.2 (CH3CH2), 15.9 (CH3CH), 20.3 (CH3C ), 24.8 (CH3CH2),
38.2 (CH3CH), 67.2 (C-5), 103.9 (C-3), 175.2 (C-2), 187.5 (C-1ꢀ),
=
=
0.9, CH2), 5.36 (1 H, dd, J 18.5, 0.9, CH2), 5.95 (1 H, m,
=
CH), 6.37 (1 H, br s, NH), 6.65 (2 H, d, J 7.7, ArH), 6.94
(2 H, d, J 7.7, ArH), 7.99 (1 H, s, OH); dC (75 MHz; CDCl3)
199.2 (C-4).
37.2 (5-CH2), 59.1 (C-5), 72.1 (OCH2), 93.4 (C-3), 115.5 (ArC),
Acknowledgements
=
=
119.5 ( CH2), 126.5, 130.9 (ArC), 132.7 ( CH), 156.8 (COH),
172.1 (C-2), 176.6 (C-4); m/z (EI, 70 eV) 245 (M+, 18%), 139
(45%), 107 (100%).
Financial support from the Deutsche Forschungsgemeinschaft
(Grant Scho 402/7–1) and Bayer CropScience, Monheim (Ger-
many), is gratefully acknowledged. We are indebted to Professor
Dr Walter Bauer, University of Erlangen, for recording MAS
TOSS NMR spectra.
4-Benzyloxy-1-methylpyrrolin-2-one 12f. Colourless solid
(190 mg, 93%) from sarcosine◦benzyl ester◦tosylate 9f (315 mg),
Rf 0.23 (ethyl acetate), mp 84 C (lit.,40 85 C); mmax(ATR)/cm−1
3032, 1675, 1616; dH (300 MHz; CDCl3) 2.89 (3 H, s, NCH3),
3.81 (2 H, s, CH2), 4.89 (2 H, s, OCH2), 5.07 (1 H, s, 3-H),
7.37–7.40 (5 H, m, ArH); m/z (EI, 70 eV) 203 (M+, 18%), 91
(100%).
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O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 5 2 4 – 3 5 2 9

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