Phosphorus ylide based functionalizations of tetronic and tetramic acids

Article abstract of DOI:10.1055/s-2006-950310

The versatility of the ylide (triphenylphosphoranylidene)ketene (Ph ₃P=C=C=O, 3) in the construction of tetronic and tetramic acids from various carboxylic acid derivatives is demonstrated by new reactions and extensions of known ones. With α-h

Full text of DOI:10.1055/s-2006-950310

3902
FEATURE ARTICLE
Phosphorus Ylide Based Functionalizations of Tetronic and Tetramic Acids
T
etronic and Tetr
aamic acidsiner Schobert,* Matthias Dietrich, Gillian Mullen, Juan-Manuel Urbina-Gonzalez
Organic Chemistry Laboratory, University of Bayreuth, Universitaetsstrasse 30, 95440 Bayreuth, Germany
Fax +49(921)552671; E-mail: Rainer.Schobert@uni-bayreuth.de
Received 30 June 2006; revised 2 August 2006
In memory of Hans-Jürgen Bestmann
logical properties than the heterocyclic core itself. For ex-
Abstract: The versatility of the ylide (triphenylphosphoranyl-
idene)ketene (Ph3P=C=C=O, 3) in the construction of tetronic and
tetramic acids from various carboxylic acid derivatives is demon-
strated by new reactions and extensions of known ones. With a-hy-
ample, the Streptomyces metabolite tetronasin is an
ionophore antibiotic due to its extended polyether moiety
attached at C3,11 and the yellow pigment physarorubinic
droxy or a-amino esters, 3 affords tetronates or tetramates. A two- acid, an antimicrobial metabolite of Physarum polyceph-
alum,12 owes its color to the conjugated oligoenoyl side
step synthesis of (–)-epi-blastmycinolactol shows that allyl a-hy-
droxy esters can be domino Wittig–Claisen reacted to give 3-al-
chain at C3. While the biosyntheses of such functional-
lyltetronic acids. More extended Wittig–Claisen–Conia cascades
ized tetronic and tetramic acids are short and stereoselec-
can produce 3-alkylidenefuran-2,4-diones, the photooxygenation of
tive, the total laboratory syntheses are often not. In the
which furnishes lactone endoperoxides with antiplasmodial poten-
biosynthesis of tetramic acids, the segment N1–C5–C4
normally originates from the respective a-amino acids,
e.g. leucine in reutericyclin, while the source of the C2–
C3 segment as well as of potential 3-polyenoyl side chains
has been found to be acetate in most cases.13–18 Usually,
the preformed polyketides are then linked to the amino
acid by peptide synthetases and the lactam ring is closed
in the final step between C3 and C4 either enzymatically
or spontaneously in the cytoplasm (Figure 1, bottom).
tial. Tetronic acids can be acylated by 3 at C3 to give the corre-
sponding acyl ylides. Their saponification yields the respective 3-
acetyl compounds, e.g. the fungal metabolite pesthetoxin. a-Hy-
droxy acids react with 3 to afford the corresponding 3-phosphora-
nylidenefuran-2,4-diones. The antibiotic (R)-reutericyclin was built
up from benzyl D-leucinate and 3 in four steps by downstream acy-
lation first at C3, then at N1 without racemization.
Key words: domino reactions, phosphorus ylides, tetramic acids,
lactones, reutericyclin
(CH2)6CH3
Introduction
O
O
O
OH
Several hundred natural products containing either the 4-
hydroxyfuran-2(5H)-one (also known as tetronic acid) or
the pyrrolidine-2,4-dione (also known as tetramic acid)
ring systems have been isolated from a variety of marine
and terrestrial organisms, such as bacteria, moulds, algae,
fungi, lichens, and sponges.1–4 Typical of these com-
pounds, and of the 3-acyl derivatives in particular, is a
high incidence of biological activity including antibiotic,
antiviral, antineoplastic, and anticoagulant effects. This
has been explained by their ability to chelate biologically
important metal ions and to mimic phosphate groups in
the binding sites of kinases. Prominent examples are the
mould metabolite RK-682 (1),5,6 which inhibits HIV-1
protease and various dual-specificity phosphatases, and
the Lactobacillus reuteri metabolite reutericyclin (2),7
which inhibits Helicobacter pylori, the causative agent of
stomach ulcers (Figure 1, top). Many more natural prod-
ucts are known where additional functional groups at-
tached to positions C3, C5, or 4-O in tetronic acids, or to
N1, C3, or C5 in tetramic acids confer further biological
properties.8–10 Sometimes, these functional appendages
are even more determinant for the chemical and physio-
1O
2
O
1N
2
3
3
4
4
5
5
(CH2)14CH3
OH
O
OH
RK-682 (1)
reutericyclin (2)
1 polyketide synthase
O
2 peptidase
O
•
C2 C1
•
2
= acetate
HN
3
•
5
4
3 spontaneous
or enzymatic
R
O
Figure 1 RK-682 (1) and reutericyclin (2) as typical natural tetronic
and tetramic acids (top), and the general biosynthetic assembly of 3-
acyltetramic acids (bottom).
In contrast, total synthesis faces two intricate problems:
1. The ring-closure step. Conditions have to be mild
enough not to cause racemization at C5. The hydrogen at
C5 is relatively acidic due to the adjacent heteroatom and
an inherent tendency to aromatize. In the widely used
Lacey protocol,19 3-acyltetramic acids are obtained by al-
kaline Dieckmann condensation of N-(b-oxoacyl)-a-ami-
no esters, frequently with (partial) racemization.
SYNTHESIS 2006, No. 22, pp 3902–3914
x
x
.x
x
.
2
0
0
6
Advanced online publication: 09.10.2006
DOI: 10.1055/s-2006-950310; Art ID: T09606SS
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Tetronic and Tetramic acids
3903
Although variants have been published where racemiza- ters, as obtained by Blaise reaction of O-silylated cyano-
tion could be suppressed by carefully controlled condi- hydrins with Reformatsky reagents, under acidic
tions,20–22 the method still lacks generality and conditions to afford enantiomerically pure tetronic ac-
predictability. Safer, truly pH-neutral, methods are few ids.27
and far between. Jouin’s protocol23–26 condenses Mel-
2. Downstream 3-acylation. Its success very much de-
pends on the system to be acylated. C5- or N1-unsubsti-
tuted tetramic acids are particularly hard to react. Another
problem is the introduction of long-chain, conjugated
drum’s acid with a-hydroxy or a-amino acids, respective-
ly, in the presence of N,N¢-dicyclohexylcarbodiimide and
4-(dimethylamino)pyridine. Heating the intermediate g-
amino-b-oxo ester leads to the corresponding tetramic
polyunsaturated acyl residues. Each of the four most used
acid with concomitant formation of acetone and carbon
methods has its shortcomings. The Jones acylation28 using
dioxide. Effenberger cyclized chiral g-hydroxy-b-oxo es-
acyl halides and boron trifluoride–diethyl ether complex
Biographical Sketches
Rainer Schobert studied istry with Prof Steve Ley, of Organic Chemistry at the
chemistry at the University then at the Imperial College University of Bayreuth, Ba-
of Erlangen (Dipl.-Chem., in London, he went back to varia. His research interests
1982). He received his doc- Erlangen to finish his habil- span a wide range with a fo-
toral degree in 1985 for itation on early transition cus on the synthesis of bio-
works on macrolide antibi- metallocenes in 1993. Be- active natural and synthetic
otics under the guidance of tween 1999 and 2001 he drugs and the development
Prof Hans-Jürgen Best- was a senior lecturer at The of new domino reactions
mann. After a postdoctoral Queen’s University Belfast. and oligofunctional re-
project on organoiron chem- He currently holds the Chair agents.
Matthias Dietrich was ary level teacher of chemis- doperoxides, he decided to
born in 1980 in Tirschen- try and biology on
a
postpone his educational ca-
reuth, Bavaria. In 2001 he concurrent route. Having reer and to continue his re-
began his studies at the Uni- just finished an optional search as part of a Ph.D.
versity of Bayreuth towards third year project in chemis- project.
a qualification as a second- try on the synthesis of en-
Gillian Mullen was born in with a B.Sc. in 2001. Later mic acids. Since January
1980 in Co Down, Northern that year she moved to 2006 she has been a re-
Ireland. She studied chemis- Bayreuth with the Schobert search chemist with Pfizer
try at The Queen’s Universi- group to explore new syn- in Cork, Ireland.
ty Belfast and graduated thetic routes to natural tetra-
Juan Manuel Urbina- from the Universidad Indus- research at the University of
Gonzalez was born in 1974 trial de Santander under the Bayreuth under the supervi-
in Pamplona, Colombia. He supervision
of
Prof sion of Prof Schobert work-
received his B.Sc. and Vladimir Kouznetsov. He ing on the synthesis of fused
M.Sc. degrees in Chemistry then carried out his Ph.D. and spiro furanones.
Synthesis 2006, No. 22, 3902–3914 © Thieme Stuttgart · New York

3904
R. Schobert et al.
FEATURE ARTICLE
does not work well for 5-unsubstituted tetramic and
tetronic acids and is unsuitable for the introduction of
Lewis acid sensitive highly unsaturated side arms. The
Yoshii protocol,29 which works best for tetronic acids,
employs free carboxylic acids and N,N¢-dicyclohexylcar-
bodiimide/triethylamine. It is basically a domino se-
quence comprised of an initial 4-O acylation followed by
a Fries-type 4-O→C3 acyl shift. It tends to fail erratically,
mostly in the shift step and particularly in the case of un-
substituted systems. The high yielding palladium-cata-
lyzed acylation of 3-stannyl-substituted tetronates
requires harsh conditions during their preparation and has
not yet been applied to C5-chiral tetronate targets.30
Boeckman’s approach31 of introducing polyenoyl resi-
dues via Horner alkenation of 3-b-phosphonylacetyl tetra-
mic and tetronic acids also implies basic conditions both
for the ring-closure and the phosphonate anion generation
steps, which compromises potential stereocenters.
O
O
PPh3
O
O
PhMe, 180 °C
MW, 10 min
O
(86%)
– Ph3PO
O
O
6
(74%)
3
THF, 60 °C
δ− δ+
Ph3P=C=C=O
O
O
O
3
HO
PhMe, 180 °C
MW, 10 min
(65%)
O
OH
4
5
H2 (50 bar)
Rh/Al2O3 (20 mol%)
EtOAc, 60 °C, 5 d
O
Bu
O
This paper presents some new approaches to bioactive tet-
ramates and tetronates that exploit mild ring-closure
methods and selective ways for the simultaneous genera-
tion or, at least facile downstream introduction, of fre-
quently occurring functional groups. An emphasis will be
laid on phosphorus ylide based domino reactions.
OH
7
(70%; 92% ee)
Scheme 1 A short synthesis of (–)-epi-blastmycinolactol (7) via do-
mino addition–Wittig alkenation–Claisen rearrangement of methallyl
lactate 4 with ylide 3.
3- and 3,4-Functionalized Systems
This approach is reminiscent of the biosynthesis of tetron-
ic acids. Ylide 3 formally replaces acetate as the C2O-
building block, and the ring gets closed between C3 and
C4. Analogously, 3-acetyltetronic acids can be built up by
using two equivalents of 3, one for the cyclization proper,
and the other for attaching the 3-acetyl group. For exam-
ple, the racemic 5-n-alkyltetronic acids 10 were readily
obtained in two steps from the corresponding benzyl 2-hy-
droxyalkanoates 8 and ylide 3 (Scheme 2). Remarkably,
they exist as 3:2 mixtures of enol and keto forms in deu-
The direct synthesis of 3-functionalized tetronic and tetra-
mic acids from a-hydroxy or a-amino acid derivatives and
phosphorus ylides is possible in different ways. Their es-
ters react with the air-stable, pH-neutral (triphenylphos-
phoranylidene)ketene (Ph3P=C=C=O, 3),32 which is also
available in a resin-bound form,33 to give the correspond-
ing tetronates or tetramates, respectively.34 While not
Wittig-active itself, 3 adds the OH or NRH groups of hy-
droxy and amino esters across its C=C bond to give acyl
ylides that in turn undergo rapid ring-closing intra-Wittig
alkenation. We have exploited this domino process for the
construction of various optically pure natural products,
e.g. 135 or the sponge-produced cytotoxic melophlins.36 In
the case of allyl esters, further pericyclic reactions may
follow the cyclization step, depending on the temperature
and solvent polarity.37 For example, one-pot reaction of
methallyl (S)-lactate (4) and 3 in toluene under microwave
irradiation (sealed vial, 180 °C, 10 min) afforded the 3-
(but-2-enyl)-5-methyltetronic acid 5 in 65% yield. The re-
action can also be carried out stepwise by first preparing
the methallyl tetronate 6 in tetrahydrofuran and then rear-
ranging it under microwave irradiation as above. Yields
are similar but the byproduct triphenylphosphine oxide is
more easily separated from 6 than from 5. Simultaneous
hydrogenation of both C–C double bonds with hydrogen
gas (50 bar) using a rhodium/alumina catalyst (20 mol%)
in analogy to Node et al.38 afforded the natural g-lactone
(–)-3-epi-blastmycinolactol (7) with 92% ee (GC; Lipo-
dex-E; comparison with base-line separated authentic
racemate) (Scheme 1).
1
terochloroform, which are clearly discernable in the H
NMR spectra. Tetronic acids 10 are also CH-acidic com-
pounds and thus were amenable to acetylation at C3 with
another equivalent of 3 in refluxing tetrahydrofuran.39 The
resulting acyl ylides 11 can be isolated if desired, or hy-
drolyzed with aqueous sodium hydroxide at room temper-
ature to leave the corresponding 3-acetyltetronic acids 12
and phosphine oxide as the byproduct. The acyl ylides 11
exist as mixtures of an enol–ylide tautomer (a) and a pre-
vailing oxo–phosphonium tautomer (b) in the more com-
mon organic solvents. In dipolar, aprotic solvents such as
dimethyl sulfoxide, only the b-tautomer is visible in the
NMR. Low temperature 13C and 31P NMR studies re-
vealed that the b-tautomer actually exists as a mixture of
two distinct rotamers, presumably differing in the oxygen
atom of the formal 1,3-dioxo-enolate moiety that interacts
with the phosphorus atom of the phosphonium group. At
room temperature these rotamers interconvert too rapidly
to be resolved by NMR. The hydrolysis product 12b is the
natural phytotoxin pesthetoxin, a leaf necrosis inducing
metabolite of the grey blight fungus Pestalotiopsis theae
which regularly infects tea crops.40 In solution, 3-
Synthesis 2006, No. 22, 3902–3914 © Thieme Stuttgart · New York

FEATURE ARTICLE
Tetronic and Tetramic acids
3905
acetyltetronic acids 12, like the acyl ylides 11, exist as of lactic acid reacted with the water-sensitive ylide 3 to af-
mixtures of two tautomers. In the case of 12 these tau- ford 15a, if a drying agent, e.g. sodium sulfate, was added
tomers differ in the ring-bound oxygen atom (2-O vs. 4- to the mixture in refluxing tetrahydrofuran. This leaves
O) that forms a H-chelate with the exocyclic carbonyl ox- room for the extension of this chemistry to carbohydrate
ygen atom. According to NMR, in the usual organic sol- derivatives such as uronic acids with unprotected remote
vents the tautomer featuring a H-chelate between the hydroxy groups.
exocyclic and the 4-carbonyl groups is dominant (e.g., by
1.6:1 in CDCl3). Either tautomer encompasses a subset of
two so-called internal tautomeric forms with differently
Table 1 Synthesis of 3-Phosphoranylidenefuran-2,4-diones 15
from a-Hydroxy Acids 13 and Ylide 3
localized double bonds. However, these are interconvert-
ing too rapidly on the NMR time scale to be resolved,
even at temperatures as low as –60 °C. This is in agree-
ment with previous spectroscopic and ab initio studies of
3-acyltetronic acids.41
PPh3
O
O
O
3, THF
60 °C, 8 h
H
HO
PPh3
O
OH
O
OH
– H2O
R
R
O
R
O
13
14
15a–c
O
O
3, THF
60 °C, 8 h
3, THF
60 °C, 24 h
15
R
Yield (%)
HO
O
OBn
(70–75%)
a
b
c
Me
65
67
R1
R1
OR2
n-C6H13
8a: R1 = Bu
9: R2 = Bn
10: R2 = H
H2, Pd/C
(95–99%)
b: R1 = n-Hex
Ph
72a
a (5S)-Enantiomer (95% ee) from L-(+)-mandelic acid.
O
O
O
PPh3
O
Although ylides 15 are too stable to undergo Wittig alk-
enations under any conditions they should be amenable to
follow-up reactions. Those reactions replacing the entire
triphenylphosphine group would be most attractive. For
instance, their oxidation with ozone, dimethyldioxirane,
or oxaziridines should lead to the corresponding furan-
2,3,4-triones, which are valuable building blocks for the
construction of diverse heterocycles.44
H
H
R1
PPh3
R1
OH
O
O
O
α-tautomer
β-tautomer
11
(pair of rotamers)
2 M NaOH
r.t., 2 h
(85%)
O
O
O
H
O
O
We had already reported that 4-O-allyltetronates can be
rearranged under forced conditions to the corresponding
3-spirocyclopropylfuran-2,4-diones 16 by a sequence
comprised of a Claisen rearrangement to give the respec-
tive 3-allyltetronic acid and a Conia oxaene reaction of the
latter.37 The compounds 16 had proved quite useful. A
wide range of carbon and heteroatom nucleophiles opened
the three-membered ring in such a way as to produce 3-
(syn-1,2-disubstituted-alkyl)tetronic acids 17.37,45 Now
we have found that some nucleophiles such as ylides like
methylenetriphenylphosphorane (Ph3P=CH2, 18), sodium
borohydride, and alkyllithium compounds react with the
4-oxo group of diastereopure37a racemic ( )-16a while
leaving the cyclopropane ring unaffected (Scheme 3,
Table 2). The resulting 3,4-difunctionalized furan-2-ones
represent structural patterns occurring in bioactive natural
products. For example, alkene ( )-19, obtained in over
80% yield from reaction of 16a with freshly prepared
methylide 18, resembles the 4-methylene-3-spirocyclo-
alkylfuran-2-one core of the bakkenolide family of ses-
quiterpenes.46,47 The reduction of diastereopure ( )-16a
with 1.5 equivalents of sodium borohydride in methanol
gave an easy to separate 3:2 mixture of diastereomeric al-
cohols 20 in 90% overall yield. The shown structure was
tentatively assigned to the major isomer as it results from
R1
R1
O
O
O
H
12a: R1 = Bu
b: R1 = n-Hex
major
minor
Scheme 2 Synthesis of 3-acetyltetronic acids 12 from a-hydroxy
esters 8 and two equivalents of ylide 3 as a C2O source.
Ylide-based cyclization of a-hydroxycarboxylic acid de-
rivatives is also possible with retention of the phosphorus
ylide functionality at C3. While the reaction of cumulated
ylide 3 with free carboxylic acids leads to highly reactive
anhydride ylides that are prone to decomposition yielding
mixtures of various phosphorus containing species,42 the
reaction of 3 with a-hydroxy acids 13 took an unexpect-
edly clear-cut course producing 3-phosphoranylidenefu-
ran-2,4-diones 1543 in good yields and without
racemization; (S)-15c was obtained in 95% ee according
to chiral HPLC from L-(+)-mandelic acid (Table 1). The
reaction presumably starts with the addition of the alcohol
group across the C=C bond of 3 to give an ester ylide 14.
In contrast to the reaction of a-hydroxy esters with 3, this
intermediate ylide now eliminates water rather than un-
dergoing an intra-Wittig alkenation. The product bisacyl
ylides 15 are very stable and so do not react further with
the byproduct water. Amazingly, even aqueous solutions
1
attack of hydride from the least hindered side. The H
Synthesis 2006, No. 22, 3902–3914 © Thieme Stuttgart · New York

3906
R. Schobert et al.
FEATURE ARTICLE
NMR signal of its proton H4 peaks at a normal d = 3.92, pounds were tested for antiplasmodial activity51 and
while the analogous signal of the minor isomer is distinct- found to be as effective as the natural antimalarial lead ar-
ly high-field shifted to d = 3.35 presumably due to a temisinin.52
shielding by the nearby phenyl ring. The reaction with
alkyllithium compounds is more diastereoselective.
Table 3 Structure of Endoperoxide Hemiketals 22
O
Ph
Nu
OH
O
O
Me
Ph
O
O
O
OH
O
Nu-Y
R1
R2
O
Nu = RO, RNH, R
= H, MgX,
Cu(CN)ZnI
O
22
Y
22
R1
Ph
R2
H
IC50a (nM)
( )-16a
( )-17a
a
b
c
–(CH2)5–
–(CH2)4–
3.9
6.0
5.9
Ph3P=CH2
(18)
NaBH4, MeOH, r.t.
or
RLi, THF, r.t.
(84%)
THF, r.t.
Ph
O
Ph
a Tested against Plasmodium falciparum POW according to the WHO
O
protocol with artemisinin (IC50 4.3 nM) as a standard.
R
4
O
O
OH
To more closely mimic the tetracyclic framework and the
presence of a full ketal in artemisinin we now prepared the
tricyclic bislactone endoperoxide ketal 29 as outlined in
Scheme 4. The 4-O-(3-methylbut-2-enyl)tetronate 26 was
readily accessible by sequential esterification of malic
acid first with 3-methylbut-2-ene-1-ol then with trimeth-
ylsilylethanol (TMSEOH), followed by Wittig cyclization
of hydroxy ester 25 with ylide 3. It was submitted to a
thermal cascade conversion to give the corresponding 3-
alkylidenefuran-2,4-dione 27. Desilylation with tetrabu-
tylammonium fluoride provided furan-2,4-dione 28,
which upon photooxygenation in the presence of 4-tolu-
enesulfonic acid cyclized directly to product 29. However,
contrary to the reports by other groups on similar couples
of hemiketal/full ketal endoperoxides,53 compound 29
proved to be not more active than 22 but virtually inactive
against Plasmodium falciparum. Figure 2 depicts the mo-
lecular structure of 29 as obtained from a single-crystal X-
ray structural analysis.54 It demonstrates that steric con-
gestion around the O–O bond is probably not responsible
for this lack of activity. The cleavage of this labile bond
by contact with heme molecules, which originate from the
decay of parasite-infested erythrocytes, is thought to be
crucial for antimalarial activity.
20, 21a,b
( )-19
Scheme 3 4-Functionalization of 3-spirocyclopropylfuran-2,4-di-
one ( )-16a
Table 2 Structures and Yields for Products 20, 21a,b
Product
20
R
Yield (%)
H
90a
90
58
21a
Me
Ph
21b
a Overall yield of a 3:2 mixture of diastereomers.
With one equivalent of methyllithium or 1.5 equivalents
of phenyllithium in tetrahydrofuran at room temperature a
single isomer was formed in good yield, which we ascribe
the shown structures 21a,b based on the NMR spectra.
Similar yields and stereoselectivities were obtained in re-
actions with butyllithium and various alkynyllithium
compounds. Analogues of 16 with residues other than spi-
rocyclohexyl at C5 reacted equally well. The tertiary alco-
hols 21, with adjacent carbonyl and spirocyclopropyl
rings which are susceptible to attack by (bio-)nucleo-
philes, bear some resemblance to the natural antitumoral
alkylants illudin M and S that were extracted from the
Jack o’Lantern mushroom (Omphalotus illudens)48 and to
the carcinogen ptaquiloside, isolated from the fern Pterid-
ium aquilinum.49
1,3-Difunctionalized Systems: Reutericyclin
The 1,3-bisacyl-substituted tetramic acid reutericyclin
[(5R)-2] exhibits antibiotic activity against a wide variety
of Gram-positive bacteria, including common sourdough
lactic acid bacteria. It was first obtained from a sourdough
isolate of Lactobacillus reuteri by Jung et al.7a,b Like all 3-
acyltetramic acids,55,56 2 usually exists as a mixture of var-
ious tautomers the ratio of which is dependent mainly on
the solvent polarity. Some of these tautomers are strong
chelate ligands with binding constants for various metal
As reported previously, tetronates bearing 4-O-allyl resi-
dues with trisubstituted alkenes undergo an extended
Claisen–Conia–retro-Conia–isomerization rearrangement
to 3-alkylidenefuran-2,4-diones when heated. They are
amenable to oxidation with singlet oxygen affording en-
doperoxide hemiketals 22 (Table 3);50 some of these com-
Synthesis 2006, No. 22, 3902–3914 © Thieme Stuttgart · New York

FEATURE ARTICLE
Tetronic and Tetramic acids
3907
lenge of avoiding racemization at C5. The Jung group
published two syntheses of 2, which differ in the proce-
dure of the ring closure and in the order of introduction of
the acyl residues at N1 and C3. The first one7c submitted
an N-dec-2-enoylleucine to the condensation–cyclization
reaction with Meldrum’s acid as described by Jouin et
al.23 The 3-acetyl group was introduced last with acetyl
chloride and catalytic amounts of titanium(IV) chloride
and this led to racemization at C5. In the second7d synthe-
sis of 2, N-acetoacetylleucinate was cyclized under basic
Lacey–Dieckmann conditions.19 The resulting 3-acetyl-5-
isobutyltetramic acid was finally deprotonated with butyl-
lithium and N-acylated with (E)-dec-2-enoyl chloride to
give (5R)-2 with 80% ee. It remained unclear which one
of the two basic steps, Dieckmann condensation or N1-
deprotonation/acylation, had proceeded with partial race-
mization.63
OH
OH
(i)
(iii)
CO2CH2CH=CMe2
65%
75%
HO2C
CO2H
RO2C
23
24: R = H
(ii)
O
25: R = TMSE
O
(iv)
70%
O
O
OCH2CH=CMe2
O
TMSEO2C
RO2C
26
27: R = TMSE
28: R = H
(v)
O
O
O
(vi)
42%
O
O
O
We have now developed an alternative four-step synthesis
of (5R)-2 from D-leucine benzyl ester comprised of our
pH-neutral domino N-acylation–Wittig cyclization with
ylide 3, and subsequent stepwise nonracemizing acyla-
tions, first at C3 under Jones’ conditions,28 i.e. employing
acetyl chloride/boron trifluoride–diethyl ether complex,
then at N1 using sodium hexamethyldisilazanide/(E)-dec-
2-enoyl chloride at low temperature (Scheme 5). Benzyl
D-leucinate (31), which is available in near quantitative
yield from D-leucine (30) and benzyl alcohol, was cy-
clized with ylide 3 to give the 4-O-benzyltetramate 32 in
70% yield. Hydrogenolytic debenzylation of the latter af-
forded the rather polar and delicate tetramic acid 33 that
crystallized from ethyl acetate as the pure keto tautomer
shown in Scheme 5. Compound 33 was then treated with
an excess of both boron trifluoride–diethyl ether complex
and acetyl chloride to give the difluoroboryl-chelate com-
plex 34 of the corresponding 3-acetyltetramic acid. Com-
plex 34 was stable and sufficiently unpolar to allow for its
purification by column chromatography on silica gel. In
solution it may exist as a mixture of tautomers. Conve-
niently, it is also stable to base with the difluoroboryl che-
late acting as a built-in protecting group for the acetyl
residue. Hence compound 34 could be deprotonated/acy-
lated at N1 right away. To safely circumvent racemization
at C5 in the course of this procedure some experimenta-
tion was necessary. We found that deprotonation at N1 by
treatment of 34 with sodium hexamethyldisilazanide for
five minutes at –78 °C in tetrahydrofuran solution fol-
lowed by immediate quenching with (E)-dec-2-enoyl
chloride and final aqueous workup produced a sample of
reutericyclin virtually void of the (5S)-enantiomer (i.e.
>95% ee) as to chiral HPLC on permethylated b-cyclo-
dextrin when compared with an authentic racemic sample.
29
Scheme 4 Synthesis of bislactone endoperoxide ketal 29. Reactions
and conditions: (i) TFAA, then Me2C=CHCH2OH, neat, r.t.; (ii)
TMSEOH, DCC, THF, r.t. to 65 °C, 16 h, 60%; (iii) Ph3P=C=C=O
(3), THF, 55 °C, 16 h; (iv) sealed glass tube, 170 °C, 24 h; (v)
TBAF·3H2O, THF, r.t., 2 h, 90%; (vi) O3, CH2Cl2, PTSA, CuSO4, hn,
r.t., 1 h.
Figure 2 Molecular structure of 29 (ORTEP representation, 50%
probability ellipsoids); hydrogen atoms are omitted; selected bond
lengths [Å] and dihedral angles [°]: C1–C2 1.471(3), C2–C3
1.334(3), C3–C5 1.521(3), C2–C8 1.487(3), C5–O2 1.443(3), O2–O3
1.481(2), C8–O3 1.389(3), C8–O4 1.441(2), C5–O2–O3–C8
75.00(19), C3–C2–C8–O4 –103.8(2), O3–C8–C11–C10 –99.5(2).
25
This and the optical rotation of [a]D +18 (c 3.0, EtOH)
are in keeping with the data reported7d by the Jung group
for the product of their most recent synthesis [80% ee,
[a]D25 +13 (c 0.29, EtOH)]. NMR spectra in acetonitrile-
d3 revealed the presence of two, very likely external, tau-
tomers in ca. 3:2 ratio.
cations in the range of siderophores.57–61 The proton-ion-
ophoric properties were also drawn on to explain the bio-
activity of 2.62 Synthetic approaches towards 2 have to
sort out the optimum order and methods of attaching the
two acyl residues at N1 and C3 with the additional chal-
Synthesis 2006, No. 22, 3902–3914 © Thieme Stuttgart · New York

3908
R. Schobert et al.
FEATURE ARTICLE
O
O
Microwave irradiations were carried out in sealed vials in an MLS
Microchemist system. Melting points were recorded in a Gallenka-
mp apparatus and are uncorrected. Optical rotations were recorded
at 589 nm with a Perkin-Elmer polarimeter 241. IR spectra were re-
corded on a Perkin-Elmer Spectrum One FT-IR spectrophotometer
equipped with an ATR sampling unit. NMR spectra were recorded
under conditions as indicated on a Bruker Avance 300 spectrometer
using TMS as internal standard. The assignments of 1D NMR sig-
nals were verified with the aid of 2D spectra (HH-COSY, HET-
COR–HSQC). In 1H NMR spectra of isomeric mixtures, the quoted
signal integrations refer to the hypothetically pure individual iso-
mers. MS were recorded using a Varian MAT 311A (EI, 70 eV).
Microanalyses were carried out with a Perkin-Elmer 2400 CHN el-
emental analyzer. Analytical chromatography of nonracemic sam-
ples was conducted on chiral permethylated b-cyclodextrin (HPLC)
or Lipodex-E (GC) columns from Macherey–Nagel. For flash chro-
matography, Merck silica gel 60 (230–400 mesh) was used. Starting
compounds were prepared according to literature procedures or pur-
chased from Fluka and Aldrich and used as such without further pu-
rification.
H2N
HN
CO2R
HN
(ii)
(iii)
70%
99%
OBn
O
30: R = H
33
32
(i)
(95%)
31: R = Bn
F2
B
H
O
O
O
O
O
(iv)
(v)
74%
HN
H15C7
N
61%
O
O
34
(5R)-2
major tautomer
(ee >95%)
Scheme 5 Synthesis of reutericyclin [(5R)-2]. Reactions and condi-
tions: (i) BnOH, PTSA, benzene, reflux, 16 h; (ii) Ph3P=C=C=O (3),
PhCO2H (cat), THF, 60 °C, 16 h; (iii) H2 (1 bar), Pd/C (5%), MeOH,
r.t., 1 h, (iv) BF3·OEt2 (excess), AcCl (8 equiv), 70 °C, 8 h; (v) (a)
NaHMDS, THF, –78 °C, 5 min, (b) (E)-dec-2-enoyl chloride, –65 °C,
1 h, (c) aq 1 M KHSO4.
(5S)-3-(But-2-enyl)-4-hydroxy-5-methylfuran-2(5H)-one (5)
A soln of 434b (144 mg, 1.0 mmol) and 3 (330 mg, 1.1 mmol) in tol-
uene (5 mL) was placed in a sealed glass vial and irradiated in the
microwave oven at 180 °C for 10 min. The resulting mixture was
concentrated and the residue was purified by column chromatogra-
phy (silica gel, first with neat CH2Cl2 to remove Ph3PO, then with
neat Et2O; Rf = 0.54). Evaporation of the second eluate afforded 5
as a colorless oil; yield: 109 mg (65%); ratio E/Z 2.3:1.
Conclusions
IR (ATR): 3191, 2709, 1719, 1631, 1057, 964, 732 cm–1.
The cumulated ylide (triphenylphosphoranylidene)ketene
(Ph3PCCO, 3) is a versatile C2O building block for the
construction of differently functionalized tetronates and
tetramates and close derivatives thereof. Esters of a-hy-
droxy and a-amino acids can be cyclized to the corre-
sponding 4-O-alkyl systems without racemization of
positions bearing acidic hydrogen atoms. Multiple use of
ylide 3 is also possible and particularly economic. Free
tetronic and tetramic acids are acylated by 3 at C3 to give
1H NMR (CDCl3): d = 1.46 (d, J = 6.7 Hz, 3 H, 5-MeE), 1.47 (d,
J = 6.7 Hz, 3 H, 5-MeZ), 1.60 (d, J = 4.8 Hz, 3 H, =CMeZ), 1.66 (d,
Z
J = 6.4 Hz, 3 H, =CMeE), 2.86 (d, J = 5.0 Hz, 2 H, CH2 ), 2.94 (d,
E
J = 6.7 Hz, 2 H, CH2 ), 4.80 (q, J = 6.7 Hz, 1 H, H5E+Z), 5.30–5.60
(m, 2 H, =CHE+Z).
13C NMR (75.5 MHz, CDCl3): d = 12.7/17.7 (Me), 17.70/17.75
(Me), 19.2/24.0 (CH2), 75.3 (CH), 99.2/99.4 (Cq), 125.8/126.2
(CH), 126.4/126.6 (CH), 177.0/177.1 (Cq), 177.2/177.5 (Cq).
MS: m/z (%) = 168 (24) [M+], 150 (39), 127 (25), 114 (53), 95 (61),
the corresponding acyl ylides, which can be saponificated 81 (100).
to the respective 3-acetyl systems. Even unprotected a-
hydroxy acids react with 3 to afford the corresponding 3-
phosphoranylidenefuran-2,4-diones. The downstream
acylation at C3 of tetronic acids and of N1 and C3 of tet-
ramic acids is also possible by various means and methods
without racemization. Hence we are now able to attach
certain types of residues to any and all positions. Where
do conceivable and desirable extensions of this methodol-
ogy lie? The C3 acylation of N- and C5-unsubstituted tet-
ramates is still problematic as is the C3 acylation with
highly unsaturated residues in general. Neither Jones’ nor
Yoshii’s protocols work well in these cases, if at all. A
way out of this predicament could be to switch 3-acyl
ylides akin to 11 ‘Wittig-active’ and have them alkenate
unsaturated aldehydes. Ylides like 11 are unreactive, very
likely due to H-chelate formation, which, we hope, can be
broken up by deprotonation with a mild base that does not
provide a countercation that replaces hydrogen in these
chelates. Work towards this end is underway in our labo-
ratory.
Anal. Calcd for C9H12O3: C, 64.3; H, 7.2. Found: C, 64.0; H, 7.0.
(5S)-5-Methyl-4-(1-methylallyloxy)furan-2(5H)-one (6); Typi-
cal Procedure
A soln of 434b (2.41 g, 16.7 mmol), 3 (5.59 g, 18.5 mmol), and ben-
zoic acid (100 mg, 0.8 mmol) in THF (100 mL) was heated under
gentle reflux for 16 h. The resulting mixture was concentrated and
the residue was purified by column chromatography (silica gel, hex-
ane–Et2O, 1:1, Rf = 0.35). Evaporation of the eluate afforded 6 as a
colorless oil; yield: 2.10 g (74%); 1:1 mixture of diastereomers.
IR (ATR): 2986, 1753, 1617, 1292, 1083, 954 cm–1.
1H NMR (CDCl3), mixture of diastereomers a and b: d = 1.39 (d,
J = 6.8 Hz, 3 H, 5-Me), 1.40/1.41 (d, J = 6.4 Hz, 3 H, 1¢-Me), 4.60
(m, 1 H, H1¢), 4.73 (dq, J = 6.8, 1.0 Hz, 1 H, H5), 4.91/4.92 (d,
J = 1.0 Hz, 1 H, H3), 5.23 (dd, J = 17.4, 1.1 Hz, 1 H, =CHE), 5.33
(dd, J = 10.4, 1.1 Hz, 1 H, =CHZ), 5.50/5.80 (ddd, J = 17.4, 10.4, 6.5
Hz, 1 H, =CH).
13C NMR (75.5 MHz, CDCl3): d = 17.7 (Me), 20.1/20.3 (Me), 75.4
(CH), 80.0/80.2 (CH), 88.70/88.75 (CH), 117.6/117.8 (CH2), 135.9
(CH), 172.7 (Cq), 181.0 (Cq).
MS: m/z (%) = 168 (14) [M+], 150 (25), 114 (33), 95 (31), 81 (53),
55 (100).
Anal. Calcd for C9H12O3: C, 64.3; H, 7.2. Found: C, 64.5; H, 7.4.
Synthesis 2006, No. 22, 3902–3914 © Thieme Stuttgart · New York

FEATURE ARTICLE
Tetronic and Tetramic acids
3909
(3R,4S,5S)-3-Butyl-4-hydroxy-5-methyldihydrofuran-2(3H)-
one [(–)-epi-Blastmycinolactol, 7]
1H NMR (CDCl3), 3:2 mixture of enol and keto tautomers: d = 0.91
(t, J = 7.2 Hz, 3 H, Me), 1.35–1.46 (m, 4 H, CH2), 1.61–1.68 (m, 1
H, 5-CHH), 1.93–1.99 (m, 1 H, 5-CHH), 3.20 (d, J = 6.6 Hz, 2 H,
H3keto), 4.76–4.79 (m, 1 H, H5keto), 4.80–4.83 (m, 1 H, H5enol), 5.04
(s, 1 H, H3enol).
13C NMR (75.5 MHz, CDCl3): enol: d = 13.8 (Me), 22.3 (CH2), 26.2
(CH2), 31.1 (CH2), 80.7 (CH), 88.7 (CH), 177.7 (Cq), 184.0 (Cq); ke-
to: d = 13.6 (Me), 22.1 (CH2), 26.5 (CH2), 31.0 (CH2), 37.5 (CH2),
86.5 (CH), 169.9 (Cq), 205.6 (Cq).
A mixture of 5 (252 mg, 1.5 mmol), 5% Rh/Al2O3 catalyst (100 mg;
20 mol%), EtOAc (20 mL), and AcOH (10 mL) was placed in an au-
toclave and stirred at 60 °C for 5 d pressurized with H2 gas (50 bar).
The mixture was filtered through Celite and the filtrate was concen-
trated and purified by column chromatography (silica gel, Et2O,
Rf = 0.76) to give colorless crystals; yield: 181 mg (70%); 92% ee
(GC; Lipodex-E); mp 97 °C (Lit.38 101–102 °C); [a]D25 –82 (c 0.6,
MeOH) [Lit.38 [a]D25 –84.8 (c 0.66, MeOH)].
MS: m/z (%) = 156 (2) [M+], 128 (4), 100 (72), 86 (41), 43 (100).
IR (ATR): 3427, 2959, 1741, 1187, 1063 cm–1.
Anal. Calcd for C8H12O3: C, 61.5; H, 7.7. Found: C, 61.5; H, 7.4.
1H NMR (CDCl3): d = 0.89 (t, J = 6.9 Hz, 3 H, Me), 1.30–1.41 (m,
2 H, CH2), 1.39 (d, J = 6.5 Hz, 3 H, 5-Me), 1.35–1.44 (m, 2 H, CH2),
1.53–1.69 (m, 1 H, 3-CHH), 1.69–1.84 (m, 1 H, 3-CHH), 2.53 (dt,
J = 10.0, 4.9 Hz, 1 H, H3), 2.84 (br s, 1 H, OH), 4.28 (dd, J = 4.9,
3.0 Hz, 1 H, 4H), 4.43 (dq, J = 6.5, 3.0 Hz, 1 H, H5).
13C NMR (75.5 MHz, CDCl3): d = 13.6 (Me), 13.8 (Me), 22.5
(CH2), 22.9 (CH2), 29.7 (CH2), 47.6 (CH), 71.1 (CH), 79.2 (CH),
178.3 (Cq).
5-Hexyl-4-hydroxyfuran-2(5H)-one (10b)
White solid from 9b (3.48 g, 12.7 mmol), analogously to the synthe-
sis of 10a; yield: 2.38 g (99%); mp 99 °C [Lit.66 101–103 °C].
IR (ATR): 3129, 2926, 1692, 1567, 1277 cm–1.
1H NMR (CDCl3), 3:2 mixture of enol and keto tautomers: d = 0.92
(t, J = 7.2 Hz, 3 H, Me), 1.35–1.54 (m, 8 H, CH2), 1.61–1.68 (m, 1
H, 5-CHH), 1.90–1.97 (m, 1 H, 5-CHH), 3.22 (d, J = 6.6 Hz, 2 H,
H3keto), 4.76–4.80 (m, 1 H, H5keto), 4.80–4.83 (m, 1 H, H5enol), 5.04
(s, 1 H, H3enol).
MS: m/z (%) = 172 (2) [M+], 155 (8), 116 (87), 99 (69), 85 (37), 57
(100).
MS: m/z (%) = 184 (6) [M+], 156 (1), 142 (2), 114 (12), 100 (100).
4-(Benzyloxy)-5-butylfuran-2(5H)-one (9a)
Colorless oil from 8a64 (2.22 g, 10.0 mmol) and 3 (3.90 g, 13.0
mmol) in THF (50 mL), reflux for 8 h, analogously to the synthesis
of 6; yield: 1.72 g (70%); Rf = 0.62 (Et2O–n-pentane, 2:1).
5-Butyl-4-hydroxy-3-[1-oxo-2-(triphenylphosphoranyl)eth-
yl]furan-2(5H)-one (11a)
A soln of 3 (2.00 g, 6.6 mmol) and 10a (0.80 g, 5.1 mmol) in THF
(20 mL) was refluxed for 12 h. Upon cooling, colorless crystals of
11a precipitated; yield: 1.87 g (80%); mp >192 °C (dec.). In soln,
mixture of enol–ylide (a) and two rotameric oxo–phosphonium (b)
tautomers, the latter only discernable at low temperature:
IR (ATR): 3119, 3035, 2957, 2872, 1755, 1629, 1230, 1016 cm–1.
1H NMR (CDCl3): d = 0.89 (t, J = 7.2 Hz, 3 H, Me), 1.32–1.43 (m,
4 H, CH2), 1.57–1.66 (m, 1 H, 5-CHH), 1.88–1.97 (m, 1 H, 5-CHH),
4.77–4.80 (m, 1 H, H5), 5.04 (2 d, J = 16.5 Hz, 2 H, OCH2), 5.12 (s,
1 H, H3), 7.35–7.43 (m, 5 H, Ph).
13C NMR (75.5 MHz, CDCl3): d = 13.7 (Me), 22.2 (CH2), 26.2
(CH2), 31.4 (CH2), 74.2 (CH2), 78.9 (CH), 90.0 (CH), 127.8, 128.7,
128.9 (ar-CH), 133.9 (ar-Cq), 172.6 (Cq), 181.0 (Cq).
13C NMR (125.7 MHz, CDCl3, –58 °C); tautomer a: d = 14.12
(Me), 22.29 (CH2, CMe), 26.80 (CH2, CCMe), 31.01 (CH2; 5-C),
56.01 (d, 1JPC = 107.51 Hz, P=CH), 83.26 (CH, C5), 89.26 (Cq, C3),
122.61 (d, 1JPC = 92.03 Hz, C-ipso), 129.23 (d, 3JPC = 12.70 Hz, C-
2
meta), 132.82 (d, JPC = 10.81 Hz, C-ortho), 133.29 (C-para),
MS: m/z (%) = 246 (3) [M+], 212 (4), 189 (8), 132 (20), 105 (11), 91
(100).
171.78, 176.74, 196.38 (Cq, 3-C, C2, C4); tautomer b: d = 14.00/
14.04 (Me), 22.35/22.39 (CH2, CMe), 26.39/26.69 (CH2, CCMe),
1
Anal. Calcd for C15H18O3: C, 73.1; H, 7.4. Found: C, 72.8; H, 7.0.
31.23/31.34 (CH2, 5-C), 34.58/34.60 (each d, JPC = 51.06/52.02
Hz, P-CH2), 80.33/80.64 (CH, C5), 96.83/97.29 (Cq, C3), 118.59/
1
4-(Benzyloxy)-5-hexylfuran-2(5H)-one (9b)
118.20 (each d, JPC = 88.90/88.53 Hz, C-ipso), 129.68/129.74
Colorless oil from 8b65 (4.27 g, 17.1 mmol) and 3 (5.42 g, 17.9
mmol) in THF (150 mL), reflux for 8–16 h; yield: 3.50 g (75%);
Rf = 0.42 (Et2O–n-hexane, 3:2).
3
(each d, JPC = 12.83/12.70 Hz, C-meta), 133.50/133.61 (each d,
2JPC = 11.82/11.44 Hz, C-ortho), 134.43/134.54 (C-para), 173.32/
173.55, 179.33/179.64, 197.63/197.81 (Cq, 3-C, C2, C4).
IR (ATR): 2928, 1752, 1625, 1300, 1155 cm–1.
31P NMR (202.4 MHz, H3PO4 ext., CDCl3, –58 °C): d = 16.87 (a),
23.70/23.93 (b).
31P NMR (121.4 MHz, H3PO4 ext., DMSO-d6, 32 °C): d = 23.93
(tautomer b only).
MS: m/z (%) = 458 (24) [M+], 415 (4), 402 (17), 301 (19), 277
(100), 262 (32), 201 (24), 183 (41).
1H NMR (CDCl3): d = 0.86 (t, J = 6.8 Hz, 3 H, Me), 1.15–1.45 (m,
8 H, CH2), 1.51–1.66 (m, 1 H, 5-CHH), 1.80–1.96 (m, 1 H, 5-CHH),
4.76 (ddd, J = 7.7, 3.7, 1.0 Hz, 1 H, H5), 4.99 (d, J = 11.6 Hz, 1 H,
4-OCH), 5.04 (d, J = 11.6 Hz, 1 H, 4-OCH), 5.09 (d, J = 1.0 Hz, 1
H, H3), 7.30–7.42 (m, 5 H, Ph).
13C NMR (75.5 MHz, CDCl3): d = 13.9 (Me), 22.4 (CH2), 24.0
(CH2), 28.8 (CH2), 31.4 (CH2), 31.7 (CH2), 79.0 (CH), 89.5 (CH),
127.8, 128.7, 128.9 (ar-CH), 133.9 (ar-Cq), 172.6 (Cq), 181.0 (Cq).
Anal. Calcd for C28H27O4P: C, 73.4; H, 5.9. Found: C, 73.0; H, 5.6.
3-Acetyl-5-butyl-4-hydroxyfuran-2(5H)-one (12a) from 10a;
Typical Procedure
MS: m/z (%) = 274 (2) [M+], 256 (1), 190 (5), 91 (100).
A soln of 3 (0.97 g, 3.2 mmol) and 10a (0.46 g, 2.9 mmol) in THF
(50 mL) was heated under reflux for 24 h. After cooling to r.t. the
resulting mixture was treated dropwise with aq 2 M NaOH (20 mL).
Stirring was continued at r.t. for 2 h, then 47% aq HBr soln was add-
ed carefully until the volume was twice the original. This mixture
was extracted with Et2O (3 × 20 mL), the combined organic phases
were washed with H2O (2 × 10 mL), dried (Na2SO4), and concen-
trated in vacuo. Sublimation of the residue at 80 °C/6.7 mbar afford-
ed white crystals; yield: 495 mg (85%); mp 54 °C.
Anal. Calcd for C17H22O3: C, 74.4; H, 8.1. Found: C, 74.7; H, 8.0.
5-Butyl-4-hydroxyfuran-2(5H)-one (10a); Typical Procedure
White solid from 9a (984 mg, 4.0 mmol) upon hydrogenation with
10% Pd/C (150 mg) as a catalyst in MeOH and H2 (1 atm) for 12 h
followed by filtration through a short plug of Celite and recrystalli-
zation (Et2O); yield: 587 mg (95%); mp 79–80 °C.
IR (KBr): 3443, 2959, 2931, 1719, 1623, 1458, 1275 cm–1.
IR (ATR): 3079, 2958, 2923, 1746, 1666, 1597, 1165, 1012 cm–1.
Synthesis 2006, No. 22, 3902–3914 © Thieme Stuttgart · New York

3910
R. Schobert et al.
FEATURE ARTICLE
1H NMR (CDCl3), 1.6:1 mixture of two tautomers a/b: d = 0.84 (t,
J = 7.3 Hz, 3 H, Meb), 0.85 (t, J = 7.1 Hz, 3 H, Mea), 1.20–1.45 (m,
4 H, CH2), 1.57–1.74 (m, 1 H, 5-CHH), 1.82–1.96 (m, 1 H, 5-CHH),
2.48 (s, 3 H, MeCO), 4.55 (dd, J = 8.0, 4.2 Hz, 1 H, H5b), 4.68 (dd,
J = 8.0, 4.4 Hz, 1 H, H5a), 10.9 (br s, 1 H, OH).
1.84–1.98 (dd, J = 3.8, 7.5 Hz, 1 H, 5-CH), 4.52 (m, 1 H, H5), 7.44–
7.63 (m, 15 H, Ph).
13C NMR (75.5 MHz, CDCl3): d = 13.9, 22.3, 24.5, 28.9, 31.5, 31.8,
61.2 (d, 1JPC = 122 Hz), 83.3, 121.6 (d, 1JPC = 94 Hz), 128.9, 133.2,
133.9, 175.0, 197.4.
31P NMR (121.4 MHz, H3PO4 ext., CDCl3): d = 11.56.
13C NMR (75.5 MHz, CDCl3): d = 13.7 (Me), 19.5 (Meb), 22.2
a
b
b
(CH2), 22.4 (Mea), 26.4 (CH2 ), 26.5 (CH2 ), 30.9 (CH2 ), 31.0
a
(CH2 ), 80.0 (CHa), 85.6 (CHb), 97.8 (Cqb), 100.7 (Cqa), 167.9 (Cqa),
MS: m/z (%) = 444 (38), 373 (16), 360 (100), 301 (40), 262 (51),
183 (34).
175.9 (Cqb), 188.1 (Cqb), 194.3 (Cqa), 194.9 (Cqb), 199.8 (Cqa).
MS: m/z (%) = 199 (1), 198 (8) [M+], 155 (14), 142 (100).
Anal. Calcd for C10H14O4: C, 60.6; H, 7.1. Found: C, 60.5; H, 7.1.
Anal. Calcd for C28H29O3P: C, 75.7; H, 6.6. Found: C, 75.7; H, 6.3.
5-Phenyl-3-(triphenylphosphoranylidene)furan-2,4(3H,5H)-di-
one (15c)
From DL-mandelic acid (3.42 g, 22.5 mmol); chromatography (cy-
clohexane–EtOAc, 1:5) gave ( )-15c as colorless crystals; yield:
6.22 g (72%); mp 178–180 °C. L-(+)-Mandelic acid gave (+)-15c;
95% ee; [a]D25 +58 (c 1.2, CHCl3).
IR (ATR): 3056, 1726, 1626, 1435, 1347, 722, 688 cm–1.
1H NMR (CDCl3): d = 5.48 (s, 1 H, H5), 7.25–7.60 (m, 20 H, Ph).
3-Acetyl-5-hexyl-4-hydroxyfuran-2(5H)-one (Pesthetoxin, 12b)
from 10b
From 3 (0.63 g, 2.1 mmol) and 10b (0.35 g, 1.8 mmol) analogously
to the synthesis of 12a; yield: 359 mg (85%); mp 58 °C [Lit.40 no
mp reported].
IR (ATR): 3078, 1747, 1665, 1601, 1581, 1166, 1078 cm–1.
1H NMR (CDCl3), 1.6:1 mixture of two tautomers a/b: d = 0.84 (t,
J = 6.7 Hz, 3 H, Me), 1.17–1.36 (m, 6 H, CH2), 1.36–1.52 (m, 2 H,
CH2), 1.61–1.77 (m, 1 H, 5-CHH), 1.83–1.98 (m, 1 H, 5-CHH),
2.51 (s, 3 H, COMeb), 2.52 (s, 3 H, COMea), 4.59 (dd, J = 8.0, 4.3
Hz, 1 H, H5b), 4.71 (dd, J = 7.7, 4.5 Hz, 1 H, H5a), 12.5 (br s, 1 H,
OH).
1
13C NMR (75.5 MHz, CDCl3): d = 61.3 (d, JPC = 122 Hz), 84.1,
1
121.5 (d, JPC = 94 Hz), 125.7, 127.9, 128.3, 129.2, 133.4, 134.1,
136.5, 175.2, 194.8.
31P NMR (121.4 MHz, H3PO4 ext., CDCl3): d = 11.99.
Anal. Calcd for C28H21O3P: C, 77.1; H, 4.8. Found: C, 76.8; H, 4.6.
13C NMR (75.5 MHz, CDCl3): d = 14.0 (Mea+b), 19.5 (Meb), 22.4
a
b
a
(Mea), 22.5 (CH2a+b), 24.3 (CH2 ), 24.4 (CH2 ), 28.7 (CH2 ), 28.8
( )-1-Methyl-4-methylene-2-phenyl-11-oxa-
dispiro[2.1.5.2]dodecan-12-one [( )-19]
b
b
a
(CH2 ), 31.2 (CH2 ), 31.3 (CH2 ), 31.4 (CH2a+b), 80.0 (CHa), 85.6
(CHb), 97.8 (Cqb), 100.7 (Cqa), 167.9 (Cqa), 175.9 (Cqb), 188.0 (Cqb),
194.3 (Cqa), 194.9 (Cqb), 199.8 (Cqa).
To a slurry of methyltriphenylphosphonium bromide (750 mg, 2.11
mmol) in THF (20 mL), 1.6 M BuLi in hexane (1.3 mL, 2.08 mmol)
was slowly added. The dark orange soln was stirred at r.t. for 30 min
and then treated with a soln of diastereopure racemic ( )-16a37a
(500 mg, 1.76 mmol) in THF (10 mL). After stirring for a further 4
h the resulting mixture was filtered through a small plug of silica
gel, the filtrate was concentrated in vacuo and the residue was puri-
fied by column chromatography (silica gel; Et2O–hexane, 1:1, Rf =
0.78) to give colorless solid 19; yield: 422 mg (84%).
MS: m/z (%) = 227 (2), 226 (9) [M+], 155 (23), 142 (100).
3-(Triphenylphosphoranylidene)furan-2,4(3H,5H)-diones 15;
General Procedure
A mixture of ylide 3 (6.00 g, 19.8 mmol), a-hydroxycarboxylic acid
13 (22.5 mmol), and THF (150 mL) was heated under gentle reflux
for ca. 8 h. When employing aqueous solns of lactic acid, some dry-
ing agent (Na2SO4, ca. 3–5 g) was also added. After cooling to r.t.
the mixture was concentrated and the remainder was purified by
column chromatography (silica gel).
IR (ATR): 2931, 1753, 1315, 1267, 1127, 968 cm–1.
1H NMR (CDCl3): d = 1.18–1.88 (m, 10 H, CH2), 1.59 (d, J = 6.3
Hz, 3 H, Me), 1.96 (dq, J = 8.5, 6.3 Hz, 1 H, HCMe), 3.12 (d, J = 8.5
Hz, 1 H, HCPh), 3.69 (d, J = 1.1 Hz, 1 H, =CHH), 4.39 (d, J = 1.1
Hz, 1 H, =CHH), 7.12–7.33 (m, 5 H, Ph).
13C NMR (75.5 MHz, CDCl3): d = 11.9, 21.9, 22.1, 25.0, 33.0, 34.7,
37.4, 37.7, 45.6, 86.7, 101.6, 127.3, 128.2, 129.9, 134.2, 150.6,
175.8.
5-Methyl-3-(triphenylphosphoranylidene)furan-2,4(3H,5H)-di-
one (15a)
From DL-lactic acid (2.02 g, 22.5 mmol); chromatography (THF–
CH2Cl2, 1:2) gave 15a as colorless crystals; yield: 4.82 g (65%); mp
113–115 °C.
MS: m/z (%) = 283 (17), 282 [M+] (100), 267 (11), 237 (34), 195
IR (ATR): 2921, 1708, 1637, 1588, 1437, 1183, 1119, 719 cm–1.
(22), 115 (23), 105 (46).
1H NMR (CDCl3): d = 1.44 (d, J = 6.8 Hz, 3 H, Me), 4.58 (q, J = 6.8
Hz, 1 H, CH), 7.45–7.65 (m, 15 H, Ph).
Anal. Calcd for C19H22O2: C, 80.8; H, 7.9. Found: C, 80.4; H, 7.6.
13C NMR (75.5 MHz, CDCl3): d = 17.9, 60.5 (d, JPC = 125 Hz),
1
4-Hydroxy-1-methyl-2-phenyl-11-oxadispiro[2.1.5.2]dodecan-
12-one (20)
79.4, 121.3 (d, 1JPC = 93 Hz), 128.0, 133.1, 133.8, 174.6, 198.0.
31P NMR (121.4 MHz, H3PO4 ext., CDCl3): d = 11.62.
A soln of ( )-16a (290 mg, 1.0 mmol) in MeOH (20 mL) was
chilled to 0 °C and slowly treated with NaBH4 (65 mg, 1.7 mmol).
After stirring at r.t. for 24 h, the mixture was quenched with sat. aq
NaHCO3 soln to pH 8–9 and then repeatedly extracted with CH2Cl2.
The combined extracts were dried, concentrated, and purified by
chromatography (silica gel, hexane–Et2O, 3:1) to give 20 as a col-
orless solid; yield: 263 mg (90%); 3:2 mixture of diastereomers; mp
201 °C. The diastereomers were separated by column chromatogra-
phy (hexane–Et2O, 1:1); Rf = 0.30 and 0.43.
MS: m/z (%) = 374 (27), 301 (52), 275 (76), 262 (100), 183 (50).
Anal. Calcd for C23H19O3P: C, 73.8; H, 5.1. Found: C, 73.7; H, 5.2.
5-Hexyl-3-(triphenylphosphoranylidene)furan-2,4(3H,5H)-di-
one (15b)
From 13b (3.61 g, 22.5 mmol); chromatography (hexane–Et2O, 3:2)
gave 15b as a colorless solid; yield: 5.90 g (67%); mp 80 °C.
IR (ATR): 2925, 1717, 1632, 1343, 1107, 998, 748 cm–1.
Minor Isomer
1H NMR (CDCl3): d = 0.83 (t, J = 6.7 Hz, 3 H, Me), 1.16–1.35 (m,
6 H, CH2), 1.40–1.54 (m, 2 H, CH2), 1.62–1.72 (m, 1 H, 5-CH),
IR (ATR): 3394, 2933, 1735, 1499, 1197, 1028, 952 cm–1.
Synthesis 2006, No. 22, 3902–3914 © Thieme Stuttgart · New York

FEATURE ARTICLE
Tetronic and Tetramic acids
3911
1H NMR (CDCl3): d = 1.15–1.80 (m, 10 H, CH2), 1.49 (d, J = 6.3
Hz, 3 H, Me), 1.50 (d, J = 6.8 Hz, 1 H, OH), 2.25 (dq, J = 7.8, 6.3
Hz, 1 H, HCMe), 2.74 (d, J = 7.8 Hz, 1 H, HCPh), 3.39 (d, J = 6.8
Hz, 1 H, H4), 7.11–7.35 (m, 5 H, Ph).
13C NMR (75.5 MHz, CDCl3): d = 11.5, 21.8, 22.0, 22.8, 24.9, 30.3,
35.5, 38.6, 39.0, 74.1, 86.1, 127.2, 128.1, 128.6, 135.8, 175.3.
HHCC=O), 4.47 (dd, J = 6.6, 4.4 Hz, 1 H, HCOH), 4.63 (d, J = 7.3
Hz, 2 H, H2C-O), 5.23–5.35 (m, 1 H, =CH).
13C NMR (75.5 MHz, CDCl3): d = 17.9, 25.6, 38.5, 62.8, 67.2,
117.7, 140.2, 173.3, 175.5.
MS: m/z (%) = 202 (2), 187 (1), 85 (60), 71 (14), 69 (100).
Anal. Calcd for C9H14O5: C, 53.5; H, 6.9. Found: C, 53.7; H, 6.7.
MS: m/z (%) = 286 [M+], 268 (55), 257 (80), 223 (62), 181 (31), 118
(100).
1-(3-Methylbut-2-enyl) 4-[2-(Trimethylsilyl)ethyl] 2-Hydroxy-
butanedioate (25)
HRMS (EI): m/z [M+] calcd for C18H22O3: 286.15689; found:
286.15690.
A mixture of DCC (5.19 g, 25.2 mmol), 2-(trimethylsilyl)ethanol
(3.70 g, 25.0 mmol), and a catalytic amounts of CuCl2 was stirred at
r.t. for 6 h. Then a soln of 24 (4.95 g, 24.5 mmol) in THF (50 mL)
was added and the resulting mixture was heated under reflux for 16
h. Byproduct urea was precipitated in a fridge and removed by fil-
tration. The filtrate was concentrated in vacuo and the remainder
was purified by chromatography (silica gel; cyclohexane–EtOAc,
5:1); yield: 4.40 g (60%).
( )-4-Hydroxy-1,4-dimethyl-2-phenyl-11-oxa-
dispiro[2.1.5.2]dodecan-12-one (21a)
A soln of ( )-16a (300 mg, 1.06 mmol) in THF (20 mL) was slowly
treated at r.t. with 1.6 M MeLi in Et2O (0.75 mL, 1.20 mmol). The
resulting mixture was stirred for a further 16 h and then filtered
through a small plug of silica gel. Evaporation of the filtrate and col-
umn chromatography of the residue (silica gel 60, Et2O–hexane,
1:1) left pure crystalline 21a; yield: 288 mg (90%); mp 190 °C.
IR (ATR): 3491, 1734, 1249, 1165 cm–1.
1H NMR (CDCl3): d = –0.03 (s, 9 H, SiMe), 0.87–0.97 (m, 2 H,
SiCH2), 1.65 (s, 3 H, Me), 1.69 (s, 3 H, Me), 2.68 (dd, J = 16.3, 6.2
Hz, 1 H, HHCC=O), 2.76 (dd, J = 16.3, 4.5 Hz, 1 H, HHCC=O),
3.32 (s, 1 H, OH), 4.07–4.17 (m, 2 H, OCH2), 4.36–4.44 (m, 1 H,
HCOH), 4.62 (d, J = 7.3 Hz, 2 H, H2CO), 5.27 (t, J = 7.3 Hz, 1 H,
=CH).
IR (KBr): 3423, 1724, 961 cm–1.
1H NMR (CDCl3): d = 0.79 (s, 3 H, Me), 1.34 (d, J = 6.3 Hz, 3 H,
Me), 1.38–1.78 (m, 11 H), 2.09–2.16 (m, 1 H), 2.89 (d, J = 7.8 Hz,
1 H, HCPh), 7.23–7.34 (m 5 H, Ph).
13C NMR (75.5 MHz, CDCl3): d = 11.8, 20.5, 21.2, 21.5, 25.0, 25.3,
27.2, 33.3, 34.8, 42.0, 80.0, 89.2, 127.1, 127.6, 128.1, 128.6, 134.6,
175.2.
13C NMR (75.5 MHz, CDCl3): d = –1.6, –1.5, 17.2, 18.0, 25.7, 38.8,
62.7, 63.2, 67.2, 117.7, 140.0, 169.3, 173.3.
MS: m/z (%) = 301 (1), 300 [M+] (6), 283 (13), 282 (44), 237 (22),
MS: m/z (%) = 302 [M+] (1), 217 (1), 173 (18), 131 (27), 73 (100).
194 (27), 117 (51), 43 (100).
HRMS (EI): m/z [M+] calcd for C19H24O3: 300.17255; found:
Anal. Calcd for C14H26O5Si: C, 55.6; H, 8.6. Found: C, 55.7; H, 8.4.
300.17258.
4-(3-Methylbut-2-enyloxy)-5-({[2-(trimethylsilyl)ethoxy]carbo-
nyl}methyl)furan-2(5H)-one (26)
( )-4-Hydroxy-1-methyl-2,4-diphenyl-11-oxa-
dispiro[2.1.5.2]dodecan-12-one (21b)
Analogously to the synthesis of 21a, 21b was obtained from ( )-16a
(150 mg, 0.5 mmol) and 1.6 M PhLi in toluene (0.60 mL, 1.0
mmol). Chromatography (silica gel 60, Et2O–hexane, 1:4) gave 21b
as a white solid; yield: 110 mg (58%); mp 183 °C.
A mixture of 3 (2.12 g, 7.0 mmol), 25 (1.65 g, 5.5 mmol), benzoic
acid (133 mg, 1.1 mmol), and THF (50 mL) was heated at 55 °C for
16 h. All volatiles were removed and the residue was purified by
column chromatography (silica gel, cyclohexane–EtOAc 3:1). Con-
centration of the eluate left tetronate 26 as a colorless oil; yield: 1.23
g (65%).
IR (KBr): 3429, 2932, 1732, 1447, 1274, 1101, 766 cm–1.
IR (ATR): 1762, 1735, 1628, 1312, 1249, 1166, 1151, 1040, 858
cm–1.
1H NMR (CDCl3): d = 1.33 (d, J = 6.5 Hz, 3 H, Me), 1.04–1.96 (m,
10 H), 2.11 (d, J = 8.2 Hz, 1 H, HCPh), 2.39 (dq, J = 8.2, 6.5 Hz, 1
H, HCMe), 2.85 (s, 1 H, OH), 7.09–7.85 (m, 10 H, Ph).
13C NMR (75.5 MHz, CDCl3): d = 13.5, 21.1, 21.3, 24.7, 26.4, 32.8,
34.4, 45.1, 50.0, 83.2, 126.8, 126.9, 127.0, 127.7, 128.3, 128.5,
135.4, 142.6, 175.5.
MS: m/z (%) = 344 [M+ – H2O] (14), 264 (12), 255 (100), 173 (19),
105 (74), 77 (15).
HRMS (EI): m/z [M+] calcd for C24H26O3: 362.46144; found:
362.46138.
1H NMR (CDCl3): d = –0.08 (s, 9 H, SiMe), 0.80–0.92 (m, 2 H,
SiCH2), 1.60 (s, 3 H, Me), 1.67 (s, 3 H, Me), 2.43 (dd, J = 16.3, 8.4
Hz, 1 H, HHCC=O), 2.71 (dd, J = 16.3, 4.0 Hz, 1 H, HHCC=O),
4.03–4.12 (m, 2 H, OCH2), 4.44 (d, J = 7.1 Hz, 2 H, =CCH2), 4.96
(s, 1 H, H3), 4.99–5.05 (m, 1 H, H5), 5.23–5.32 (t, J = 7.1 Hz, 1 H,
=CH).
13C NMR (75.5 MHz, CDCl3): d = –2.2, –2.0, –1.9, 17.0, 17.8, 25.4,
37.0, 63.1, 69.3, 74.8, 88.8, 116.6, 140.9, 168.0, 171.7, 179.8.
MS: m/z (%) = 326 [M+] (1), 283 (38), 235 (14), 239 (22), 208 (42),
181 (26), 164 (42), 149 (62), 137 (23), 95 (23), 73 (100).
3-Hydroxy-4-(3-Methylbut-2-enyl)oxybutanoic acid (24)
Anal. Calcd for C16H26O5Si: C, 58.9; H, 8.0. Found: C, 59.1; H, 7.8.
A mixture of malic acid (23, 5.43 g, 40.5 mmol) and TFAA (34.00
g, 161.9 mmol) was stirred at r.t. for 90 min and then concentrated
in vacuo to give a precipitate of the mixed anhydride. This was
treated with 3-methylbut-2-en-1-ol (10.49 g, 122.0 mmol), the re-
sulting mixture was stirred at r.t. for 3.5 h and then evaporated to
leave an oil. This was purified by column chromatography (silica
gel, cyclohexane–EtOAc–AcOH, 5:2:1); Rf = 0.26 (cyclohexane–
EtOAc, 1:1). The eluate was evaporated and residual TFA was re-
moved azeotropically with toluene (3 × 5 mL); yield: 6.13 g (75%).
3-(1,2-Dimethylpropylidene)-5-({[2-(trimethylsilyl)ethoxy]car-
bonyl}methyl)furan-2,4(3H,5H)-dione (27)
A soln of 26 (307 mg, 0.94 mmol) in toluene (10 mL), placed in a
sealed glass bomb tube, was heated at 170 °C for 24 h. The resulting
yellow to brownish soln was concentrated in vacuo and the oily res-
idue was purified by column chromatography (silica gel, cyclohex-
ane–EtOAc 5:1). Evaporation of the eluate afforded 27 as a faintly
yellow oil as an Z/E mixture; yield: 214 mg (70%).
IR (ATR): 3441, 3207, 1715, 1263, 1180, 1101 cm–1.
IR (ATR): 1767, 1714, 1609, 1249, 1208, 1170, 1070, 858 cm–1.
1H NMR (CDCl3): d = 1.64 (s, 3 H, Me), 1.68 (s, 3 H, Me), 2.75 (dd,
J = 16.6, 6.6 Hz, 1 H, HHCC=O), 2.85 (dd, J = 16.6, 4.4 Hz, 1 H,
1H NMR (CDCl3): d = –0.03 (s, 9 H, SiMe), 0.86–0.93 (m, 2 H,
SiCH2), 1.07/1.11 (d, J = 6.9 Hz, 6 H, HCMe2), 2.43/2.46 (s, 3 H,
Synthesis 2006, No. 22, 3902–3914 © Thieme Stuttgart · New York

3912
R. Schobert et al.
FEATURE ARTICLE
MeC=), 2.89–2.95 (m, 2 H, H2CC=O), 4.06–4.15 (m, 2 H, OCH2),
4.38 (sept, J = 6.9 Hz, 1 H, CHMe2), 4.65–4.71 (m, 1 H, H5).
13C NMR (75.5 MHz, CDCl3): d = –1.7, 15.7, 17.1, 19.7, 19.9, 20.0,
30.1, 31.4, 35.9, 63.6, 77.6, 115.3, 168.9, 189.5, 190.0, 196.9,
201.1.
17; m = 0.117 mm–1; Siemens P4 diffractometer, 7370 unique re-
flections, 2067 with I > 2s(I), 154 refined parameters. Structure so-
lution: direct methods (SHELXS97); structure refinement: full-
matrix least squares on F2 (SHELXL97); R1 = 0.0414,
wR2 = 0.0938. CCDC reference number 616240.
MS: m/z (%) = 326 [M+] (1), 311 (2), 238 (39), 239 (25), 208 (40),
181 (25), 164 (45), 149 (67), 95 (32), 73 (100).
Benzyl D-Leucinate (31)
A mixture of D-leucine (30, 2.62 g, 20.0 mmol), BnOH (8.64 g, 80.0
mmol), PTSA·H2O (4.96 g, 26.0 mmol), and benzene (150 mL) was
stirred for 16 h with azeotropic removal of H2O. The benzene was
finally distilled off until approx. 30 mL remained. The residue was
poured into vigorously stirred precooled Et2O. The ammonium ester
salt precipitated and was collected and washed with Et2O (3 × 30
mL) in a filter funnel. The solid was dried on an oil pump, dissolved
in CH2Cl2 and shaken with an excess of aq 1 M Na2CO3. The organ-
ic phase was separated, shaken with brine, separated, and dried
(Na2SO4). Drying in vacuo gave 31; yield: 4.33 g (95%).
Anal. Calcd for C16H26O5Si: C, 58.9; H, 8.0. Found: C, 58.8; H, 8.2.
5-(Carboxymethyl)-3-(1,2-dimethylpropylidene)furan-
2,4(3H,5H)-dione (28)
A soln of 27 (382 mg, 1.2 mmol) in THF (20 mL) was treated with
1 M TBAF in THF (4.70 mL, 4.7 mmol) and the resulting mixture
was stirred at r.t. until all starting material had gone by TLC (ca. 2
h). All volatiles were removed in vacuo and the remainder was par-
titioned between H2O (40 mL) and Et2O (20 mL). The ethereal
phase was discarded, the aqueous one was adjusted to a pH of 3 by
addition of 7% aq HCl. It was then extracted with EtOAc (2 × 80
mL), the combined extracts were washed with brine and dried
(Na2SO4). Evaporation in vacuo left 28 as a colorless oil as an E/Z
mixture; yield: 237 mg (90%).
IR (ATR): 3383, 2955, 1731, 1164, 1140, 696 cm–1.
1H NMR (CDCl3): d = 0.87 (t, J = 6.5 Hz, 6 H, Me), 1.40 (ddd,
J = 13.5, 8.6, 6.2 Hz, 1 H, HCCMe2), 1.54 (ddd, J = 13.5, 8.0, 5.2
Hz, 1 H, HCCMe2), 1.73 (m, 1 H, HCMe2), 1.81 (s, 2 H, NH2), 3.48
(dd, J = 8.6, 5.7 Hz, 1 H, HCN), 5.10 (s, 2 H, OCH2), 7.27–7.33 (m,
5 H, ar-H).
IR (ATR): 3225, 2931, 1709, 1645, 1605, 1208, 1171, 1069 cm–1.
1H NMR (CDCl3): d = 1.08/1.10 (d, J = 6.9 Hz, 6 H, HCMe2), 2.45/
2.47 (s, 3 H, MeC=), 2.95–3.03 (m, 2 H, H2CC=O), 4.38/4.39 (sept,
J = 6.9 Hz, 1 H, CHMe2), 4.68–4.75 (m, 1 H, H5).
13C NMR (75.5 MHz, CDCl3): d = 15.9, 16.1, 19.7, 19.9, 20.0, 20.1,
31.0, 31.2, 35.6, 77.3, 115.4, 115.6, 174.2, 190.8, 191.4, 196.6,
201.1.
(5R)-4-(Benzyloxy)-5-isobutyl-1,5-dihydro-2H-pyrrol-2-one
(32)
Benzyl D-leucinate (31, 3.32 g, 15.0 mmol) was dissolved in THF
(50 mL), treated with 3 (4.35 g, 15 mmol) and benzoic acid (0.36 g,
3 mmol) and the mixture was stirred at 60 °C for 16 h. The solvent
was removed and the remainder was purified by column chromatog-
raphy (silica gel). Eluting first with 5% acetone–CH2Cl2 gave the
byproduct Ph3PO, then eluting with 25% acetone–CH2Cl2 gave 32
as a white solid; yield: 2.57 g (70%); mp 86–88 °C; [a]D25 +8.5 (c 3,
CHCl3).
MS: m/z (%) = 226 [M+] (13), 208 (100), 193 (43), 181 (64), 164
(24), 149 (69), 137 (29), 95 (65).
Anal. Calcd for C11H14O5: C, 58.4; H, 6.2. Found: C, 58.5; H, 6.2.
4,4,5-Trimethyl-2,3,8,12-tetraoxatricyclo[7.3.0.01,6]dodec-5-en-
7,11-dione (29)
IR (ATR): 1678, 1620, 1354, 1219 cm–1.
1H NMR (CDCl3): d = 0.79 (d, J = 6.6 Hz, 3 H, Me), 0.80 (d, J = 6.6
Hz, 3 H, Me), 1.35 (ddd, J = 13.5, 9.8, 4.9 Hz, 1 H, HCCMe2), 1.59
(ddd, J = 13.5, 9.3, 3.7 Hz, 1 H, HCCMe2), 1.75 (m, 1 H, HCMe2),
4.14 (m, 1 H, H5), 4.89 (s, 2 H, OCH2), 4.92 (s, 1 H, H3), 7.18–7.23
(m, 5 H, ar-H), 7.77 (s, 1 H, NH).
13C JMOD NMR (75.5 MHz, CDCl3): d = 21.6 (Me), 23.5 (Me),
25.1 (CMe2), 41.4 (CCMe2), 56.3 (C5), 72.9 (OCH2), 94.2 (C3),
127.6, 128.5, 128.6, 134.9 (ar-C), 174.8 (C2), 177.6 (C4).
Under an atmosphere of N2, a flame-dried Schlenk tube was
charged with 28 (185 mg, 0.82 mmol), CH2Cl2 (60 mL), anhyd
CuSO4 (12 mg) and PTSA (29 mg, 0.18 mmol), stoppered and then
pressurized with dry O2 (10 mL). It was placed ca. 8 cm from a
glass-jacketed Heraeus low-pressure Hg lamp within a shared cool-
ing bath kept at r.t. and entirely wrapped in aluminum foil and irra-
diated for 1 h while vigorously stirring. The resulting yellow
mixture was filtered over a fritted Schlenk-type funnel and the fil-
trate was concentrated in vacuo at r.t. to give a yellow crude oil.
This was purified by column chromatography [1 × 15 cm, silica gel
60 (5% H2O); cyclohexane–THF, 1:1], Rf = 0.75 (cyclohexane–
THF, 1:2) to give a colorless viscous oil which solidified upon
standing; yield: 82 mg (42%); mp 120 °C (CHCl3–hexane, dec.).
MS: m/z (%) = 245 [M+] (5), 228 (2), 217 (5), 202 (4), 189 (57), 154
(8), 132 (7), 92 (22), 91 (100).
Anal. Calcd for C15H19NO2: C, 73.4; H, 7.8; N, 5.7. Found: C, 73.3;
H, 7.7; N, 5.8.
IR (ATR): 1772, 1762, 1685, 1242, 1062, 1016, 955 cm–1.
1H NMR (CDCl3): d = 1.41 (s, 3 H, Me), 1.50 (s, 3 H, Me), 2.25 (s,
3 H, Me), 2.98–3.00 (m, 2 H, CH2), 4.72–4.75 (m, 1 H, CH).
13C JMOD NMR (75.5 MHz, CDCl3): d = 14.0 (Me), 21.3 (Me),
23.2 (Me), 34.4 (CH2), 76.6 (CH), 81.4 (Cq), 105.6 (Cq), 115.6 (Cq),
158.9 (Cq), 164.4 (Cq), 171.3 (Cq).
MS: m/z (%) = 240 [M+] (3), 208 (32), 193 (12), 169 (13), 165 (13),
153 (10), 137 (22), 67 (19), 43 (100).
(5R)-5-Isobutylpyrrolidine-2,4-dione (33)
Dihydro-2H-pyrrol-2-one (32, 490 mg, 2.0 mmol) was dissolved in
MeOH (50 mL) and treated with 5% Pd/C (40 mg). The reaction
vessel was repeatedly evacuated and flushed with H2 and left to stir
at r.t. for 1 h, pressurized with 1 atm of H2. The resulting mixture
was filtered through a short plug of Celite which was washed with
MeOH (150 mL) and EtOAc (50 mL). The combined filtrates were
concentrated on an oil pump and the remainder recrystallized
(EtOAc) to give the pure keto tautomer of 33 as a yellowish solid;
yield: 307 mg (99%); mp 106 °C [Lit.67 114–116 °C for rac-33];
[a]D25 52 (c 1, CH2Cl2) [Lit.68 –55 (c 0.87, CH2Cl2) for ent-33].
HRMS (EI): m/z calcd for C11H12O6; 240.06339; found: 240.06340.
Crystal data: Clear, colorless crystals from CHCl3–hexane upon
cooling. Empirical formula C11H12O6, M = 240.21, monoclinic,
space group P2(1)/c, crystal size 0.28 × 0.24 × 0.18 mm3,
a = 7.2615(15), b = 9.6131(19), c = 16.433(3) Å, a = 90°,
b = 102.10(3)°, g = 90°, V = 1121.6(4) Å3, Z = 4, q-range 2.47–
26.01°, w/q-scans, index ranges –8 < h < 8, –11 < k < 11, –20 < l <
IR (KBr): 3176, 1769, 1682, 1288, 797 cm–1.
1H NMR (CDCl3): d = 0.90 (d, J = 6.5 Hz, 3 H, Me), 0.91 (d, J = 6.5
Hz, 3 H, Me), 1.45 (ddd, J = 13.7, 9.4, 5.5 Hz, 1 H, HCCMe2), 1.60
(ddd, J = 13.7, 8.9, 4.4 Hz, 1 H, HCCMe2), 1.70–1.77 (m, 1 H,
HCMe2), 2.98 (s, 2 H, H3), 3.98 (dd, J = 9.4, 4.4 Hz, 1 H, H5).
Synthesis 2006, No. 22, 3902–3914 © Thieme Stuttgart · New York

FEATURE ARTICLE
Tetronic and Tetramic acids
3913
13C JMOD NMR (75.5 MHz, CDCl3): d = 21.3 (Me), 23.1 (Me),
24.8 (CMe2), 40.5 (C3), 41.2 (CCMe2), 62.8 (C5), 171.7 (C2), 208.0
(C4).
MS (EI): m/z (%) = 350 [M+ + 1] (2), 349 [M+] (9), 348 [M+ – H]
(32), 333 (3), 319 (4), 305 (10), 293 (18), 292 (96), 277 (12), 263
(9), 249 (18), 221 (10), 207 (15), 193 (9), 182 (20), 153 (27), 141
(7), 140 (100), 139 (12), 112 (11), 84 (11), 69 (18).
3-[1-(Difluoroboryloxy)ethylidene]-5-isobutylpyrrolidine-2,4-
dione (34)
Acknowledgment
To a stirred soln of 33 (0.30 g, 1.9 mmol) in ethereal BF3·OEt2 (2
mL) was added AcCl (0.61 g, 7.8 mmol). After heating the mixture
at 70 °C for 4 h, further AcCl (0.61 g, 7.8 mmol) was added and
heating was continued for a further 4 h at the same temperature. The
cooled mixture was then treated with sat. aq NH4Cl (20 mL) and im-
mediately extracted with EtOAc (3 × 20 mL). The combined ex-
tracts were dried (Na2SO4) and evaporated to yield an oil, which
was purified by column chromatography (silica gel) Rf = 0.72 (hex-
ane–EtOAc, 1:1) to give yellow crystals; yield: 290 mg (61%); mp
116 °C.
Financial support by the Deutsche Forschungsgemeinschaft (grant
Scho 402/7) is gratefully acknowledged. We are indebted to Dr
Wolfgang Milius, Bayreuth, for carrying out X-ray structure analy-
ses, and to Dipl.-Ing. Sabine Dittrich, Tropeninstitut der Charité,
Berlin, and Dr Sergio Wittlin, Tropeninstitut der Universität Basel,
Switzerland, for in vitro tests of endoperoxides. Minor contribu-
tions from the group members Dr Gary Gordon (compounds 19,
21a) and Georg Rapp (compounds 20, 21b) are also acknowledged.
IR (KBr): 1704, 1648, 1026, 878, 686 cm–1.
References
1H NMR (CDCl3): d = 0.97 (d, J = 6.4 Hz, 3 H, Me), 0.98 (d, J = 6.4
Hz, 3 H, Me), 1.53–1.56 (m, 1 H, HCCMe2), 1.76–1.81 (m, 2 H,
HCCMe2 and HCMe2), 2.53 (s, 3 H, H3C-C=), 4.07 (m, 1 H, H5),
7.14 (s, 1 H, NH).
13C JMOD NMR (75.5 MHz, CDCl3): d = 21.2 (Me), 21.5 (Me),
23.1 (Me), 25.3 (CMe2), 39.9 (CCMe2), 63.3 (C5), 99.2 (C3), 173.4
(C2), 187.4 (O-C=), 191.4 (C4).
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(5R)-Reutericyclin {(5R)-3-Acetyl-1-[(E)-dec-2-enoyl]-4-hy-
droxy-5-isobutyl-1,5-dihydro-2H-pyrrol-2-one} (2)
Compound 34 (123 mg, 0.50 mmol) was placed in a Schlenk tube
and dissolved in anhyd THF (25 mL). The soln was blanketed with
argon, cooled to –78 °C and slowly treated with a 1 M NaHMDS in
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sticky solid; yield: 129 mg (74%); melting range 150–157 °C [Lit.7d
25
13
161–164 °C]; [a]D 18 (c 3, EtOH) [Lit.7d [a]D (c 0.29, EtOH)];
>95% ee (chiral HPLC on permethylated b-cyclodextrin; MeCN–
0.3% TEAA in H2O, 40:60) when compared with an authentic race-
mic sample.
IR (KBr): 2956, 2926, 2856, 1715, 1635, 1518, 1466, 1349, 1325,
1225, 1155, 1128, 1041, 980, 893, 716 cm–1.
1H NMR (CD3CN), 3:2 mixture of tautomers a/b: d = 0.86–0.93 (m,
9 Ha+b, Me2C, MeCH2), 1.23–1.35 (m, 8 Ha+b, CH2), 1.40–1.51 (m,
2 Ha+b, CH2CMe2), 1.74–1.83 (m, 1 Ha+b, CHMe2), 2.24 (q, J = 7.1
Hz, 2 Ha+b, H2CC=C), 2.45 (s, 3 Ha+b, MeCO), 4.21 (dd, J = 6.2, 4.4
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d = 13.4 (Me), 20.1/20.9 (Me), 21.9/22.0 (Me), 23.0 (Me), 24.1/
24.2 (CH2), 28.0 (CH2), 28.8 (CH2), 28.9 (CH2), 31.5 (CH2), 32.2
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Synthesis 2006, No. 22, 3902–3914 © Thieme Stuttgart · New York

3914
R. Schobert et al.
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Synthesis 2006, No. 22, 3902–3914 © Thieme Stuttgart · New York