Quinone - Annonaceous acetogenins: Synthesis and complex I inhibition studies of a new class of natural product hybrids

Article abstract of DOI:10.1002/1521-3765(20010302)7:5<993::AID-CHEM993>3.0.CO;2-S

The natural product hybrids quinone-mucocin and quinone- squamocin D were synthesized. In these hybrids, the butenolide unit of the annonaceous acetogenins mucocin and squamocin D is exchanged for the quinone moiety of the natural complex I substrate ubiq

Full text of DOI:10.1002/1521-3765(20010302)7:5<993::AID-CHEM993>3.0.CO;2-S

FULL PAPER
Quinone ± Annonaceous Acetogenins: Synthesis and Complex I Inhibition
Studies of a New Class of Natural Product Hybrids**
Sabine Arndt,[a] Ulrich Emde,[a] Stefan Bäurle,[a] Thorsten Friedrich,[b] Lutz Grubert,[a] and
Ulrich Koert*[a]
Abstract: The natural product hybrids
quinone ± mucocin and quinone- squa-
mocin D were synthesized. In these
hybrids, the butenolide unit of the
annonaceous acetogenins mucocin and
squamocin D is exchanged for the qui-
none moiety of the natural complex I
substrate ubiquinone. For both synthe-
ses, a modular, highly convergent ap-
proach was applied. Quinone ± mucocin
was constructed out of a tetrahydropyr-
an (THP) component 1, a tetrahydrofur-
an (THF) unit 2, and a quinone precur-
sor 3. A stereoselective, organometallic
coupling reaction was chosen for the
addition of the THP unit to the rest of
the molecule. In the final step, the
oxidation to the free quinone was ach-
ieved by using cerium(iv) ammonium
nitrate (CAN) as the oxidizing agent.
Quinone ± squamocin D was assembled
in a similar manner, from the chiral side
chain bromide 16, the central bis-THF
core 17, and the quinone precursor 18.
Inhibition of complex I (isolated from
bovine heart mitochondria) by the qui-
none acetogenins and several smaller
building blocks was examined; qui-
none ± mucocin and quinone ± squamo-
cin D act as strong inhibitors of complex
I. These results and the data from the
smaller substructures indicate that other
substructures of the acetogenins besides
the butenolide group, such as the poly-
ether component and the lipophilic left-
hand side chain, are necessary for the
strong binding of the acetogenins to
complex I.
Keywords: annonaceous acetoge-
nins ´ complex I inhibitors ´ natural
products
design
´ quinones ´ synthesis
Total syntheses of squamocin D[3] and mucocin[4] have
Introduction
recently been accomplished in our group.[5, 6] Squamocin D is
a typical member of the bis-THFacetogenins, which are known
to be among the most potent annonaceous acetogenins in cyto-
toxicity tests. Mucocin belongs to a small subgroup of
acetogenins bearing a tetrahydropyran (THP) ring.
The annonaceous acetogenins are a class of natural products
isolated from various plant species of the Annonaceae
(custard apple) family. They show cytotoxic, immunosuppres-
sive, pesticidal, and antimicrobial activities.[1]
Structurally, the annonaceous acetogenins are a series of
C-35/C-37 natural products. They are usually characterized by
a long aliphatic chain bearing a terminal a,b-unsaturated g-
butyrolactone with one, two, or three tetrahydrofuran (THF)
rings located along the hydrocarbon chain. To date, over 350
annonaceous acetogenins have been isolated from 37 species
and several efficient synthetic approaches to this class of
natural products have been developed.[1, 2]
O
HO
O
HO
O
O
H
H
OH OH H
H
C8H17
mucocin
O
9
O
[a] Prof. U. Koert, Dr. S. Arndt, Dr. U. Emde, Dr. S. Bäurle,
Dr. L. Grubert
H11C5
O
O
HO
OH
OH
H
H
H
H
Institut für Chemie, Humboldt-Universität zu Berlin
Hessische Strasse 1 ± 2, 10115 Berlin (Germany)
Fax : (‡49)30-20937266
squamocin D
E-mail: koert@chemie.hu-berlin.de
[b] Dr. T. Friedrich
The main mode of action of the annonaceous acetogenins is
the blockage of mitochondrial complex I (NADH: ubiqui-
none oxidoreductase).[7] Complex I of the respiratory chain is
by far the largest and most complicated of the proton-
Institut für Biochemie, Heinrich-Heine Universität
Universitätsstrasse 1, 40225 Düsseldorf (Germany)
Supporting information for this article is available on the WWW under
http://www.wiley-vch.de/home/chemistry/ or from the author.
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993

U. Koert et al.
FULL PAPER
translocating enzymes involved in oxidative phosphorylation.
Mammalian complex I has an L-shaped structure with more
than 40 subunits, possessing an NADH binding site in the
soluble domain and an ubiquinone binding site in the
membraneous domain (Figure 1). Many details of the electron
The annonaceous acetogenins are among the most potent
inhibitors of mammalian complex I.[8] They may possibly act
at the terminal electron transfer step of complex I between
the Fe ± S cluster N2 and the ubiquinone reduction step.[7]
With the goals of further investigation of the mode of action
of the annonaceous acetogenins and of providing molecular
probes for complex I studies, we designed natural product
hybrids in which the butenolide subunit of the annonaceous
acetogenins is exchanged for the quinone portion of the
natural complex I substrate ubiquinone. On the basis of our
previous synthetic work we chose quinone ± mucocin and
quinone ± squamocin D as synthetic targets. The butenolide
OMe
O
OMe
O
HO
O
O
H
H
OH OH H
H
C8H17
quinone–mucocin
OMe
O
OMe
O
H11C5
9
O
O
HO
OH
OH
H
H
H
H
Figure 1.
quinone–squamocin D
unit has some structural similarities to the quinone group, and
our goal was to investigate whether the two natural product
hybrids quinone ± mucocin and quinone ± squamocin D were
also potent complex I inhibitors.
pathway from NADH (matrix) to ubiquinone (membrane)
and the links betwee this process and the translocation of
protons are still not fully understood and are under active
investigation.[7]
Abstract in German: Berichtet wird über die Synthese der
Naturstoffhybride Chinomucocin und Chinosquamocin D. In
diesen Verbindungen ist die Butenolideinheit der Annonin-
Acetogenine Mucocin und Squamocin D durch die Chinon-
Gruppierung des natürlichen Komplex I-Substrats Ubichinon
ersetzt worden. Für die Synthese beider Verbindungen wurde
ein modularer, hoch-konvergenter Zugang angewandt. Chino-
mucocin wurde aus einem THP-Abschnitt 1, einem THF-Teil 2
und dem Chinon-Vorläufer 3 hergestellt. Eine metallorgani-
sche Additionsreaktion diente zur stereoselektiven Anküpfung
des THP-Teils an den Rest des Moleküls. Im letzten Synthese-
schritt lieû sich die freie Chinongruppierung durch eine CAN-
Oxidation generieren. Chinosquamocin D wurde auf einem
ähnlichen Weg aus dem chiralen Seitenkettenbromid 16, dem
zentralen Bis-THF-Teil 17 und dem Chinon-Vorläufer 18
aufgebaut. Die Inhibierung von aus Rinderherz-Mitochon-
drien isoliertem Komplex I durch die Chino-Annonine und
einige andere, kleinere Bausteine wurde untersucht. Chinomu-
cocin und Chinoquamocin D erwiesen sich dabei als starke
Komplex I Inhibitoren. Die Resultate weisen darauf hin, dass
neben der Butenolid-Gruppierung andere Annonin-Substruk-
turen wie etwa der Polyether-Teil oder die lipophile linke
Seitenkette für eine starke Bindung der Annonin-Acetogenine
an Komplex I notwendig sind.
Results and Discussion
Syntheses of the quinone ± acetogenins: The syntheses of the
quinone natural product hybrids were based on the modular
strategy developed for our total syntheses of mucocin[6a,b] and
squamocin D.[5] A retrosynthetic analysis of quinone ± muco-
cin implied the three building blocks 1, 2, and 3 (Scheme 1).
The advantage of this modular approach was that we could
make use of the known iodide 1 from the mucocin synthesis.
The starting point for the synthesis of the aromatic building
block 3 was treatment of ortho-lithiated 2,3,4,5-tetramethoxy-
toluene 4[9] with succinic anhydride to provide the keto
carboxylic acid 5 (Scheme 2). Reduction of 5 to a diol with
LiAlH4, followed by deoxygenation of the benzylic alcohol
function with Et3SiH/BF3 ´ OEt2 gave the primary alcohol 6.[10]
A Swern oxidation of 6 afforded the aldehyde 3.
The THF-building block 2 could be prepared from the
known THF aldehyde 7 (Scheme 3).[11] A Wittig reaction
between 7 and a C-4 phosphonium salt gave the alkene 8
(Z/E ˆ 20:1). The latter could be hydrogenated over Pt/C to 9,
which was converted into the primary alcohol 10 by cleavage
of the benzyl ether with H2 and Pd/C. One-step transforma-
tion of 8 into 10 using H2 and Pd/C had severe drawbacks,
because of side reactions at the THF moiety arising from
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Chem. Eur. J. 2001, 7, No. 5

Quinone ± Annonaceous Acetogenins
993±1005
OMe
b
H
a
O
OMe
O
O
O
HO
RO
O
RO
H
H
H
H
OBn
7
8
O
O
H
H
OH OH H
H
R = tBuPh2Si
C8H17
quinone–mucocin
c
OH
OBn
O
O
RO
RO
H
H
H
H
OMe
TBSO
9
10
MeO
OMe
OMe
H
I
OTBS
O
H
H
O
C8H17
d
1
3
PPh3
I
O
RO
H
H
2
PPh3
I
O
TBDPSO
H
H
Scheme 3. Synthesis of THF-building block 2. a) BnO(CH2)4PPh3I
(2 equiv), THF, 308C, NaHMDS (1.3 equiv), 1 h, 788C, 7 (1 equiv),
08C, 1 h, 79%; b) Pt/C, H2, EtOAc, 6 h, 95%, c) Pd/C, H2, MeOH, 16 h,
92%; d) 1. imidazole (3 equiv), PPh3 (1.1 equiv), I2 (1.2 equiv) 08C, 88%; 2.
PPh3 (3 equiv), toluene, 89%; NaHMDS ˆ sodium hexamethyldisilazide.
2
Scheme 1. Retrosynthetic analysis of quinone ± mucocin. TBS ˆ tert-butyl-
dimethylsilyl.
OMe
OMe
OMe
MeO
MeO
OMe
MeO
MeO
OMe
b
MeO
OMe
OMe
a
OH
a
b
c
O
2
O
O
TBDPSO
TBDPSO
H
H
4
5
11
12
OMe
MeO
OMe
OMe
OMe
OMe
MeO
MeO
OMe
MeO
MeO
OMe
c
H
O
H
H
OH
O
6
3
OMe
MeO
OMe
OMe
Scheme 2. Synthesis of building block 3. a) nBuLi (1.5 equiv), TMEDA, n-
hexane, 08C, 30 min, succinic anhydride (1.1 equiv), THF, 2 h, 63%; b) 1.)
LiAlH4 (5.0 equiv), THF, 3 h, 72%; 2.) Et3SiH (3 equiv), BF3 ´ OEt2
(4.5 equiv), CH2Cl2, 12 h, 88%; c) (COCl)2 (2.0 equiv), DMSO (4.0 equiv),
NEt3 (5.0 equiv), CH2Cl2, 408C, 2.5 h, 78%; TMEDA ˆ tetramethyl-
ethylenediamine.
H
O
O
H
H
13
Scheme 4. Synthesis of aldehyde 13. a)
2
(1.6 equiv), NaHMDS
(1.1 equiv), THF, 08C, 20 min, then 3 (1.0 equiv), 08C, 1 h, 87%; b) Pt/C
(0.02 equiv), H2, EtOAc, 6 h, 97%; c) 1.) TBAF (4.3 equiv), THF, 2.5 h,
95%; 2.) (COCl)2 (2.0 equiv), DMSO (4.0 equiv), NEt3 (5.0 equiv), CH2Cl2,
408C, 1.5 h, 89%. TBAF ˆ tetrabutylammonium fluoride, TBDPS ˆ tert-
butyldiphenylsilyl.
reductive cleavage of the allyl ether. After conversion of the
alcohol 10 into the corresponding iodide, the phosphonium
salt 2 was obtained by using PPh3 in toluene.
The next sequence (Scheme 4) started with a Wittig
reaction to connect the THF phosphonium salt 2 with the
aromatic aldehyde 3. The desired alkene 11 could be obtained
in 87% yield with a Z/E selectivity of 20:1. After hydro-
genation of the double bond (11 ! 12), a subsequent fluoride-
mediated removal of the TBDPS group afforded the corre-
sponding primary alcohol, which was transformed into the
aldehyde 13 by a Swern oxidation.
The final part of the synthesis required the stereoselective
coupling of the iodide 1 with the aldehyde 13 (Scheme 5). To
this end, a chelation-controlled addition of an organomagne-
sium compound prepared from the iodide 1[6a,b] to the
aldehyde 13 was examined. Because of the small scale of the
coupling reaction, the organomagnesium compound was not
produced by using magnesium turnings but by a homogeneous
method via the corresponding organolithium compound,
followed by transmetallation using MgBr2 ´ OEt2. With use
of this method, the desired alcohol 14 was obtained in 47%
yield, with 7:1 stereoselectivity. (The stereoselectivity for the
related coupling step in the mucocin synthesis was 4:1.)[6a,b]
The undesired minor epimer could be separated by chroma-
tography. After deprotection to give the triol 15, the final step
of the synthesis required the oxidation of the hydroquinone
dimethyl ether to the quinone. Cerium(iv) ammonium nitrate
(CAN)[12] was the reagent of choice, producing the target
molecule quinone ± mucocin in 68% yield.
Chem. Eur. J. 2001, 7, No. 5
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U. Koert et al.
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a
1
O
O
O
O
HO
OH
HO
OBn
H
H
H
H
H
H
H
H
a
OMe
17
19
MeO
OMe
OMe
TBSO
H
O
b
c
O
O
O
O
OBn
H
H
O
OH H
H
H
H
H
H
14
15
C8H17
TBS
20
OMe
b
MeO
OMe
OMe
HO
d
O
O
OBn
OBn
O
TBSO
H
H
H
H
O
O
H
H
OH OH H
H
21
C8H17
c
e
O
O
O
O
HO
TBSO
TBSO
H
H
H
H
H
H
22
quinone–mucocin
Scheme 5. Synthesis of quinone ± mucocin. a)
(2.4 equiv), Et2O, 1058C, 4 min, MgBr2 ´ OEt2 (2.8 equiv),
408C, 2 h, 788C, 13 (1.0 equiv) ! 108C, 2 h, 47%, diastereomer ratio
7:1, chromatographic separation of epimers; b) HF (3.8 equiv), CH3CN/
CH2Cl2, 1 h, 90%; c) pyridine-2,6-dicarboxylic acid (9.4 equiv), CAN
(8 equiv), CH3CN/H2O, 0 8C, 4 h, 68%. CAN ˆ cerium(iv) ammonium
nitrate, TBS ˆ t-butyldimethylsilyl.
1
(1.3 equiv), tBuLi
100 !
H
O
TBSO
H
H
23
Scheme 7. Synthesis of aldehyde 23. a) NaH (1.5 equiv), THF, 08C, 29%;
b) (COCl)2 (2.5 equiv), DMSO (5.5 equiv), NEt3 (7.8 equiv), CH2Cl2,
458C, 1.5 h, 89%; c) 1.) Mg, 16, 1,2-dibromoethane, 358C, 30 min, CuBr´
Me2S, 20, Et2O, 12 h; 74% 2.) Pyridinium chlorochromate, 208C, 1 h, 60%;
d) L-selectride (5 equiv), THF, 608C, 1.5 h, 77%; e) 1.) TBDMSOTf
(3.5 equiv) 2,6-lutidine (10 equiv), CH2Cl2, 08C, 2 h, 99%; 2.) Pd/C, H2,
EtOAc, 4 h, 86%; 3.) (COCl)2 (6.0 equiv), DMSO (30 equiv), NEt3
(38 equiv), CH2Cl2, 408C, 1.5 h, 89%. TBS ˆ tert-butyldimethylsilyl.
Our retrosynthetic analysis of quinone ± squamocin D sug-
gested a bis-THF core 17 and the two side chains 16 and 18
(Scheme 6).
The trans-threo-trans bis-THF diol 17 had been used
previously as a key building block in the syntheses of squa-
OMe
corresponding Grignard reagent. Addition of this Grignard
reagent to the aldehyde 20 gave two epimeric alcohols in a 2:1
ratio (Rf ˆ 0.60 and 0.63, PE/MTBE 1:1), which were oxidized
by Pyridinium chlorochromate to the ketone 21. A subsequent
stereoselective L-selectride reduction[14] of 21 afforded the
alcohol 22 in 77% yield. The stereoselectivity of the
L-selectride reduction was >98:2, as determined by NMR
spectroscopy. TBS-protection of the secondary hydroxy group
in 22, followed by the hydrogenolytic cleavage of the benzyl
ether and a subsequent Swern oxidation, provided the
aldehyde 23.
O
OMe
O
9
O
O
HO
OH
OH
H
H
H
H
quinone–squamocin D
OMe
MeO
9
OMe
OMe
Br
I
OTBS
The C-12 aldehyde 24[15] was a suitable precursor for the
right-hand side chain building block 18 (Scheme 8). Treat-
ment of 24 with the ortho-lithiated compound 4 provided 25.
Use of Et3SiH/BF3 ´ OEt2 permitted simultaneous deoxyge-
nation and removal of the trityl group[16] to afford the alcohol
26 in 81% yield. Treatment of 26 with PPh3/I2 produced the
iodide 18.
16
18
O
O
HO
OH
H
H
H
H
17
Scheme 6. Retrosynthetic analysis of quinone ± squamocin D. TBS ˆ tert-
butyldimethylsilyl.
The subsequent Grignard reaction was again carried out by
means of a homogeneous method (Scheme 9). The iodide 18
was lithiated and then transmetallated by using MgBr2 ´ OEt2.
Addition to the aldehyde 23 (mixture of epimers at the new
stereogenic center: 2:1) and a subsequent Swern oxidation
gave the ketone 27. L-selectride reduction of the ketone
provided the corresponding alcohols in 99% yield. The
mocin A and squamocin D.[5] Monobenzylation (Scheme 7) to
the benzyl ether 19 (29% 19, 32% dibenzylated compound,
17% recovered diol) and subsequent Swern oxidation pro-
vided the aldehyde 20. For the attachment of the left-hand
side chain, the bromide 16[5, 13] was converted into the
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Quinone ± Annonaceous Acetogenins
993±1005
synthesis was the oxidation of the hydroquinone dimethyl
ether 29 with CAN to provide the target compound quinone ±
squamocin D in 70% yield.
OMe
MeO
9
OMe
OMe
a
H
4
+
TrO
O
TrO
9
OH
Complex I inhibition studies: Mucocin, quinone ± mucocin,
quinone ± squamocin D, and the compounds 13 and 25 were
tested as inhibitors of complex I (Table 1). In addition, the
synthetic building blocks 30 ± 37 were also tested (Table 2).
25
24
OMe
c
b
MeO
9
OMe
OMe
18
HO
Table 1. Inhibition of the mitochondrial complex I by natural acetogenins
and quinone ± natural product hybrids.
[19]
Compound
Ki(50) IC(50)
[nm]
IC(50)
26
[mmolmg 1 protein] [mmolmg protein]
1
Scheme 8. Synthesis of iodide 18. a) nBuLi (2.2 equiv), TMEDA,
n-hexane, 08C, 2.5 h, 54%; b) Et3SiH (5 equiv), BF3 ´ OEt2 (7.5 equiv),
CH2Cl2, 14 h, 81%; c) imidazole (3 equiv), PPh3 (1.1 equiv), I2 (1.2 equiv)
08C, 4 h, 65 %.
mucocin
15
34
45
33.3
123
163
quinone ± mucocin
squamocin A
Squamocin D
29
quinone ± squamocin D
rotenone
3.6
4.9
1.0
1.3
8.7
18
4.7
1.7
1.0
6.2
2.3
1.3
a
OMe
MeO
9
OMe
OMe
H11C5
TBSO
Table 2. Inhibition of the mitochondrial complex I by annonaceous
acetogenin fragments.
O
O
O
TBSO
TBSO
HO
H
H
H
H
Compound
Ki(50) [nm]
27
30
31
32
33
34
35
36
37
> 300000
94000
173
b
OMe
42000
32000
19500
16700
2500
MeO
9
OMe
OMe
H11C5
O
O
OH
TBSO
H
H
H
H
28
c
OMe
For the complex I studies, bovine heart mitochondria were
prepared as described previously.[17] The inhibition of oxygen
uptake was measured. A Clark-type oxygen electrode
(100 mM sodium phosphate pH ˆ 7.4, 1 mm EDTA, 1 mm
MeO
9
OMe
OMe
H11C5
O
O
OH
OH
H
H
H
H
1
MgCl2, 0.5 mg mL protein) was used.[18] The known strong
29
inhibitor rotenone served as reference sample.
It was found that most of the smaller annonaceous
acetogenin fragments were only weak inhibitors of complex I
(Table 2). This suggests that all the different structural parts of
these natural productsÐthe ether core, the butenolide unit,
and two aliphatic hydrocarbon chainsÐ contribute to the
activity. Smaller units such as 30, 33, and 34, showed either no
or only very weak activity. Compounds 35 and 36 also
exhibited weak activity. If the butenolide unit and an ether
component were located in the same molecule, however,
more activity was found (37). It is remarkable that a
carboxylic acid in place of the butenolide 32 resulted in a
good inhibitor, while the corresponding benzyl ether 31 was
nearly inactive. On the basis of structural data relating to the
ubiquinone binding site of the bacterial reaction center,[21] one
could postulate a participation of the carboxylic acid in the
hydrogen bond network involved in the binding to ubiqui-
none.
d
quinone–squamocin
Scheme 9. Synthesis of quinone ± squamocin D. a) 1.) 18 (2.1 equiv), tBuLi
(3.9 equiv), Et2O, 1058C, 4 min, MgBr2 ´ OEt2 (4.9 equiv),
100 !
408C, 1.5 h, 788C, 23 (1.0 equiv) ! 08C, 3.5 h, 52%, diastereomer ratio
1:1, 2.) (COCl)2 (75 equiv), DMSO (150 equiv), NEt3 (250 equiv), CH2Cl2,
408C, 1,5 h, 96%; b) L-selectride (15 equiv), THF, 708C, 1.5 h, 99%,
diastereomer ratio 88:12, chromatographic separation of epimers; c) HF,
CH3CN/CH2Cl2, 1.5 h, 77%; d) pyridine-2,6-dicarboxylic acid (6 equiv),
CAN (12 equiv), CH3CN/H2O, 0 8C, 4 h, 70%. TBS ˆ tert-butyldimethyl-
silyl.
stereoselectivity of the reduction, determined by NMR
spectroscopy, was 88:12. The desired epimer 28 could be
isolated by column chromatography, and cleavage of its silyl
protecting groups gave the triol 29. The last step of the
Chem. Eur. J. 2001, 7, No. 5
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997

U. Koert et al.
FULL PAPER
that, apart from the electron transfer, there must be other
important structural factors involved in the binding of the
annonaceous acetogenins with complex I. The ether core and/
or lipophilic interactions with the aliphatic side chains might
also play an important role.[23]
O
O
O
OH
OH
HO
H
H
H
H
30[5]
H13C6
OBn
It has been reported that the ubiquinone reduction site is
quite large, so that the two acetogenin subunits, the buteno-
5
5
O
HO
HO
HO
H
H
H
H
lide, and the ether core could all probably bind there.[24]
A
31[5]
systematic variation of both structural featuresÐthe buteno-
lide and the ether componentsÐwould potentially be helpful
for evaluation of the critical factors for the interaction of the
annonaceous acetogenins with complex I.
H13C6
HO
CO2H
O
O
OH
H
H
H
H
32[5]
HO
HO
OH
Conclusion
H17C8
O
H17C8
O
OH
OH
H
H
H
H
33[6a,b]
34[6a,b]
The synthesis of these natural product hybrids was success-
fully accomplished by combining the ether component of the
annonaceous acetogenins with the quinone component of
ubiquinone. Our modular approach to these hybrid natural
products allows efficient synthetic access to compounds with
different moieties substituting for the butenolide moiety. The
novel natural product hybrids are strong inhibitors of com-
plex I of the respiratory chain. Natural product hybrids like
quinone ± mucocin and quinone ± squamocin D offer the po-
tential to be useful probes for complex I studies. It has been
demonstrated that the butenolide moiety of the annonaceous
acetogenins can be exchanged for the quinone of ubiquinone.
Considering all the facts, it is becoming clearer that more than
one structural entity is responsible for enzyme inhibition in
the interaction of complex I with the annonaceous acetoge-
nins.
O
HO
O
35[25]
OBn
5
O
H
O
HO
OH
H
H
H
36[5]
O
HO
O
H
O
O
H
H
37[6a,b]
Experimental Section
The quinone ± acetogenins are very good inhibitors of
complex I: quinone ± mucocin is ten times more active than
mucocin itself. In contrast, the hydroquinone ± mucocin
dimethyl ether 13 showed less activity than the natural
product. Quinone ± squamocin D and the hydroquinone ±
squamocin dimethyl ether 25 also displayed activities in the
nanomolar range.
These results emphasize the importance of the butenolide
unit for inhibitor activity.[20] However, it is possible to
substitute this structural unit with a quinone group without
loss of activity, and by a carboxylic acid with only a little loss
of activity. Therefore, these structural features probably
interact with complex I in a related fashion.
Despite these structural similarities, the reduction poten-
tials of ubiquinone and a butenolide unit are very different.
The reduction potential of an a-alkyl-a,b-unsaturated butyro-
lactone (Ep ˆ 2.69 V (irreversible), CH3CN versus SCE) is
much more negative than the reduction potentials of the
quinone group (Ep(cI) ˆ 0.75 V, Ep(cII) ˆ 1.48 V, CH3CN
versus SCE).[22]
Therefore, an electron transfer from the ubiquinone
reduction side cannot be ruled out in the case of the
quinone-natural product hybrids, while the butenolide unit
of the annonaceous acetogenins should not be reduced under
physiological conditions. It is therefore reasonable to assume
General: All boiling points and melting points are uncorrected values. IR:
Biorad FTS 3000MX. NMR: Bruker AC-300, DPX-300, and AMX-600.
For 1HNMR, CDCl3 as solvent dH ˆ 7.24; for 13CNMR, CDCl3 as solvent
dc ˆ 77.0. Elemental analysis: CHN Rapid (Heraeus), CHNS-932 Analy-
sator (Leco). HR-MS: Finnigan MAT 95. All reactions were performed
under an inert atmosphere of argon in oven- or flame-dried glassware.
HPLC: Rainin ± Dynamax, SD-200 and SD-1, PDA1. Dry solvents: THF,
Et2O, benzene, and toluene were distilled from sodium benzophenone.
Pyridine, Et3N, and CH2Cl2 were distilled from CaH2. All commercially
available reagents were used without purification unless otherwise noted.
All reactions were monitored by thin layer chromatography (TLC) carried
out on Merck F-254 silica glass plates viewed under UV light and/or by
heat-gun treatment with 5% phosphomolybdic acid in ethanol. Column
chromatography and flash column chromatography were performed with
Merck silica gel 60 (70 ± 200 mesh and 230 ± 400 mesh). PE: light petroleum
ether, b.p. 40 ± 608C; MTBE: methyl tert-butyl ether.
4-(2',3',4',5'-Tetramethoxy-6'-methylphenyl)-4-oxo-butyric acid (5): Tetra-
methoxytoluene 4 (0.48 g, 2.26 mmol) was dissolved in n-hexane (5 mL).
TMEDA (0.67 mL, 4.52 mmol) and nBuLi (1.34 mL, 3.30 mmol) were
added slowly at 08C. After 30 min, the yellow suspension was diluted with
THF (25 mL) and succinic anhydride (236 mg, 2.36 mmol) in THF (5 mL)
was added. After 2 h, the reaction was quenched by the addition of
saturated aqueous NH4Cl (5 mL). The aqueous layer was extracted with
MTBE (2 Â 15 mL). The combined organic layers were dried with MgSO4
and the solvents were evaporated. The residue contained unconsumed
tetramethoxytoluene
4 (321 mg, 1.51 mmol). The aqueous layer was
acidified with NaHSO4 solution (1m) and extracted with ethyl acetate
(3 Â 10 mL). The combined organic layers were washed with saturated
998
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0947-6539/01/0705-0998 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 5

Quinone ± Annonaceous Acetogenins
993±1005
aqueous NaCl (10 mL) and dried with MgSO4. The solvents were removed
in vacuo. The crude product was purified by column chromatography (20 g
silica, CH2Cl2/acetone/HOAc 220:20:1) to provide 5 (147 mg, 0.47 mmol,
63% yield based on conversion) as a colorless solid. Rf ˆ 0.39 (CH2Cl2/
acetone 11:1, 1% HOAc); IR (film): nÄ ˆ 3516(s), 2939(s), 2874(m), 1710(s),
6.33 mmol, 1m in THF) was added dropwise. After stirring for 1 h at 20oC,
the orange solution was cooled to
788C and aldehyde 7 (1.80 g,
4.87 mmol), dissolved in THF (5 mL) and cooled to 788C, was added.
After 1 h at 08C, the reaction was quenched by the addition of saturated
aqueous NH4Cl (20 mL). The aqueous layer was extracted with MTBE
(3 Â 40 mL) and the combined organic layers were washed with saturated
aqueous NaCl (30 mL) and dried with MgSO4. The solvents were removed
in vacuo. The residue was purified by column chromatography (100 g silica,
PE/MTBE 20:1) to yield the alkene 8 (1.97 g, 3.83 mmol, 79%) as a
colorless oil. Z/E ˆ 20:1 (1HNMR); Rf ˆ 0.18 (n-hexane/MTBE 20:1); [a]D23
1585(w), 1467(s), 1360(s), 1275(m), 1091(m), 1040(m), 1000(m), 962(m),
1
846(w), 842(w) cm
;
1HNMR (300 MHz, CDCl3): d ˆ 2.05 (s, 3H; Me),
2.74 (t, J ˆ 6.5 Hz, 2H; 3-H2), 3.07 (t, J ˆ 6.5 Hz, 2H; 2-H2), 3.76 (s, 3H;
OMe), 3.78 (s, 3H; OMe), 3.87 (s, 3H; OMe), 3.90 (s, 3H; OMe); 13CNMR
(75 MHz, CDCl3): d ˆ 11.9 (6-Me), 27.7, 39.4 (C-2, C-3), 60.7, 61.1, 61.2, 61.9
(2', 3', 4', 5'-OMe), 123.3, 131.1 (C-1', C-6'), 144.5, 146.0, 148.0, 148.2 (C-2',
C-3', C-4', C-5'), 177.7 (C-1), 204.3(C-4); elemental analysis (%) for
C15H20O7 (312.32): calcd: C 57.69, H 6.46; found: C 57.42, H 6.94.
15.2 (c ˆ 0.52, CHCl3); IR (film): nÄ ˆ 3446(s), 2930(s), 2857(s), 1639(m),
1
1428(m), 1362(w), 1113(s), 1074(m), 739(m), 701(s), 613(m), 505(m) cm
;
1HNMR (300 MHz, CDCl3): d ˆ 1.05 (s, 9H; SiC(CH3)3), 1.48 ± 1.74 (m,
3H; 4,4'-H2), 1.79 ± 1.95 (m, 1H; 3-H2), 1.97 ± 2.11 (m, 2H; 3,4-H2), 2.11 ±
2.21 (m, 2H; 3'-H2), 3.43 (t, J ˆ 6.6 Hz, 2H; 5'-H2), 3.66 (d, J ˆ 5.8 Hz, 2H;
CH2-OTBDPS), 4.09 ± 4.24 (m, 1H; 2-H), 4.46 (s, 2H; CH2-Ph), 4.66 ± 4.79
(m, 1H; 5-H), 5.36 ± 5.55 (m, 2H; 1',2'-H), 7.29 ± 7.39 (m, 11H; Ph,SiPh),
7.65 ± 7.70 (m, 4H; SiPh); 13CNMR (75 MHz, CDCl3): d ˆ 19.3 (SiC(CH3)3),
24.3 (C-3'), 26.8 (SiC(CH3)3), 28.5 (C-3), 29.8 (C-4'), 33.3 (C-4), 66.6 (CH2-
OTBDPS), 69.7 (C-5'), 72.9 (CH2-Ph), 75.0 (C-5), 79.1 (C-2), 127.6 (SiPh),
128.3 (Ph), 129.5 (SiPh), 131.4, 131.5 (C-1', C-2'), 133.7 (SiPh), 135.6 (SiPh),
1-(4'-Hydroxybutyl)-2,3,4,5-tetramethoxy-6-methylbenzene (6): Com-
pound 5 (256 mg, 0.82 mmol), dissolved in THF (1 mL), was added
dropwise to a suspension of LiAlH4 (156 mg, 4.10 mmol) in THF (7 mL) at
08C. After stirring for 3 h at 20oC, the reaction was quenched by slow
addition of H2O (0.16 mL), 2 n NaOH (0.48 mL), and H2O (0.16 mL). The
suspension was refluxed for 10 min, filtered through a pad of Celite, and
washed with THF. Solvent was removed in vacuo. Column chromatography
(10 g silica, MTBE) of the residue afforded the diol (1.77 mg, 0.59 mmol,
72%) as a colorless oil.
‡
138.6 (Ph); HRMS: (EI): found: 513.2818 [M H] ; calcd: 513.2825.
(2S,5R)-2-tert-Butyldiphenylsilyloxymethyl-5-(5'-benzyloxypentyl)tetra-
hydrofuran (9): Pt/C (37 mg, 10 mmol, 5% Pt on C) was suspended in
AcOEt (25 mL). The mixture was degassed and stirred under hydrogen
atmosphere. Alkene 8 (831 mg, 1.61 mmol), dissolved in AcOEt (1 mL),
was added and the mixture was stirred vigorously for 6 h. Then the solution
was filtered through a pad of silica gel, which was washed with AcOEt
1-(1',4'-Dihydroxybutyl)-2,3,4,5-tetramethoxy-6-methylbenzene: Rf ˆ 0.21
(MTBE); IR (film): nĈ 3395(s), 2938(s), 2868(m), 1584(w), 1467(s),
1343(s), 1264(w), 1196(m), 1108(s), 1083(s), 1036(s), 962(m),
1
884(w) cm
;
1HNMR (300 MHz, CDCl3): d ˆ1.65 ± 1.89 (m, 4H; 2', 3'-
H2), 2.14 (s, 3H; Me), 3.62 ± 3.71 (m , 2H; 4'-H2), 3.73 (s, 3H; OMe), 3.84 (s,
3H; OMe), 3.88 (s, 3H; OMe), 3.92 (s, 3H; OMe), 4.77 ± 4.83 (m, 1H; 1'-
H); 13CNMR (75 MHz, CDCl3): d ˆ 11.5 (6-Me), 30.3, 35.6 (C-2', C-3'), 60.7,
60.9, 61.0, 61.4 (2,3,4,5-OMe), 62.8, 71.4 (C-1', C-4'), 123.8, 130.0 (C-1, C-6),
144.6, 146.1, 147.7, 147.8 (C-2, C-3, C-4, C-5).
(40 mL), and the solvent was evaporated. The residue
9 (790 mg,
1.53 mmol, 95%) was a colorless oil; it was spectroscopically pure and
needed no further purification. Rf ˆ 0.38 (n-hexane/MTBE 10:1); [a]D23
ˆ
1.6 (c ˆ 0.52, CHCl3); IR (film): nĈ 3446(s), 2933(s), 2857(s), 1425(m),
The diol (196 mg, 0.65 mmol) was dissolved in CH2Cl2 (4 mL) and cooled to
788C. Et3SiH (0.31 mL, 1.96 mmol) and BF3 ´ OEt2 (0.37 mL, 2.94 mmol)
were added and the reaction mixture was stirred for 12 h. Then a saturated
aqueous sodium bicarbonate solution (4 mL) was added and the aqueous
layer was extracted with MTBE (3 Â 5 mL). The combined organic layers
were washed with saturated aqueous NaCl (5 mL) and dried with MgSO4,
and the solvents were removed in vacuo. The residue was purified by flash
column chromatography (10 g silica, MTBE) to yield alcohol 6 (163 mg,
1362(w), 1193(w), 1110(s), 1002(m), 822(m), 739(m), 702(s), 613(w),
1
506(m) cm
;
1HNMR (300 MHz, CDCl3): d ˆ 1.04 (s, 9H; SiC(CH3)3),
1.25 ± 1.51 (m, 7H; 4,1',2',3'-H2),1.53 ± 1.67 (m, 2H; 4'-H2), 1.74 ± 1.88 (m,
1H; 3-H2), 1.94 ± 2.06 (m, 2H; 3,4-H2), 3.45 (t, J ˆ 6.8 Hz, 2H; 5'-H2), 3.60 ±
3.65 (m, 2H; CH2-OTBDPS), 3.84 ± 3.95 (m, 1H; 5-H), 4.09 ± 4.15 (m, 1H;
2-H), 4.49 (s, 2H; CH2-Ph), 7.26 ± 7.39 (m, 11H; Ph, SiPh), 7.65 ± 7.70 (m,
4H; SiPh); 13CNMR (75 MHz, CDCl3): d ˆ 19.2 (SiC(CH3)3), 26.2, 26.3 (C-
2', C-3'), 26.8 (SiC(CH3)3), 28.1 (C-3), 29.7 (C-4'), 32.0 (C-4), 35.8 (C-1'),
66.6 (CH2-OTBDPS), 70.4 (C-5'), 72.8 (CH2-Ph), 78.8 (C-2), 79.5 (C-5),
127.6 (SiPh), 128.3 (Ph), 129.5 (SiPh), 133.7 (SiPh), 135.6 (SiPh), 138.7 (Ph);
elemental analysis calcd (%) for C33H44O3Si (516.80): C 76.70, H 8.58;
found: C 76.59, H 8.61.
0.57 mmol, 88%) as
a
colorless oil. Rf ˆ 0.79 (MTBE); IR (film):
nÄ ˆ 3432(s), 2937(s), 2864(m), 1584(w), 1467(s), 1352(m), 1260(m),
1
1196(m), 1106(s), 1059(s), 1033(s), 976(m), 880(m) cm
;
1HNMR
(300 MHz, CDCl3): d ˆ 1.40 ± 1.72 (m, 4H; 2',3'-H2), 2.14 (s, 3H; Me),
2.58 ± 2.65 (m, 2H; 1'-H2), 3.68 ± 3.72 (m, 2H; 4'-H2), 3.76 (s, 3H; OMe),
3.80 (s, 3H; OMe), 3.87 (s, 3H; OMe), 3.88 (s, 3H; OMe); 13CNMR
(75 MHz, CDCl3): d ˆ 11.6 (6-Me), 26.3, 26.4 (C-2', C-3'), 32.7 (C-1'), 60.6,
61.0, 61.1, 61.1 (2,3,4,5-OMe), 62.8 (C-4'), 124.9, 129.7 (C-1, C-6), 144.6,
145.1, 147.6, 147.7 (C-2, C-3, C-4, C-5); elemental analysis calcd (%) for
C15H24O5 (284.35): C 63.36, H 8.51; found: C 63.60, H 8.64.
(2S,5R)-2-tert-Butyldiphenylsilyloxymethyl-5-(5'-hydroxypentyl)tetrahy-
drofuran (10): Pd on activated carbon (10%, 61 mg, 57 mmol) was
suspended in MeOH (2 mL) at 08C. The mixture was degassed and stirred
under a hydrogen atmosphere for 5 min. A solution of the benzyl ether 9
(390 mg, 0.755 mmol) in AcOEt (1 mL) was added, and the mixture was
vigorously stirred at room temperature for 16 h. The suspension was
filtered through a pad of silica gel, which was washed with AcOEt (30 mL).
The solvents were removed in vacuo and the residue was purified by
column chromatography (15 g silica, PE/MTBE 2:1). The alcohol 10
(297 mg, 0.696 mmol, 92%) was obtained as a colorless oil. Rf ˆ 0.25 (n-
hexane/MTBE 2:1); [a]2D3 ˆ 3.4 (c ˆ 0.96, CHCl3); IR (film): nĈ 3401(m),
2931(s), 2858(s), 1428(m), 1188(w), 1113(s), 1084(m), 1006(m), 824(m),
741(m), 702(s), 614(m), 505(m) cm 1; 1HNMR (300 MHz, CDCl3): d ˆ 1.04
(s, 9H; SiC(CH3)3), 1.25 ± 1.51 (m, 7H; 4,1',2',3'-H2),1.52 ± 1.62 (m, 2H; 4'-
H2), 1.74 ± 1.87 (m, 1H; 3-H2), 1.93 ± 2.04 (m, 2H; 3,4-H2), 3.57 ± 3.66 (m,
4H; CH2-OTBDPS, 5'-H2), 3.85 ± 3.95 (m, 1H; 5-H), 4.07 ± 4.15 (m, 1H;
2-H), 7.29 ± 7.44 (m, 6H; SiPh), 7.63 ± 7.71 (m, 4H; SiPh); 13CNMR
(75 MHz, CDCl3): d ˆ 19.2 (SiC(CH3)3), 25.8, 26.2 (C-2', C-3'), 26.8
(SiC(CH3)3), 28.1 (C-3), 32.0 (C-4), 32.7 (C-4'), 35.8 (C-1'), 62.9 (C-5'),
66.6 (CH2-OTBDPS), 78.8 (C-2), 79.5 (C-5), 127.6, 129.5, 133.7, 135.6
(SiPh); elemental analysis calcd (%) for C26H38O3Si (426.67): C 73.19, H
8.98; found: C 73.11, H 8.99.
1-(4'-Oxo-butyl)-2,3,4,5-tetramethoxy-6-methylbenzene
(3):
DMSO
(0.17 mL, 2.55 mmol) was added at 788C to a solution of oxalyl chloride
(0.11 mL, 1.28 mmol) in CH2Cl2 (10 mL). After 5 min stirring, a solution of
the alcohol 6 (180 mg, 0.63 mmol) in CH2Cl2 (1 mL) was added dropwise.
After stirring for 15 min, NEt3 (0.44 mL, 3.19 mmol) was added dropwise.
The mixture was stirred for 2.5 h ( 788C ! 408C). The reaction was
quenched by addition of water (10 mL). The aqueous layer was extracted
with MTBE (3 Â 15 mL) and the combined organic layers were washed
with saturated aqueous NaCl (15 mL) and dried with MgSO4. The solvents
were removed in vacuo and the residue was purified by column
chromatography (10 g silica, PE/MTBE 2:1) to yield aldehyde 3 (138 mg,
0.49 mmol, 78%) as a colorless oil. Rf ˆ 0.31 (n-hexane/MTBE 2:1);
1HNMR (300 MHz, CDCl3): d ˆ 1.74 ± 1.79 (m, 2H; 2'-H2), 2.14 (s, 3H;
Me), 2.44 ± 2.48 (m, 2H; 3'-H2), 2.56 ± 2.64 (m, 2H; 1'-H2), 3.74 (s, 3H;
OMe), 3.78 (s, 3H; OMe), 3.86 (s, 3H; OMe), 3.87 (s, 3H; OMe), 9.74 ± 9.76
(m, 1H; 4'-H); 13CNMR (75 MHz, CDCl3): d ˆ 11.6 (6-Me), 22.3, 26.0 (C-1',
C-2'), 43.4 (C-3'), 60.6, 60.9, 61.0, 61.0 (2,3,4,5-OMe), 125.0, 128.6 (C-1,
C-6), 144.5, 145.1, 147.7, 147.8 (C-2, C-3, C-4, C-5), 202.5 (C-4').
Preparation of the phosphonium salt (2): Iodine (536 mg, 2.11 mmol) was
added to a solution of imidazole (359 mg, 5.27 mmol) and PPh3 (509 mg,
1.94 mmol) in CH2Cl2 (10 mL) at 08C. The solution was stirred for 5 min,
and the alcohol 10 (750 mg, 1.76 mmol), dissolved in CH2Cl2 (2 mL), was
then added slowly. The reaction mixture was stirred for 4 h with exclusion
(2S,5R,Z)-2-tert-Butyldiphenylsilyloxymethyl-5-(5'-benzyloxypent-1'-
enyl)tetrahydrofuran (8): BnO-(CH2)4-PPH3I (5.38 g, 9.74 mmol) was
dissolved in THF (50 mL) and cooled to 308C. NaHMDS (6.33 mL,
Chem. Eur. J. 2001, 7, No. 5
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0705-0999 $ 17.50+.50/0
999

U. Koert et al.
FULL PAPER
of light. It was then quenched by the addition of an aqueous Na2S2O3
solution (10 mL). The aqueous layer was extracted with MTBE (3 Â
20 mL). The combined organic layers were washed with saturated aqueous
NaCl (10 mL) and dried with MgSO4. The solvents were removed in vacuo.
The crude product was purified by flash column chromatography (20 g
silica, PE/MTBE 20:1) to yield the iodide (836 mg, 1.54 mmol, 88%) as a
colorless oil.
a colorless oil, which was spectroscopically pure and needed no further
purification. Rf ˆ 0.19 (n-hexane/MTBE 10:1); [a]2D3 ˆ 0.4 (c ˆ 1.01,
CHCl3); IR (film): nĈ 2930(s), 2857(s), 1586(w), 1466(s), 1411(m),
1
1352(m), 1110(s), 880(w), 821(w), 740(w), 704(m), 614(w), 502(m) cm
;
1HNMR (300 MHz, CDCl3): d ˆ 1.03 (s, 9H; SiC(CH3)3), 1.24 ± 1.59 (m,
17H; 4, 1',2',3',4',5',6',7',8'-H2), 1.73 ± 1.88 (m, 1H; 3-H2), 1.92 ± 2.02 (m, 2H;
3, 4-H2), 2.14 (s, 3H; 6''-Me), 2.51 ± 2.57 (m, 2H; 9'-H2), 3.61 ± 3.65 (m, 2H;
CH2-OTBDPS), 3.76 ± 3.88 (m, 13H; 5-H, 2'',3'',4'',5''-OMe), 4.11 ± 4.19 (m,
1H; 2-H), 7.29 ± 7.44 (m, 6H; SiPh), 7.63 ± 7.71 (m, 4H; SiPh); 13CNMR
(75 MHz, CDCl3): d ˆ 11.6 (6''-Me), 19.2 (SiC(CH3)3), 26.4 (C-2'), 26.8
(SiC(CH3)3), 27.0, 28.1, 29.5, 29.6, 29.7, 29.8, 30.1, 30.4 (C-3, 3',4',5',6',7',8',9'),
32.0 (C-4), 35.9 (C-1'), 60.6, 61.0, 61.0, 61.1 (2'',3'',4'',5''-OMe), 66.6 (CH2-
OTBDPS), 78.8 (C-2), 79.6 (C-5), 124.9, 130.4 (C-1'', C-6''), 127.6, 129.5,
133.8, 135.6 (SiPh), 144.3, 144.4, 147.7, 147.7 (C-2'', C-3'', C-4'', C-5''); calcd
(%) for C41H60O6Si (677.01): C 72.74, H 8.93; found: C 72.59, H 8.85.
(2S,5R)-2-Formyl-5-(9'-(2'',3'',4'',5''-tetramethoxy-6''-methylphenyl)-nonyl)-
tetrahydrofuran (13): Silyl ether 12 (224 mg, 0.33 mmol) and TBAF
(460 mg, 1.45 mmol) were dissolved in THF (30 mL). After 2.5 h, the
reaction was quenched by addition of saturated aqueous NH4Cl (10 mL).
AcOEt (10 mL) was added, the phases were separated, and the aqueous
layer was extracted with AcOEt (4 Â 20 mL). The combined organic layers
were washed with saturated aqueous NaCl (2 Â 20 mL), dried with MgSO4,
and the solvents were removed in vacuo. The residue was purified by
column chromatography (20 g silica, PE/MTBE 1:1) to yield the alcohol
(136 mg, 0.31 mmol, 95%) as a colorless oil.
(2S,5R)-2-tert-Butyldiphenylsilyloxymethyl-5-(5'-iodopentyl)tetrahydro-
furan: Rf ˆ 0.23 (n-hexane/MTBE 20:1); [a]2D3 ˆ 2.0, (c ˆ 0.35, CHCl3); IR
(film): nĈ 3071(w), 2958(m), 2931(s), 2858(s), 1472(w), 1428(m), 1188(w),
1
1113(s), 1084(m), 1006(m), 824(m), 741(m), 702(s), 613(m), 505(m) cm
;
1HNMR (300 MHz, CDCl3): d ˆ 1.04 (s, 9H; SiC(CH3)3), 1.25 ± 1.60 (m,
7H; 4,1',2',3'-H2), 1.78 ± 1.89 (m, 3H; 3,4'-H2), 1.92 ± 2.05 (m, 2H; 3,4-H2),
3.16 (t, J ˆ 7.1 Hz, 2H; 5'-H2), 3.60 ± 3.66 (m, 2H; CH2-OTBDPS), 3.85 ±
3.90 (m, 1H; 5-H), 4.06 ± 4.15 (m, 1H; 2-H), 7.29 ± 7.44 (m, 6H; SiPh), 7.63 ±
7.71 (m, 4H; SiPh); 13CNMR (75 MHz, CDCl3): d ˆ 7.1 (C-5'), 19.3
(SiC(CH3)3), 25.4 (C-2'), 26.8 (SiC(CH3)3), 28.1 (C-3), 30.6 (C-3'), 32.0
(C-4), 33.5 (C-4'), 35.6 (C-1'), 66.6 (CH2-OTBDPS), 78.9 (C-2), 79.4 (C-5),
127.6, 129.5, 133.7, 135.6 (SiPh); HR-MS (EI): found: 479.0910 [M
‡
C4H9] ; calcd: 479.0903.
The iodide (836 mg, 1.56 mmol) and PPh3 (1.23 g, 4.67 mmol) were
dissolved in toluene (15 mL). The mixture was stirred for 4 d at 808C,
then cooled to room temperature, and the solvent was removed in vacuo.
The residue was washed with Et2O until the rinsing liquid was free of PPh3
(TLC). The phosphonium salt 2 (1.10 g, 1.38 mmol, 89%) was dried in
vacuo and used in the Wittig reaction without further purification; 1HNMR
(300 MHz, CDCl3): d ˆ 0.99 (s, 9H; SiC(CH3)3), 1.25 ± 1.47 (m, 5H; 4, 1', 2'-
H2), 1.55 ± 1.84 (m, 5H; 3, 3', 4'-H2), 1.88 ± 2.00 (m, 2H; 3, 4-H2), 3.50 ± 3.73
(m, 4H; CH2-OTBDPS, 5'-H2), 3.76 ± 3.86 (m, 1H; 5-H), 4.00 ± 4.09 (m, 1H;
2-H), 7.29 ± 7.41 (m, 6H; SiPh), 7.60 ± 7.81 (m, 4H; SiPh); 13CNMR
(75 MHz, CDCl3): d ˆ 19.2 (SiC(CH3)3), 22.7 (C-5'), 23.4 (C-4'), 25.9 (C-
2'), 26.8 (SiC(CH3)3), 28.1 (C-3), 30.4 (C-3'), 31.9 (C-4), 35.2 (C-1'), 66.5
(CH2-OTBDPS), 78.8 (C-2), 79.3 (C-5), 117.5, 118.7, 130.4, 130.6, 133.6,
135.0, 135.1 (PPh3), 127.6, 129.5, 133.7, 135.0 (SiPh).
(2S,5R)-2-Hydroxymethyl-5-(9'-(2'',3'',4'',5''-tetramethoxy-6''methylphen-
yl)-nonyl)-tetrahydrofuran: Rf ˆ 0.24 (n-hexane/MTBE 1:1); [a]2D3 ˆ 4.2
(c ˆ 0.81, CHCl3); IR (film): nĈ 3445(m), 2929(s), 2857(s), 1586(w),
1466(s), 1411(m), 1351(m), 1195(w), 1108(s), 1060(s), 1039(s), 974(m),
880(w), 724(w) cm 1; 1HNMR (300 MHz, CDCl3): d ˆ 1.23 ± 1.70 (m, 17H;
4,1',2',3',4',5',6',7',8'-H2), 1.90 ± 2.09 (m, 3H; 3, 4-H2), 2.13 (s, 3H; 6''-Me),
2.49 ± 2.55 (m, 2H; 9'-H2), 3.44 ± 3.50 (m, 1H; CH2-OH), 3.57 ± 3.64 (m, 1H;
CH2-OH), 3.76 ± 3.88 (m, 13H; 5-H, 2'',3'',4'',5''-OMe), 4.07 ± 4.12 (m, 1H;
2-H); 13CNMR (75 MHz, CDCl3): d ˆ 11.6 (6''-Me), 26.2, 27.0, 27.5, 29.4,
29.5, 29.6, 29.7, 30.1, 30.3 (C-3, 2', 3', 4', 5', 6', 7', 8', 9'), 32.0 (C-4), 35.7 (C-1'),
60.6, 61.0, 61.1, 61.1 (2'',3'',4'',5''-OMe), 65.1 (CH2-OH), 78.8 (C-2), 79.5 (C-
5), 124.8, 130.3 (C-1'', C-6''), 144.6, 144.7, 147.6, 147.7 (C-2'', C-3'', C-4'',
C-5''); calcd (%) for C25H42O6 (438.61): C 68.46, H 9.65; found: C 68.44, H
9.68.
(2S,5R)-2-tert-Butyldiphenylsilyloxymethyl-5-(9'-(2'',3'',4'',5''-tetrame-
thoxy-6''-methylphenyl)non-5'-enyl)tetrahydrofuran (11): The phosphoni-
um salt 2 (951 mg, 1.19 mmol) was suspended in THF (10 mL) and cooled
to 408C. After addition of NaHMDS (0.82 mL, 0.82 mmol, 1m in THF),
the orange solution was stirred for 20 min at 08C, and then cooled to
788C. Aldehyde 3 (210 mg, 0.74 mmol), dissolved in THF (1 mL), was
added. Stirring was maintained for 20 min at 308C and 20 min at 08C. The
reaction was quenched by addition of semisaturated aqueous NH4Cl
(5 mL). After addition of H2O (10 mL) and Et2O (10 mL), the phases were
separated and the aqueous layer was extracted with Et2O (3 Â 10 mL). The
combined organic layers were washed with saturated aqueous NaCl (2 Â
10 mL) and dried with MgSO4. The solvents were removed in vacuo. The
crude product was purified by column chromatography (20 g silica, PE/
MTBE 10:1) to afford alkene 11 (439 mg, 0.65 mmol, 87%) as a colorless
oil. Z/E ˆ 20:1 (1HNMR). Rf ˆ 0.19 (n-hexane/MTBE 10:1); [a]2D3 ˆ 0.7
(c ˆ 1.10, CHCl3); IR (film): nĈ 2933(s), 2859(s), 1586(w), 1466(s),
Oxalyl dichloride (0.052 mL, 0.59 mmol) was dissolved in CH2Cl2 (7 mL)
and the solution was cooled to 788C. DMSO (0.084 mL, 0.59 mmol) was
added. After 5 min stirring, a solution of the alcohol (130 mg, 0.296 mmol)
in CH2Cl2 (1 mL) was added dropwise. The reaction mixture was stirred for
15 min and NEt3 (0.21 mL, 1.48 mmol) was added dropwise. The mixture
was stirred for 1.5 h ( 788C ! 358C). The reaction was quenched by
addition of phosphate buffer solution (10 mL, pH ˆ 7). The aqueous layer
was extracted with MTBE (3 Â 15 mL) and the combined organic layers
were washed with saturated aqueous NaCl (20 mL) and dried with MgSO4.
The solvents were removed in vacuo and the residue was purified by
column chromatography (10 g silica, PE/MTBE 2:1) to yield aldehyde 13
(115 mg, 0.263 mmol, 89%) as a colorless oil. Rf ˆ 0.32 (n-hexane/MTBE
2:1); 1HNMR (300 MHz, CDCl3): d ˆ 1.26 ± 1.69 (m, 17H;
4,1',2',3',4',5',6',7',8'-H2), 1.85 ± 2.09 (m, 3H; 3, 4-H2), 2.12 (s, 3H; 6''-Me),
2.49 ± 2.54 (m, 2H; 9'-H2), 3.74 ± 3.88 (m, 13H; 5-H, 2'',3'',4'',5''-OMe),
1411(m), 1352(m), 1110(s), 882(w), 823(w), 740(w), 704(m), 613(w),
1
505(m) cm
;
1HNMR (300 MHz, CDCl3): d ˆ 1.03 (s, 9H; SiC(CH3)3),
1.25 ± 1.59 (m, 9H; 4, 1',2',3',8'-H2), 1.73 ± 1.89 (m, 1H; 3-H2), 1.95 ± 2.12 (m,
6H; 3,4,4',7'-H2), 2.13 (s, 3H; 6''-Me), 2.51 ± 2.57 (m, 2H; 9'-H2), 3.61 ± 3.66
(m, 2H; CH2-OTBDPS), 3.76 ± 3.88 (m, 13H; 5-H, 2'',3'',4'',5''-OMe),
4.10 ± 4.15 (m, 1H; 2-H), 5.37 ± 5.41 (m, 2H; 5', 6'-H), 7.29 ± 7.44 (m, 6H;
SiPh), 7.63 ± 7.71 (m, 4H; SiPh); 13CNMR (75 MHz, CDCl3): d ˆ 11.6 (6''-
Me), 19.2 (SiC(CH3)3), 26.1, 26.7 (C-2', C-9'), 26.8 (SiC(CH3)3), 27.3, 27.6
(C-3', C-8'), 28.1 (C-3), 29.9, 30.3 (C-4', C-7'), 32.0 (C-4), 32.7 (C-4'), 35.8
(C-1'), 60.6, 61.0, 61.1, 61.1 (2'',3'',4'',5''-OMe), 66.6 (CH2-OTBDPS), 78.8
(C-2), 79.5 (C-5), 124.9, 129.5 (C-1'', C-6''), 129.4, 130.2 (C-5', C-6'), 127.6
129.5, 133.7, 135.6 (SiPh), 144.6, 144.6, 147.8, 147.8 (C-2'', C-3'', C-4'', C-5'');
calcd (%) for C41H58O6Si (674.99): C 72.96, H 8.66; found: C 72.68, H 8.68.
ˆ
3.90 ± 4.01 (m, 2H; CH2C O), 4.25 ± 4.31 (m, 1H; 2-H), 9.63 (s, 1H;
HC O); 13CNMR (75 MHz, CDCl3): d ˆ 11.5 (6''-Me), 26.1, 27.0, 27.2, 29.4,
ˆ
29.5, 29.6, 29.7, 30.0, 30.3, 31.1 (C-3, 4, 2', 3', 4', 5', 6', 7', 8', 9'), 35.3 (C-1'),
ˆ
60.5, 60.9, 61.0, 61.1, 61.1 (2'',3'',4'',5''-OMe, CH2C O), 81.2 (C-5), 82.3 (C-
2), 124.8, 130.3 (C-1'', C-6''), 144.5, 144.6, 147.6, 147.7 (C-2'', C-3'', C-4'',
‡
ˆ
C-5''), 203.2 (C O); HRMS (EI): found: 436.2827 [M] ; calcd: 436.2825;.
19-O,23-O-Di-(tert-Butyldimethylsilyl)hydroquinone ± mucocin dimethyl
ether (14): Iodide 1 (206 mg, 0.314 mmol) was dissolved in diethyl ether
(5 mL) and the solution was cooled to 1058C. tBuLi (0.38 mL, 0.57 mmol,
1.5 m in pentane) was added, followed after 4 min by magnesium bromide
etherate (0.36 mL, 0.66 mmol, 1.83m in Et2O), and the solution was allowed
to warm to 408C over 2 h. Then the mixture was cooled to 788C and a
solution of aldehyde 13 (105 mg, 0.241 mmol) in Et2O (1 mL) was added.
The mixture was stirred for 2 h ( 788C ! 108C). The reaction was
quenched by addition of phosphate buffer solution (1m, pH ˆ 7, 2 mL). The
mixture was diluted with water (5 mL) and MTBE (10 mL). The aqueous
layer was extracted with MTBE (5 Â 7 mL) and the combined organic
(2S,5R)-2-tert-Butyldiphenylsilyloxymethyl-5-(9'-(2'',3'',4'',5''-tetrame-
thoxy-6''-methylphenyl)nonyl)tetrahydrofuran (12): Pt/C (26 mg, 7.0 mmol,
5% Pt on C) was suspended in AcOEt (6 mL) at 08C. The mixture was
degassed and stirred under hydrogen atmosphere (1 atm) for 10 min.
Alkene 11 (246 mg, 0.364 mmol), dissolved in AcOEt, (4 mL) was added
and the mixture was stirred vigorously for 6 h. Then the solution was
filtered through a pad of silica, which was washed with AcOEt (40 mL), and
the solvent was evaporated. The residue 12 (240 mg, 0.354 mmol, 97%) was
1000
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0705-1000 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 5

Quinone ± Annonaceous Acetogenins
993±1005
layers were washed with saturated aqueous NaCl (2 Â 5 mL) and dried with
MgSO4. The solvents were removed in vacuo and the residue was purified
by flash column chromatography (20 g silica, PE/MTBE 5:1 ! 3:1 !
MTBE) to yield the coupling product 14 (109 mg, 0.113 mmol, 47%) as a
colorless oil. The 7:1 mixture of the C-16 epimers was separated by flash
column chromatography. Major isomer 14: Rf ˆ 0.40 (n-hexane/MTBE
3.18 ± 3.32 (m, 1H; 23-H), 3.34 ± 3.52 (m, 2H; 16,19-H), 3.71 ± 3.90 (m, 2H;
12,15-H), 3.96 (s, 6H; 37,38-OMe); 13CNMR (75 MHz, CDCl3): d ˆ 11.9
(35-Me), 14.1 (C-34), 22.7, 25.5, 26.2, 26.4, 26.9, 28.3, 28.3, 28.7, 28.7, 29.3,
29.4, 29.4, 29.5, 29.6, 29.7, 29.7, 29.8, 31.9, 32.0, 32.4, 32.6, 35.6 (C-3, 4 ± 11,
13, 14, 17, 18, 21, 22, 25 ± 33), 61.1 (37, 38-OMe), 70.6 (C-23), 73.5 (C-19),
73.8 (C-16), 79.3 (C-12), 80.1 (C-20), 81.9 (C-15), 82.0 (C-24), 138.6, 143.1,
144.3 (C-2, C-35, C-37, C-38), 184.2, 184.7 (C-1, C-36); HRMS (EI): found:
5:1); [a]2D3
ˆ
25.3 (c ˆ 0.40, CHCl3); IR (film): nĈ 2927(s), 2855(s),
‡
1467(m), 1407(m), 1353(m), 1252(m), 1106(s), 836(m), 775(m)
708.5166 [M ‡ 2H] ; calcd: 708.5176.
1
669(w) cm
;
1HNMR (300 MHz, CDCl3): d ˆ 0.02 (s, 12H; SiCH3), 0.85
(all-R)-[5'-(5''-Benzyloxymethyltetrahydrofuran-2''-yl)-tetrahydrofuran-
2'-yl]-methanol (19): NaH (95%, 85 mg, 3.4 mmol) and BnBr (270 mL,
2.27 mmol), dissolved in 10 mL THF, were added to a solution of bis-THF
diol 17 (457 mg, 2.26 mmol) in THF (20 mL) at 08C. The mixture was
stirred overnight at room temperature. The reaction was quenched with a
mixture of saturated aqueous NH4Cl (10 mL) and MTBE (10 mL). The
aqueous layer was extracted with CH2Cl2 (3 Â 10 mL). The combined
organic layers were washed with saturated aqueous NaCl (40 mL) and
dried with MgSO4. Removal of the solvents and purification by column
chromatography (60 g silica, PE/MTBE 1:2, MTBE and MTBE/MeOH
20:1) afforded the bisbenzyl ether (273 mg, 714 mmol, 32%, yield based on
conversion: 38%) and alcohol 19 (190 mg, 650 mmol, 29%, yield based on
conversion: 35%) as colorless liquids. The combined aqueous layers were
extracted three times with CHCl3/2-propanol 2:1 (25 mL) and the resulting
combined organic layers were dried with MgSO4. Removal of the solvents
and purification of the residue by column chromatography (20 g silica,
CHCl3/MeOH 10:1) was performed to isolate unconverted bi-THF diol 17
(78 mg, 386 mmol). Compound 19: Rf ˆ 0.35 (silica, MTBE); [a]2D1 ˆ ‡3.0
(s, 21H; SiC(CH3)3, 34-H3), 1.23 ± 1.70 (m, 40H; alkyl), 1.82 ± 2.04 (m, 6H;
13,14,18,22-H2), 2.13 (s, 3H; 35-Me), 2.44 (d, J ˆ 2.7 Hz, 1H; 16-OH),
2.48 ± 2.54 (m, 2H; 3-H2), 2.98 (m, 1H; 24-H), 3.14 ± 3.27 (m, 2H; 20-H, 23-
H), 3.27 ± 3.38 (m, 1H; 16-H), 3.60 ± 3.64 (m, 1H; 19-H), 3.74 ± 3.88 (m,
14H; 12,15-H, 1,36,37,38-OMe); 13CNMR (75 MHz, CDCl3): D ˆ 4.6,
4.0 (SiCH3), 11.6 (35-Me), 14.1 (C-34), 18.0 (SiC(CH3)3), 25.8, 25.9
(SiC(CH3)3), 22.7, 25.1, 25.6, 26.2, 28.4, 28.7, 28.8, 29.3, 29.6, 29.7, 29.8, 30.1
31.9, 32.7, 33.5, 35.7 (C-3, 4 ± 11, 13, 14, 17, 18, 21, 22, 25 ± 33), 60.4, 61.0, 61.1,
61.1 (1,36,37,38-OMe), 71.0 (C-23), 74.2 (C-19), 74.6 (C-16), 79.3 (C-12),
79.9 (C-20), 82.0 (C-15), 82.3 (C-24), 124.7, 130.3 (C-2, C-35), 144.6, 144.7,
‡
147.6, 147.7 (C-1, 36, 37, 38); HRMS (EI): found: 964.7214 [M] ; calcd:
964.7219. Minor isomer: Rf ˆ 0.34 (n-hexane/MTBE 5:1); 1HNMR
(300 MHz, CDCl3): d ˆ 0.00 ± 0.04 (s, 12H; SiCH3), 0.82 ± 0.90 (m, 21H;
SiC(CH3)3, 34-H3), 1.18 ± 2.09 (m, 44H; alkyl), 2.13 (s, 3H; 35-Me), 2.37 (d,
J ˆ 2.5 Hz, 1H; 16-OH), 2.48 ± 2.54 (m, 2H; 3-H2), 2.94 ± 3.04 (m, 1H; 24-
H), 3.16 ± 3.26 (m, 2H; 20, 23-H), 3.57 ± 3.74 (m, 2H; 16, 19-H), 3.74 ± 3.88
(m, 14H; 12,15-H, 1,36,37,38-OMe); 13CNMR (75 MHz, CDCl3): d ˆ 4.8,
3.9 (SiCH3), 11.6 (35-Me), 14.1 (C-34), 18.2 (SiC(CH3)3), 25.8, 25.9
(SiC(CH3)3), 22.7, 25.1, 25.1, 25.3, 25.5, 26.1, 29.0, 29.1, 29.4, 29.5, 29.6, 29.6,
29.7, 29.8, 31.9, 32.3, 32.7, 33.5, 36.1, 37.0 (C-3, 4 ± 11, 13, 14, 17, 18, 21, 22,
25 ± 33), 60.6, 61.0, 61.1, 61.1 (1,36,37,38-OMe), 71.0 (C-23), 72.6 (C-16), 74.2
(C-19), 79.3 (C-12), 79.9 (C-20), 81.6 (C-15), 82.4 (C-24), 124.9, 130.3 (C-2,
C-35), 144.6, 144.7, 147.6, 147.7 (C-1, 36, 37, 38).
1
(c ˆ 0.34, CHCl3); HNMR (300 MHz, CDCl3): d ˆ 1.55 ± 1.79 (m, 4H; 3'-
H', 3''-H', 4'-H', 4''-H'), 1.87 ± 2.07 (m, 4H; 3'-H'', 3''-H'', 4'-H'', 4''-H''), 2.58
(brs, 1H; OH), 3.42 ± 3.55 (m, 3H; 1-H', 1'''-H2), 3.61 ± 3.71 (m, 1H; 1-H''),
3.84 ± 3.96 (m, 2H; 5'-H, 2''-H), 4.05 ± 4.24 (m, 2H; 2'-H, 5''-H), 4.53
(PhCH2O), 7.23 ± 7.35 (m, 5H; Ph); 13CNMR (75 MHz, CDCl3): d ˆ 27.3,
28.2, 28.5, 28.6 (C-3', C-3'', C-4', C-4''), 64.4 (C-1), 72.6 (C-1'''), 73.1
(PhCH2O), 78.2, 79.8, 81.9 (C-2', C-2'', C-5', C-5''), 127.3, 127.5, 128.1, 138.2
(Ph); elemental analysis calcd (%) for C16H32O4Si (292.37): C 69.84, H 8.27;
found: C 69.77, H 8.16.
Hydroquinone ± mucocin dimethyl ether (15): Disilylether 14 (28 mg,
29 mmol) was dissolved in CH2Cl2 (1 mL) and treated with HF (0.35 mL,
5% in CH3CN) at 08C. After stirring for 1 h at room temperature, the
reaction was quenched by addition of phosphate buffer solution (1 mL,
pH ˆ 7). The aqueous layer was extracted with CH2Cl2 (2  5 mL) and ethyl
acetate (2 Â 5 mL). Washing of the combined organic layers with saturated
aqueous NaCl (5 mL), drying with MgSO4, evaporation of the solvents and
purification by column chromatography (1 g silica, n-hexane/EtOAc 1:2)
provided 15 (19 mg, 26 mmol, 90%) as a colorless solid. M.p. 718C; Rf ˆ
(all-R)-5'-(5''-Benzyloxymethyl-tetrahydrofuran-2''-yl)-tetrahydrofuran-2'-
carbaldehyde (20): Oxalyl dichloride (140 mL, 1.61 mmol) was dissolved in
CH2Cl2 (10 mL). The solution was cooled to 608C and DMSO (250 mL,
3.54 mmol) in CH2Cl2 (5 mL) was added. At 508C a solution of alcohol 19
(188 mg, 643 mmol) in CH2Cl2 (3 mL) was added. After 45 min at 458C,
the mixture was treated with Et3N (700 mL, 5.02 mmol). After 5 min, the
temperature was allowed to rise to 08C and H2O (10 mL) was added to stop
the reaction. The aqueous layer was extracted twice with CH2Cl2 (15 mL).
The combined organic layers were washed with saturated aqueous NaCl
(15 mL) and dried with MgSO4. Removal of the solvents and purification
by column chromatography (35 g silica, MTBE) yielded aldehyde 20
0.31 (n-hexane/EtOAc 1:2); [a]D23
ˆ
22.8 (c ˆ 0.32, CHCl3); IR (film): nĈ
3445(m), 2925(s), 2854(s), 1467(m), 1407(m), 1353(m), 1263(w), 1104(m),
1063(s), 1039(s), 880(w) cm 1; 1HNMR (300 MHz, CDCl3): d ˆ 0.85 (t, J ˆ
6.8 Hz, 3H; 34-H3), 1.13 ± 1.88 (m, 42H; alkyl), 1.89 ± 2.05 (m, 2H; 13,14-
H2), 2.05 ± 2.14 (m, 4H; 22-H2, 35-Me), 2.50 ± 2.55 (m, 2H; 3-H2), 2.70 (brs,
1H; OH), 2.83 (brs, 1H; OH), 3.02 (dt, J ˆ 8.8, 2.2 Hz, 1H; 24-H), 3.08 ±
3.18 (m, 1H; 20-H), 3.18 ± 3.32 (m, 1H; 23-H), 3.34 ± 3.52 (m, 2H; 16, 19-
H), 3.74 ± 3.94 (m, 14H; 12, 15-H, 1,36,37,38-OMe); 13CNMR (75 MHz,
CDCl3): d ˆ 11.6 (35-Me), 14.1 (C-34), 22.7, 25.5, 26.2, 26.9, 27.0, 28.3, 28.3,
28.7, 28.7, 29.3, 29.5, 29.6, 29.6, 29.7, 30.1, 30.3, 31.9, 32.3, 32.6, 35.6 (C-3, 4 ±
11, 13, 14, 17, 18, 21, 22, 25 ± 33), 60.6, 61.0, 61.1, 61.1 (1,36,37,38-OMe), 70.6
(C-23), 73.5 (C-19), 73.8 (C-16), 79.4 (C-12), 80.1 (C-20), 81.9 (C-15), 82.0
(C-24), 124.9, 130.3 (C-2, C-35), 144.6, 144.7, 147.6, 147.7 (C-1, 36, 37, 38);
(166 mg, 572 mmol, 89%) as a liquid. Rf ˆ 0.35 (silica, MTBE); [a]D21
ˆ
‡30.9 (c ˆ 0.33, CHCl3); IR (film): nĈ 3030(w), 2970(m), 2872(s),
2719(w), 1733(s), 1496(w), 1454(w), 1365(w), 1314(w), 1273(w), 1202(w),
1
1070(s), 938(w), 883(w), 819(w), 739(m), 699(m), 609(w) cm
;
1HNMR
(300 MHz, CDCl3): d ˆ 1.65 ± 1.81 (m, 3H; 4'-H', 3''-H', 4''-H'), 1.87 ± 2.09
(m, 4H; 3'-H', 4'-H'', 3''-H'', 4''-H''), 2.14 ± 2.25 (m, 1H; 3''-H''), 3.44 ± 3.54
(m, 2H; 1'''-H2), 3.92 ± 4.05 (m, 2H; 5'-H, 2''-H), 4.15 ± 4.23 (m, 1H; 5''-H),
4.29 ± 4.35 (m, 1H; 2'-H), 4.54 (PhCH2O), 7.23 ± 7.32 (m, 5H; Ph), 9.66 (d,
J ˆ 1.9 Hz, 1H; CHO); 13CNMR (75 MHz, CDCl3): d ˆ 27.4, 27.9, 28.4, 28.7
(C-3', C-3'', C-4', C-4''), 72.7 (C-1'''), 73.3 (PhCH2O), 78.6 (C-5''), 81.5, 83.2,
83.3 (C-2', C-5', C-2''), 127.5, 127.6, 128.3, 138.4 (Ph), 202.9 (CHO); HRMS
‡
HRMS (EI): found: 736.5488 [M] ; calcd: 736.5489.
Quinone ± mucocin: Pyridine-2,6-dicarboxylic acid (7.0 mg, 38.5 mmol) and
15 (3.0 mg, 4.1 mmol) were dissolved in CH3CN (0.55 mL) and water
(0.2 mL) at 08C. CAN (18.0 mg, 33.0 mmol) in water/CH3CN (0.5 mL, 1:1)
was added dropwise. After the mixture had been stirred for 4 h, CHCl3/
iPrOH (1 mL, 1:1) and water (1 mL) were added and the phases were
separated. The aqueous layer was extracted with CHCl3/iPrOH (5 Â 2 mL,
1:1) and the combined organic layers were dried with MgSO4. The solvents
were removed in vacuo and the residue was purified by flash column
chromatography (0.5 g silica, n-hexane/iPrOH 9:1) to yield quinone ± mu-
cocin (2.0 mg, 2.8 mmol, 68%) as a yellow solid; Rf ˆ 0.48 (n-hexane/iPrOH
‡
(EI): found: 290.1523 [M] ; calcd: 290.1518.
(5S,2'R,5'R,2''R,5''R)-1-[5'-(5''-Benzyloxymethyl-tetrahydrofuran-2''-yl)-
tetrahydrofuran-2'-yl]-5-(tert-butyldimethylsilyloxy)undecan-1-one (21):
A three-necked flask (100 mL) equipped with a dropping funnel, a reflux
condenser, and a magnetic stirrer bar was flame-dried in vacuo and, after
cooling to room temperature, flushed with argon. The flask was charged
with Mg (541 mg, 22.3 mmol) and the same drying procedure was repeated.
Et2O (3 mL) was added and the mixture was stirred vigorously. The
dropping funnel was charged with a solution of bromide 16 (1.00 g,
2.85 mmol) in Et2O (10 mL) and 1,2-dibromoethane (350 mL, 4.06 mmol).
A quantity of this solution (7 mL) was added quickly to the vigorously
stirred mixture. After the mixture had been warmed slightly with a heat
gun, the Grignard reaction started. The remaining bromide solution was
added over 20 min and the mixture was stirred for 15 min at 358C and for
9:1); [a]2D2
ˆ
21 (c ˆ 0.044, CHCl3); IR (film): nĈ 3475(m), 2923(s),
2854(s), 1649(m), 1611(m), 1458(m), 1266(m), 1205(w), 1066(s),
947(w) cm
H3), 1.13 ± 1.88 (m, 42H; alkyl), 1.89 ± 2.14 (m, 3H; 13,14,22-H2), 1.99 (s,
3H; 35-Me), 2.42 (t, J ˆ 6.8 Hz, 2H; 3-H2), 2.69 (brs, 1H; OH), 2.82 (brs,
1H; OH), 3.02 (dt, J ˆ 8.8, 2.2 Hz, 1H; 24-H), 3.08 ± 3.18 (m, 1H; 20-H),
1
;
1HNMR (300 MHz, CDCl3): d ˆ 0.85 (t, J ˆ 6.4 Hz, 3H; 34-
Chem. Eur. J. 2001, 7, No. 5
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0705-1001 $ 17.50+.50/0
1001

U. Koert et al.
FULL PAPER
30 min at room temperature. The Grignard solution was transferred by
cannula into a Schlenk flask and cooled to 608C. CuBr´ Me2S (33mg,
161 mmol) was added and the mixture was stirred at 608C for another
15 min. A solution of aldehyde 20 (159 mg, 548 mmol) in Et2O (10 mL) was
added dropwise. The reaction mixture was stirred overnight, during which
period the temperature was allowed to rise to room temperature. Addition
of saturated aqueous NH4Cl (25 mL) and Et2O (25 mL) terminated the
reaction. The aqueous layer was extracted twice with Et2O (25 mL). The
combined organic layers were washed with saturated aqueous NaCl
(50 mL) and dried with MgSO4. Removal of the solvents and purification
by column chromatography (40 g Silica, PE/MTBE 4:1, 1:1) afforded a
mixture (2:1 by 13CNMR) of the epimeric alcohols [228 mg, 405 mmol,
74%, Rf ˆ 0.60 and 0.63 (silica, PE/MTBE 1:1)] as a colorless liquid. The
epimeric alcohols (189 mg, 336 mmol) were dissolved in CH2Cl2 (10 mL).
Molecular sieves (4 Š, 227 mg) and PCC (275 mg, 1.28 mmol) were added.
The mixture was stirred for 1 h at room temperature, then diluted with
MTBE (50 mL) and filtered through a pad of Celite. The solvents were
removed in vacuo. Purification by column chromatography (40 g silica,
PE/MTBE 4:1, 2:1) gave the desired ketone 21 (112 mg, 200 mmol, 60%) as
a colorless liquid. Rf ˆ 0.22 (silica, PE/MTBE 4:1); [a]2D3 ˆ ‡21.4 (c ˆ 1.87,
CHCl3); IR (film): nĈ 3031(w), 2955(s) (CH), 2929(s) (CH), 2857(s) (CH),
extracted twice with CH2Cl2 (10 mL). The combined organic layers were
washed with saturated aqueous NaCl (10 mL) and dried with MgSO4.
Removal of the solvents in vacuo and purification by column chromato-
graphy (25 g silica, PE/MTBE 4:1) afforded bis-TBDMS-protected triol
(83 mg, 123 mmol, 99%) as a colorless liquid.
(1R,5S,2'R,5'R,2''R,5''R)-1-[5'-(5''-Benzyloxymethyl-tetrahydrofuran-2''-
yl)tetrahydrofuran-2'-yl]-1,5-di-(tert-butyldimethylsilyloxy)undecane:
Rf ˆ 0.57 (silica, PE/MTBE 4:1); [a]2D1 ˆ ‡12.1 (c ˆ 0.43, CHCl3); IR (film):
nĈ 2955(s)/ 2929(s)/ 2857(s) (CH), 1462(m), 1361(w), 1254(m), 1092(m),
1
1074(m), 1005(w), 939(w), 890(w), 835(m), 774(m), 733(w), 697(w) cm
;
1HNMR (300 MHz, CDCl3): d ˆ 0.01, 0.01, 0.02, 0.04 (4  s, 12H; SiCH3),
0.84 ± 0.89 (m, 21H; 11-H3 and SiC(CH3)3), 1.19 ± 1.47 (m, 16H; 2-H2 to
4-H2, 6-H2 to 10-H2), 1.59 ± 1.75 (m, 4H; 3'-H', 4'-H', 3''-H', 4''-H'), 1.83 ±
2.05 (m, 4H; 3'-H'', 4'-H'', 3''-H'', 4''-H''), 3.42 ± 3.54 (m, 2H; 1'''-H2), 3.55 ±
3.68 (m, 2H; 1-H, 5-H), 3.82 ± 3.99 (m, 3H; 2'-H, 5'-H, 2''-H), 4.14 ± 4.23 (m,
1H; 5''-H), 4.55 (s, 2H; PhCH2O), 7.23 ± 7.35 (m, 5H; Ph); 13CNMR
(75 MHz, CDCl3): d ˆ 4.6, 4.5, 4.4, 4.3 (SiCH3), 14.1 (C-11), 18.1,
18.2 (SiC(CH3)3), 21.9 (C-3), 22.6 (C-10), 25.7, 26.0 (SiC(CH3)3), 25.2, 26.9,
28.2, 28.4, 28.75, 28.79, 29.5, 31.9 (C-3, C-7 to C-9, C-3', C-4', C-3'', C-4''),
32.5 (C-2), 37.0, 37.6 (C-4, C-6), 72.4 (C-5), 72.8 (C-1'''), 73.3 (PhCH2O),
74.7 (C-1), 78.4 (C-5''), 81.77, 81.79 (C-5', C-2''), 82.2 (C-2'), 127.5, 127.6,
ˆ
‡
1716(m) (C O), 1462(w), 1406(w), 1256(m), 1199(w), 1074(s), 939(w),
128.3, 138.5 (Ph); HRMS (EI): found: 676.4922 [M] ; calcd: 676.4918.
836(m), 802(w), 774(m), 735(w), 698(w) cm 1; 1HNMR (300 MHz, CDCl3):
d ˆ 0.01 (s, 6H; SiCH3), 0.82 ± 0.88 (m, 12H; 11-H3 and SiC(CH3)3), 1.18 ±
2.04 and 2.16 ± 2.25 (m, 22H; 3-H2, 4-H2, 6-H2 to 10-H2, 3'-H2, 4'-H2, 3''-H2,
4''-H2), 2.42 ± 2.64 (m, 2H; 2-H2), 3.42 ± 3.53 (m, 2H; 1'''-H2), 3.60 (quin.,
J ˆ 5.7 Hz, 1H; 5-H), 3.89 ± 4.06 (m, 2H; 5'-H, 2''-H), 4.16 ± 4.23 (m, 1H; 5''-
H), 4.37 (t, J ˆ 7.4 Hz, 1H; 2'-H), 4.53 (s, 2H; PhCH2O), 7.21 ± 7.31 (m, 5H;
Ph); 13CNMR (75 MHz, CDCl3): d ˆ 4.5 (SiCH3), 14.0 (C-11), 18.0
(SiC(CH3)3), 22.5 (C-10), 25.8 (SiC(CH3)3), 25.3, 26.9, 27.9, 28.2, 28.6, 29.2,
29.4, 31.8 (C-3, C-7 to C-9, C-3', C-4, C-3'', C-4''), 36.5, 36.9 (C-4, C-6), 38.1
(C-2), 72.0 (C-5), 72.7 (C-1'''), 73.2 (PhCH2O), 78.5 (C-5''), 81.4, 82.9 (C-5',
The bis-TBDMS-protected triol (81 mg, 121 mmol) was dissolved in AcOEt
(2 mL) and iPrOH (2 mL). After addition of Pd (10% on activated carbon,
11.3 mg), the mixture was evacuated and filled with H2 (1 bar). The mixture
was stirred for 4 h at room temperature and filtered through a pad of Celite,
washing the pad with CH2Cl2 (25 mL). Removal of the solvents and
purification by column chromatography (20 g silica, PE/MTBE 2:1)
afforded the primary alcohol (61 mg, 104 mmol, 86%) as a colorless,
viscous oil. (2'R,5'R,2''R,5''R,1'''R,5'''S)-1-[5'-(5''-(1''',5'''-Di-(tert-butyldi-
methylsilyloxy)undecan-1'''yl)tetrahydrofuran-2''-yl)tetrahydrofuran-2'-
yl]-methanol: Rf ˆ 0.35 (silica, PE/MTBE 2:1); [a]2D2 ˆ ‡7.6 (c ˆ 0.46,
CHCl3); IR (film): nĈ 3450(brm) (OH), 2955(s)/ 2929(s)/ 2857(s) (CH),
1463(m), 1361(w), 1255(m), 1067(m), 1005(w), 836(m), 809(w), 774(m),
ˆ
C-2''), 83.9 (C-2'), 127.4, 127.5, 128.2, 138.3 (Ph), 212.5 (C O); HRMS (EI):
found: 560.3901 [M] ; calcd: 560.3897.
‡
1
725(w) cm 1; HNMR (300 MHz, CDCl3): d ˆ 0.01, 0.02, 0.04 (3  s, 12 H;
(1R,5S,2'R,5'R,2''R,5''R)-1-[5'-(5''-Benzyloxymethyltetrahydrofuran-2''-
yl)tetrahydrofuran-2'-yl]-5-(tert-butyldimethylsilyloxy)undecan-1-ol (22):
L-Selectride (1m in THF, 900 mL, 900 mmol), which had been precooled
at 1108C, was added to a solution of the ketone 21 (104 mg, 185 mmol) in
THF (5 mL) at 1108C. The mixture was stirred for 1 h 30 min, during
which period the temperature was allowed to rise to 608C. At 08C, 2m
NaOH (7 mL) and 30% H2O2 (10 mL) were added carefully. The mixture
was stirred for 1 h and then treated with H2O (25 mL) and MTBE (25 mL).
The aqueous layer was extracted with MTBE (30 mL). The combined
organic layers were washed with saturated aqueous NaHCO3 (20 mL) and
saturated aqueous NaCl (20 mL), and dried with MgSO4. Removal of the
solvents and purification by column chromatography (35 g silica, PE/
MTBE 2:1) afforded alcohol 22 (80 mg, 142 mmol, 77%) as a colorless oil.
The stereoselectivity was determined by 13CNMR analysis to be better than
98:2. Rf ˆ 0.28 (silica, PE/MTBE 2:1); [a]2D0 ˆ ‡8.1 (c ˆ 1.60, CHCl3); IR
(film): nĈ 3470(brm) (OH), 3031(w), 2954(s)/ 2929(s)/ 2857(s) (C-H),
1496(w), 1463(m), 1407(w), 1305(w), 1255(m), 1198(w), 1071(s), 939(w),
836(m), 808(w), 774(m), 735(w), 698(w) cm 1; 1HNMR (300 MHz, CDCl3):
d ˆ 0.01 (s, 6H; SiCH3), 0.82 ± 0.88 (m, 12H; 11-H3 and SiC(CH3)3), 1.18 ±
1.49 (m, 16H; 2-H2 to 4-H2, 6-H2 to 10-H2), 1.56 ± 1.75 (m, 4H; 3'-H', 4'-H',
3''-H', 4''-H'), 1.88 ± 2.06 (m, 4H; 3'-H'', 4'-H'', 3''-H'', 4''-H''), 2.50 (brs, 1H;
OH), 3.31 ± 3.39 (m, 1H; 1-H), 3.41 ± 3.52 (m, 2H; 1'''-H2), 3.59 (t, J ˆ
5.0 Hz, 1H; 5-H), 3.77 ± 3.95 (m, 3H; 2'-H, 5'-H, 2''-H), 4.14 ± 4.23 (m, 1H;
5''-H), 4.53 (s, 2H; PhCH2O), 7.21 ± 7.31 (m, 5H; Ph); 13CNMR (75 MHz,
CDCl3): d ˆ 4.50, 4.46 (SiCH3), 14.0 (C-11), 18.1 (SiC(CH3)3), 21.5 (C-
3), 22.5 (C-10), 25.9 (SiC(CH3)3), 25.2, 28.27, 28.34, 28.7, 28.8, 29.4, 31.8 (C-7
to C-9, C-3', C-4', C-3'', C-4''), 33.6 (C-2), 37.0, 37.2 (C-4, C-6), 72.3 (C-5),
72.7 (C-1'''), 73.2 (PhCH2O), 73.9 (C-1), 78.4 (C-5''), 81.79, 81.82 (C-5',
C-2''), 82.9 (C-2'), 127.4, 127.5, 128.2, 138.3 (Ph); HRMS: (EI): found
SiCH3), 0.82 ± 0.88 (m, 21H; 11'''-H3 and SiC(CH3)3), 1.19 ± 1.46 (m, 16H;
2'''-H2 to 4'''-H2, 6'''-H2 to 10'''-H2), 1.56 ± 1.75 (m, 4H; 3'-H', 4'-H', 3''-H', 4''-
H'), 1.84 ± 1.98 (m, 4H; 3'-H'', 4'-H'', 3''-H'', 4''-H''), 3.45 (dd, J ˆ 11.7/
5.3 Hz, 1H; 1-H'), 3.55 ± 3.71 (m, 3H; 1-H'', 1'''-H, 5'''-H), 3.80 ± 3.99 (m,
3H; 5'-H, 2''-H, 5''-H), 4.05 ± 4.14 (m, 1H; 2'-H); 13CNMR (75 MHz,
CDCl3): d ˆ 4.6, 4.5, 4.4, 4.3 (SiCH3), 14.1 (C-11'''), 18.1, 18.2
(SiC(CH3)3), 21.9 (C-3'''), 22.6 (C-10'''), 25.9 (SiC(CH3)3), 25.2, 26.8, 27.4,
28.6, 28.7, 29.5, 31.9 (C-3', C-4', C-3'', C-4'', C-7''' to C-9'''), 32.4 (C-2'''), 37.0,
37.5 (C-4''', C-6'''), 64.6 (C-1), 72.4 (C-5'''), 74.6 (C-1'''), 79.8 (C-2'), 82.0,
‡
82.1, 82.2 (C-5', C-2'', C-5''); HRMS (EI): found: 571.4218 [M CH3] ;
calcd: 571.4214.
Oxalyl dichloride (50 mL, 573 mmol) was dissolved in CH2Cl2 (1 mL). The
solution was cooled to 608C and DMSO (200 mL, 2.82 mmol), dissolved
in dichloromethane (3 mL), was added. At 508C the alcohol (56 mg,
95 mmol), dissolved in CH2Cl2 (0.5 mL), was added. After 45 min at 458C
the mixture was treated with Et3N (500 mL, 3.59 mmol). After 5 min, the
reaction mixture was allowed to warm up to 08C and H2O (3 mL) was
added to stop the reaction. The aqueous layer was extracted twice with
CH2Cl2 (10 mL). The combined organic layers were washed with saturated
aqueous NaCl (5 mL) and dried with MgSO4. Removal of the solvents and
purification by column chromatography (10 g silica, PE/MTBE 4:1, 2:1)
yielded aldehyde 23 (50 mg, 85 mmol, 89%) as a liquid. Rf ˆ 0.49 (silica, PE/
MTBE 2:1); [a]2D2 ˆ ‡15.2 (c ˆ 1.00, CHCl3); IR (film): nĈ 2955(s)/
ˆ
2930(s)/ 2857(s) (CH), 1736(m) (C O), 1463(m), 1361(w), 1255(m),
1067(m), 872(w), 836(m), 774(m), 725(w) cm
1
;
1HNMR (300 MHz,
CDCl3): d ˆ 0.00, 0.02, 0.03 (3  s, 12H; SiCH3), 0.84 ± 0.86 (m, 21H; 11'''-
H3 and SiC(CH3)3), 1.19 ± 1.47 (m, 16H; 2'''-H2 to 4'''-H2, 6'''-H2 to 10'''-H2),
1.65 ± 1.95 (2 Â m, 7H; 3'-H', 4'-H2, 3''-H2, 4''-H2), 2.17 ± 2.21 (m, 1H; 3'-H''),
3.57 ± 3.62 (m, 2H; 1'''-H, 5'''-H), 3.87 ± 4.02 (m, 3H; 5'-H, 2''-H, 5''-H),
4.29 ± 4.34 (m, 1H; 2'-H), 9.65 (d, J ˆ 1.9 Hz, 1H; CHO); 13CNMR
(75 MHz, CDCl3): d ˆ 4.6, 4.5, 4.4, 4.3 (SiCH3), 14.1 (C-11'''),
18.10, 18.13 (SiC(CH3)3), 21.7 (C-3'''), 22.6 (C-10'''), 25.9 (SiC(CH3)3), 25.2,
27.0, 27.4, 27.9, 28.6, 29.5, 31.9 (C-3', C-4', C-3'', C-4'', C-7''' to C-9'''), 32.6 (C-
2'''), 37.0, 37.5 (C-4''', C-6'''), 72.3 (C-5'''), 74.6 (C-1'''), 81.4, 82.3, 83.2 (C-5',
C-2'', C-5''), 83.3 (C-2'), 203.0 (CHO); HRMS (EI): found: 569.4055 [M
‡
563.4119 [M] ; calcd 563.4131.
(2'R,5'R,2''R,5''R,1'''R,5'''S)-1-[5'-(5''-(1''',5'''-Di-(tert-butyldimethylsilyl-
oxy)undecan-1'''yl)tetrahydrofuran-2''-yl)-tetrahydrofuran-2'-yl]-carbalde-
hyde (23): 2,6-Lutidine (150 mL, 1.29 mmol) and TBDMSOTf (100 mL,
435 mmol) were added at 208C to a solution of alcohol 22 (69 mg,
123 mmol) in CH2Cl2 (5 mL). The mixture was stirred for 2 h, during which
period the temperature was allowed to rise to 08C. The reaction was
quenched with saturated aqueous NH4Cl (5 mL) and the aqueous layer was
‡
CH3] ; calcd: 569.4058.
1002
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0705-1002 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 5

Quinone ± Annonaceous Acetogenins
993±1005
1'-Hydroxy-12'-trityloxydodecyl-2,3,4,5-tetramethoxy-6-methylbenzene
(25): 1,2,3,4-Tetramethoxy-5-methylbenzene 4 (149 mg, 0.70 mmol) was
dissolved in n-hexane (10 mL) and cooled to 08C. TMEDA (0.27 mL,
1.82 mmol) and nBuLi (0.72 mL, 1.52 mmol) were added dropwise. After
30 min, aldehyde 24 (570 mg, 1.29 mmol) dissolved in n-hexane (5 mL) was
added to the yellow suspension. The reaction was quenched after 2 h by
addition of saturated aqueous NH4Cl (10 mL). The aqueous layer was
extracted with MTBE (3 Â 15 mL) and the combined organic layers were
washed with saturated aqueous NaCl (10 mL) and dried with MgSO4. The
solvents were removed in vacuo and the residue was purified by column
chromatography (20 g silica, PE/MTBE 5:1) to yield the alcohol 25
(246 mg, 0.38 mmol, 54%) as a colorless oil. Rf ˆ 0.18 (n-hexane/MTBE
5:1); IR (film): nĈ 3445(m), 2929(s), 2855(s), 1592(w), 1466(s), 1411(m),
mixture was then cooled to 788C and a solution of aldehyde 23 (46 mg,
79 mmol) in Et2O (1 mL) was added dropwise. The mixture was stirred for
3 h, 30 min, during which period the temperature was allowed to rise to
08C. Addition of aqueous phosphate buffer (pH 7, 2 mL) stopped the
reaction. The mixture was diluted with MTBE (10 mL) and water (5 mL).
The aqueous layer was extracted five times with MTBE (5 mL). The
combined organic layers were washed with saturated aqueous NaCl (5 mL)
and dried with MgSO4. Removal of the solvents and purification by column
chromatography (9 g silica, PE/MTBE 20:1, 2:1, MTBE) afforded a
mixture (1:1 by 13CNMR) of the epimeric alcohols [39 mg, 40 mmol, 52%,
Rf ˆ 0.38 and 0.46 (silica, PE/MTBE 2:1)] as a colorless liquid. Oxalyl
dichloride (150 mL, 1.72 mmol) was dissolved in CH2Cl2 (1 mL). The
solution was cooled to 608C and DMSO (250 > L, 3.52 mmol) dissolved
in CH2Cl2 (3 mL) was added. The epimeric alcohols (22 mg, 23 mmol)
dissolved in CH2Cl2 (2 mL) were added at 508C. After 1 h at 408C, the
mixture was treated with Et3N (800 mL, 5.74 mmol). After 5 min, the
reaction mixture was allowed to warm up to 08C and H2O (2 mL) was
added to stop the reaction. The aqueous layer was extracted three times
with CH2Cl2 (5 mL). The combined organic layers were washed with
saturated aqueous NaCl (5 mL) and dried with MgSO4. Removal of the
solvents and purification by column chromatography (10 g silica, PE/
MTBE 10:1, 4:1) yielded ketone 27 (21 mg, 22 mmol, 96%) as a colorless
liquid. Rf ˆ 0.50 (silica, PE/MTBE 4:1); [a]2D3 ˆ ‡14.8 (c ˆ 0.42, CHCl3); IR
1343(m), 1261(w), 1104(s), 1075(s), 1039(s), 897(w), 753(m), 704(s),
1
639(w) cm
;
1HNMR (300 MHz, CDCl3): d ˆ 1.19 ± 1.83 (m, 20H; alkyl),
2.15 (s, 3H; Me), 3.02 (t, 2H; J ˆ 6.6 Hz, 12'-H2), 3.74 (s, 3H; OMe), 3.86 (s,
3H; OMe), 3.89 (s, 3H; OMe), 3.93 (s, 3H; OMe), 4.73 ± 4.81 (m, 1H; 1'-
H), 7.20 ± 7.44 (m, 15H; Ph); 13CNMR (75 MHz, CDCl3): d ˆ 11.6 (6-Me),
26.3, 26.5, 27.0, 29.5, 29.6, 30.0, 38.7 (alkyl), 60.7, 60.9, 61.0, 61.3 (2,3,4,5-
OMe), 63.7 (C-12'), 71.4 (C-1'), 86.2 (CPh3), 123.7, 130.9 (C-1, C-6), 126.7,
127.6, 128.7, 144.6 (Ph), 144.5, 146.0, 147.7, 147.9 (C-2, C-3, C-4, C-5); HRMS
‡
(EI): found: 654.3925 [M] ; calcd: 654.3920.
1-(12'-Hydroxydodecyl)-2,3,4,5-tetramethoxy-6-methylbenzene (26): Al-
cohol 25 (240 mg, 0.37 mmol) was dissolved in CH2Cl2 (5 mL) and cooled
ˆ
(film): nĈ 2929(s)/ 2856(s) (CH), 1717(m) (C O), 1464(s), 1408(m),
1352(w), 1255(m), 1107(m), 1066(w), 1039(w), 1007(w), 979(w), 874(w),
to
788C. Et3SiH (0.30 mL, 1.85 mmol) and BF3 ´ OEt2 (0.35 mL,
1
836(m), 775(m), 724(w), 665(w) cm
;
1HNMR (300 MHz, CDCl3): d ˆ
2.78 mmol) were added under stirring. After 14 h ( 788C ! RT),
saturated aqueous NaHCO3 (4 mL) was added and the phases were
separated. The aqueous layer was extracted with MTBE (3 Â 10 mL) and
the combined organic layers were washed with saturated aqueous NaCl
(5 mL) and dried with MgSO4. The solvents were evaporated and the
residue was purified by column chromatography (10 g silica, PE/MTBE
2:1) to provide the alcohol 26 (117 mg, 0.30 mmol, 81%) as a colorless oil.
Rf ˆ 0.23 (n-hexane/MTBE 2:1); IR (film): nĈ 3440(m), 2928(s), 2855(s),
0.01, 0.03, 0.05 (3 Â s, 18H; SiCH3), 0.82 ± 0.88 (m, 21H; 11'''-H3,
SiC(CH3)3), 1.19 ± 1.62 (m, 36H; 3-H2 to 12-H2, 2'''-H2 to 4'''-H2, 6'''-H2 to
10'''-H2), 1.65 ± 1.96 (m, 8H; 3'-H2, 4'-H2, 3''-H2, 4''-H2), 2.14 (s, 3H; CH3-
Ph), 2.40 ± 2.64 (m, 4H; 13-H2, 2-H2), 3.55 ± 3.64 (m, 2H; 1'''-H, 5'''-H), 3.76
(s, 3H; OCH3), 3.79 (s, 3H; OCH3), 3.83 ± 4.05 (m, 9H; 5'-H, 2''-H, 5''-H,
2  OCH3), 4.38 (t, J ˆ 7.2 Hz, 1H; 2'-H); 13CNMR (75 MHz, CDCl3): d ˆ
4.6, 4.5, 4.4, 4.2 (SiCH3), 11.6 (CH3Ph), 14.1 (C-11'''), 18.1, 18.2
(SiC(CH3)3), 25.94, 25.96 (SiC(CH3)3), 21.7 (C-3'''), 22.6 (C-10'''), 23.2, 25.2,
27.0, 27.3, 28.0, 28.6, 29.2, 29.3, 29.47, 29.50, 29.53, 29.6, 29.7, 30.1, 30.3, 31.9
(C-3 to C-13, C-3', C-4', C-3'', C-4'', C-7''' to C-9'''), 32.9 (C-2'''), 37.0, 37.6
(C-4''', C-6'''), 38.2 (C-2), 60.6, 61.0, 61.08, 61.09 (4 Â OCH3), 72.3 (C-5'''),
74.9 (C-1'''), 81.3, 82.5, 82.8, 83.9 (C-2', C-5', C-2'', C-5''), 124.9, 130.4 (C-2'''',
C-6''''), 144.6, 144.7, 147.65, 147.73 (C-2'''', C-3'''', C-4'''', C-5''''), 212.9
1466(s), 1412(m), 1351(m), 1261(w), 1110(s), 1060(s), 1039(s), 975(m),
1
897(w) cm
;
1HNMR (300 MHz, CDCl3): d ˆ 1.19 ± 1.62 (m, 20H; alkyl),
2.14 (s, 3H; Me), 2.50 ± 2.55 (m, 2H; 1'-H2), 3.59 ± 3.63 (m, 2H; 12'-H2), 3.76
(s, 3H; OMe), 3.79 (s, 3H; OMe), 3.87 (s, 3H; OMe), 3.88 (s, 3H; OMe);
13CNMR (75 MHz, CDCl3): d ˆ 11.6 (6-Me), 25.7, 27.0, 29.4, 29.5, 29.6, 29.6,
30.1, 30.3, 32.8 (alkyl), 60.6, 61.0, 61.1, 61.1 (2,3,4,5-OMe), 63.1 (C-12'),
124.9, 130.3 (C-1, C-6), 144.6, 144.7, 147.6, 147.7 (C-2, C-3, C-4, C-5); HRMS
‡
ˆ
(C O); HRMS (EI): found: 962.7023 [M] ; calcd: 962.7062.
‡
(EI): found: 396.2876 [M] ; calcd: 396.2876.
(1R,2'R,5'R,2''R,5''R,1'''R,5'''S)-1-[5'-(5''-(1''',5'''-Di-(tert-butyldimethyl-
silyloxy)undecan-1'''yl)tetrahydrofuran-2''-yl)tetrahydrofuran-2'-yl]-13-
(2'''',3'''',4'''',5''''-tetramethoxy-6''''-methylphenyl)tridecan-1-ol (28): L-Se-
lectride (1 mmolmL 1 in THF, 300 mL, 300 mmol), that had been precooled
at 1108C, was added to a solution of the ketone 27 (19.2 mg, 19.9 mmol) in
THF (3 mL) at 1108C,. The mixture was stirred for 1 h, 30 min, during
which period the temperature was allowed to rise to 608C. At 08C, first
water (5 mL) and then aqueous NaOH (2m, 7 mL) and 30% H2O2 (7 mL)
were added carefully. The aqueous layer was extracted three times with
MTBE (15 mL). The combined organic layers were washed with saturated
aqueous NaHCO3 (10 mL) and saturated aqueous NaCl (10 mL), and dried
with MgSO4. Removal of the solvents and purification by column
chromatography (6 g silica, PE/MTBE 4:1) afforded alcohol 28 (16.7 mg,
17.3 mmol, 87%) as a colorless oil. The epimeric alcohol (2.3 mg, 2.4 mmol)
was also isolated. The stereoselectivity was determined to be 88:12 by the
products isolated. Major isomer 28: Rf ˆ 0.22 (silica, PE/MTBE 4:1);
[a]2D4 ˆ ‡6.1 (c ˆ 0.33, CHCl3); IR (film): nĈ 3398(brm) (OH), 2928(s)/
1-(12'-Iodododecyl)-2,3,4,5-tetramethoxy-6-methylbenzene:
Iodine
(84 mg, 0.332 mmol) was added to solution of imidazole (57 mg,
a
0.831 mmol) and PPh3 (80 mg, 0.305 mmol) in CH2Cl2 (3 mL) at 08C.
After the mixture had been stirred for 5 min, the alcohol 26 (110 mg,
0.277 mmol), dissolved in CH2Cl2 (1 mL), was added slowly. The reaction
mixture was stirred for 4 h with light excluded. An aqueous Na2S2O3
solution (10 mL) was then added. The aqueous layer was extracted with
MTBE (3 Â 10 mL). The combined organic layers were washed with
saturated aqueous NaCl (10 mL), dried with MgSO4, and the solvents were
evaporated. The residue was purified by column chromatography (8 g
silica, PE/MTBE 20:1) to yield 18 (91 mg, 0.180 mmol, 65%) as a colorless
oil. Rf ˆ 0.25 (n-hexane/MTBE 2:1); IR (film): nĈ 2926(s), 2853(s),
1465(s), 1407(s), 1351(m), 1261(w), 1196(m), 1106(s), 1064(s), 1038(s),
1
978(m), 881(w), 721(w) cm
;
1HNMR (300 MHz, CDCl3): d ˆ 1.20 ± 1.49
(m, 18H; alkyl), 1.77 ± 1.82 (m, 2H; 11'-H2), 2.14 (s, 3H; Me), 2.50 ± 2.55 (m,
2H; 1'-H2), 3.17 (t, J ˆ 7.1 Hz, 2H; 12'-H2), 3.76 (s, 3H; OMe), 3.80 (s, 3H;
OMe), 3.87 (s, 3H; OMe), 3.88 (s, 3H; OMe); 13CNMR (75 MHz, CDCl3):
d ˆ 7.4 (C-12'), 11.6 (6-Me), 27.0, 28.5, 29.4, 29.5, 29.5, 29.6, 30.1, 30.3, 30.5,
33.5 (alkyl), 60.6, 61.0, 61.1, 61.1 (2,3,4,5-OMe), 124.9, 130.3 (C-1, C-6),
144.6, 144.7, 147.6, 147.7 (C-2, C-3, C-4, C-5); HRMS (EI): found: 506.1897
2856(s) (CH), 1466(m), 1408(m), 1352(w), 1255(m), 1196(w), 1106(w),
1
1065(m), 880(w), 836(m), 774(m), 723(w) cm
;
1HNMR (300 MHz,
CDCl3): d ˆ 0.01, 0.03, 0.06 (3  s, 18H; SiCH3), 0.83 ± 0.88 (m, 21H; 11'''-
CH3, SiC(CH3)3), 1.20 ± 1.74 (m, 42H; 2-H2 to 12-H2, 3'-H', 4'-H', 3''-H', 4''-
H', 2'''-H2 to 4'''-H2, 6'''-H2 to 10'''-H2), 1.82 ± 1.98 (m, 4H; 3'-H'', 4'-H'', 3''-
H'', 4''-H''), 2.14 (s, 3H; CH3-Ph), 2.44 ± 2.56 (m, 3H; 13-H2 and OH), 3.31 ±
3.39 (m, 1H; 1-H), 3.55 ± 3.64 (m, 2H; 1'''-H, 5'''-H), 3.74 ± 3.94 (m, 16H; 2'-
H, 5'-H, 2''-H, 5''-H, 4  OCH3); 13CNMR (75 MHz, CDCl3): d ˆ 4.7,
‡
[M] ; calcd: 506.1893.
(1R,2'R,5'R,2''R,5''R,1'''R,5'''S)-1-[5'-(5''-(1''',5'''-Di-(tert-butyldimethyl-
silyloxy)undecan-1'''-yl)tetrahydrofuran-2''-yl)-tetrahydrofuran-2'-yl]-13-
(2'''',3'''',4'''',5''''-tetramethoxy-6''''-methylphenyl)tridecan-1-one (27): Io-
dide 18 (86 mg, 170 mmol) was dissolved in Et2O (3 mL) under an argon
4.5,
4.4,
4.2 (SiCH3), 11.6 (CH3Ph), 14.1 (C-11'''), 18.1, 18.2
atmosphere in a flame-dried Schlenk flask (25 mL). The solution was
(SiC(CH3)3), 25.9, 26.0 (SiC(CH3)3), 21.7 (C-3'''), 22.6 (C-10'''), 25.2, 25.7,
27.0, 27.4, 28.4, 28.7, 28.8, 29.50, 29.53, 29.65, 29.68, 29.8, 30.1, 30.3, 31.9 (C-3
to C-13, C-3', C-4', C-3'', C-4'', C-7''' to C-9'''), 32.9 (C-2'''), 33.4 (C-2), 37.0,
37.5 (C-4''', C-6'''), 60.6, 61.0, 61.08, 61.09 (4 Â OCH3), 72.4 (C-5'''), 74.1 (C-
1), 75.0 (C-1'''), 81.65, 81.72, 82.4, 82.9 (C-2', C-5', C-2'', C-5''), 124.9, 130.4
1
cooled to
1108C and tBuLi (1.48 mmolmL in n-pentane, 210 mL,
306 mmol) was added. After 4 min, MgBr2 ´ Et2O (3.88 mmolmL 1 in Et2O,
100 mL, 388 mmol) was added. The mixture was stirred for 1 h, 30 min,
during which period the temperature was allowed to rise to 408C. The
Chem. Eur. J. 2001, 7, No. 5
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0705-1003 $ 17.50+.50/0
1003

U. Koert et al.
FULL PAPER
(C-1'''', C-6''''), 144.6, 144.7, 147.65, 147.73 (C-2'''', C-3'''', C-4'''', C-5'''');
HRMS (EI): found: 964.7226 [M] ; calcd: 964.7219. Minor isomer: Rf ˆ
Acknowledgement
‡
0.10 (silica, PE/MTBE 4:1); 1HNMR (300 MHz, CDCl3): d ˆ 0.01, 0.03,
0.04 (3 Â s, 18H; SiCH3), 0.83 ± 0.88 (m, 21H; 11'''-H3, SiC(CH3)3), 1.18 ±
1.96 (m, 46H; 2-H2 to 12-H2, 3'-H2, 4'-H2, 3''-H2, 4''-H2, 2'''-H2 to 4'''-H2, 6'''-
H2 to 10'''-H2), 2.14 (s, 3H; CH3-Ph), 2.48 ± 2.56 (m, 3H; 13-H2 and OH),
3.55 ± 3.71 (m, 3H; 1-H, 1'''-H, 5'''-H), 3.74 ± 4.00 (m, 16H; 2'-H, 5'-H, 2''-H,
5''-H, 4  OCH3); 13CNMR (75 MHz, CDCl3): d ˆ 4.6, 4.44, 4.38,
4.3 (SiCH3), 11.6 (CH3Ph), 14.1 (C-11'''), 18.1, 18.2 (SiC(CH3)3), 25.9
(SiC(CH3)3), 21.9 (C-3'''), 22.6 (C-10'''), 25.2, 26.1, 27.0, 28.5, 29.50, 29.54,
29.6, 29.65, 29.68, 29.7, 30.1, 30.4, 31.9 (C-2 to C-13, C-3', C-4', C-3'', C-4'',
C-7''' to C-9'''), 32.4 (C-2'''), 37.0, 37.6 (C-4''', C-6'''), 60.6, 61.0, 61.08, 61.1
(4 Â OCH3), 71.3 (C-1), 72.4 (C-5'''), 74.5 (C-1'''), 82.2, 82.3, 82.45, 82.51 (C-
2', C-5', C-2'', C-5''), 124.9, 130.4 (C-1'''', C-6''''), 144.7, 147.7 (C-2'''', C-3'''',
C-4'''', C-5'''').
This work was supported by the Deutsche Forschungsgemeinschaft, the
Fonds der Chemischen Industrie, and ASTA-Medica AG.
[1] a) F. Q. Alali, X.-X. Liu, J. L. McLaughlin, J. Nat. Prod. 1999, 62, 504 ±
Á
540; b) M. C. Zafra-Polo, B. Figadere, T. Gallardo, J. R. Tormo, D.
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Â
Á
Chem. 1998, 11, 803 ± 827; d) A. Cave, B. Figadere, A. Laurens, D.
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Tian, M. Shi, Eur. J. Org. Chem. 2000, 349 ± 356; b) W. Q. Yang, T.
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2263; g) J. A. Marshall, H. Jiang, J. Org. Chem. 1999, 64, 971 ± 975;
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401; for work prior to 1999 including the important contributions from
Hydroquinone ± squamocin D dimethyl ether (29): Alcohol 28 (14.8 mg,
15.3 mmol) was dissolved in CH2Cl2 (300 mL). HF (5% in MeCN, 500 mL)
was added and the mixture was stirred for 1 h, 30 min at 08C. The reaction
was quenched with phosphate buffer solution (pH ˆ 7, 2 mL). The aqueous
layer was extracted four times with CHCl3/iPrOH (10 mL). The combined
organic layers were dried with MgSO4. Removal of the solvents in vacuo
and purification by column chromatography (4 g silica, MTBE/MeOH
50:1) afforded triol 29 (8.7 mg, 11.8 mmol, 77%) as a colorless oil. Rf ˆ 0.34
(silica, MTBE/MeOH 50:1); [a]D23 ˆ ‡5.3 (c ˆ 0.17, CHCl3); IR (film): nĈ
3402(brm) (OH), 2927(s)/ 2856(s) (CH), 1463(m), 1413(w), 1352(w),
1
1262(w), 1195(w), 1108(w), 1062(m), 964(w), 878(w), 802(w) cm
;
Á
the groups of T. R. Hoye, B. Figadere, and B. M. Trost see refs. [1] and
1HNMR (300 MHz, CDCl3): d ˆ 0.86 (t, J ˆ 6.6 Hz, 3H; 34-H3), 1.20 ±
1.68 (m, 42H; 4-H2 to 14-H2, 17-H', 18-H', 21-H', 22-H', 25-H2 to 27-H2,
29-H2 to 33-H2), 1.88 ± 2.00 (m, 4H; 17-H'', 18-H'', 21-H'', 22-H''), 2.13 (s,
3H; 39-H3), 2.53 (t, J ˆ 6.4 Hz, 2H; 3-H2), 3.33 ± 3.43 (m, 2H; 15-H, 24-H),
3.54 ± 3.62 (m, 1H; 28-H), 3.74 ± 3.89 (m, 16H; 16-H, 19-H, 20-H, 23-H, 4 Â
OCH3); 13CNMR (75 MHz, CDCl3): d ˆ 11.6 (C-39), 14.1 (C-34), 21.7 (C-
26), 22.6 (C-33), 25.6, 27.0, 28.4, 28.9, 29.0, 29.4, 29.5, 29.61, 29.63, 29.67,
29.73, 30.1, 30.3, 31.8 (C-3 to C-13, C-17, C-18, C-21, C-22, C-30 to C-32),
33.2 (C-25), 33.4 (C-14), 37.3, 37.5 (C-27, C-29), 60.6, 61.0, 61.08, 61.09 (4 Â
OCH3), 71.7 (C-28), 73.9, 74.1 (C-15, C-24), 81.77, 81.84, 83.1, 83.2 (C-16,
C-19, C-20, C-23), 124.9, 130.4 (C-2, C-35), 144.6, 144.7, 147.6, 147.7 (C-1,
[6b].
[3] a) G.-X. Zhao, L. R. Miesbauer, D. L. Smith, J. L. McLaughlin, J. Med.
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Emde, U. Koert, Eur. J. Org. Chem. 2000, 1889 ± 1904.
‡
C-36, C-37, C-38); HR-MS (EI): found: 736.5492 [M] ; calcd: 736.5489.
[6] a) S. Bäurle, S. Hoppen, U. Koert, Angew. Chem. 1999, 111, 1341 ±
1344; Angew. Chem. Int. Ed. 1999, 38, 1263 ± 1266; b) S. Hoppen, S.
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Chem. Soc. 1998, 120, 11279Ð11284; d) S. Takahashi, T. Nakata,
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Pestic. Sci. 1991, 33, 427 ± 438; b) T. Friedrich, P. Van Heek, H. Leif, T.
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235; c) E. Estronell, J. R. Tormo, D. Cortes, Biochem. Biophys. Res.
Quinone ± squamocin D (Quinone ± asiminacin): The triol 29 (4.0 mg,
5.4 mmol) and pyridine-2,6-dicarboxylic acid (5.5 mg, 33 mmol) were
dissolved in MeCN (0.4 mL) and water (0.4 mL). CAN (36 mg, 66 mmol)
was added at 08C. The reaction mixture was stirred for 4 h. The reaction
was quenched by adding CHCl3/iPrOH (2 mL) and water (1 mL). The
aqueous layer was extracted five times with CHCl3/iPrOH (2 mL). The
combined organic layers were dried with MgSO4. Removal of the solvents
and purification by column chromatography (2 g silica, n-hexane/iPrOH
5:1) afforded quinone ± squamocin D (2.7 mg, 3.8 mmol, 70%) as a yellow
oil. Rf ˆ 0.28 (silica, n-hexane/iPrOH 5:1); [a]2D2 ˆ ‡3.1 (c ˆ 0.13, CHCl3);
1HNMR (300 MHz, CDCl3): d ˆ 0.86 (t, J ˆ 6.6 Hz, 3H; 34-H3), 1.20 ± 1.67
(m, 42H; 4-H2 to 14-H2, 17-H', 18-H', 21-H', 22-H', 25-H2 to 27-H2, 29-H2 to
33-H2), 1.89 ± 2.10 (m, 4H; 17-H'', 18-H'', 21-H'', 22-H''), 1.99 (s, 3H; 39-
H3), 2.42 (t, J ˆ 6.4 Hz, 2H; 3-H2), 3.37 ± 3.53 (m, 2H; 15-H, 24-H) overlap
with 3.53 ± 3.62 (m, 1H; 28-H), 3.84 ± 3.98 (m, 10H; 16-H, 19-H, 20-H, 23-
H, 2  OCH3); 13CNMR (75 MHz, CDCl3): d ˆ 11.9 (CH3 ± 39), 14.1 (C-34),
21.4 (C-26), 22.6 (C-33), 25.4, 25.7, 26.4, 28.67, 28.74, 29.4, 29.5, 29.6, 29.7,
29.9, 31.9 (C-3 to C-13, C-17, C-18, C-21, C-22, C-30 to C-32), 32.6 (C-25),
33.1 (C-14), 36.8, 37.7 (C-27, C-29), 61.2 (OCH3), 71.7 (C-28), 74.4, 74.7 (C-
15, C-24), 81.7, 81.8, 82.9, 83.0 (C-16, C-19, C-20, C-23), 138.7, 143.1, 144.2
(C-2, C-35, C-37, C-38), 184.2, 184.7 (C-1, C-36); HRMS (EI): found:
Â
Commun. 1997, 240, 234 ± 238; d) M. C. Gonzalez, J. R. Tormo, A.
Bermejo, M. C. Zafra-Polo, E. Estornell, D. Cortes, Bioorg. Med.
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Shimada, J. B. Grutzner, J. F. Kozlowski, J. L. McLauglin, Biochem-
istry 1998, 37, 854 ± 866.
Â
‡
708.5177 [M ‡ 2  H] ; calcd: 708.5176.
[8] a) R. M. Hollingworth, K. I. Ahammadsahib, G. Gadelhak, J. L.
McLaughlin, Biochem. Soc. Trans. 1994, 22, 230 ± 233; b) M. Degli Es-
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Compound 35: This compound was prepared from (3S)-3-(tert-butyldime-
thylsilyloxy)-4-[(5'S)-5'-methyl-2'-oxo-2',5'-dihydro-furan-3'-yl]butanal[6a,b]
by side chain elongation by means of a Wittig reaction. Rf ˆ 0.66 (CHCl3/
MeOH 10:1); 1HNMR (300 MHz, CDCl3): d ˆ 0.85 (t, J ˆ 7.0 Hz, 3H; 14'-
H3), 1.40 (d, J ˆ 7.2 Hz, 3H; CH3), 1.11 ± 1.52 (m, 20H; 4'-13'-H2), 1.87 ± 2.32
(m, 2H; 3'-H2), 2.32 ± 2.60 (m, 2H; 1'-H2), 3.73 ± 3.91 (m, 1H; 2'-H2), 4.93 ±
5.09 (m, 1H; 5-H), 7.10 ± 7.19 (m, 1H; 4-H); 13CNMR (75 MHz, CDCl3):
d ˆ 14.1 (C-14'), 19.1 (CH3), 22.7, 25.6, 29.3, 29.6, 29.7, 31.9, 33.3, 37.4 (C-
1',3'-13'), 70.0 (C-2'), 77.9 (C-5), 124.2 (C-3), 151.8 (C-4), 174.8 (C-2);
[11] U. Koert, M. Stein, H. Wagner, Liebigs Ann. 1995, 1415 ± 1426.
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‡
HRMS (EI): found 311.2581 [M H] ; calcd: 311.2586.
1004
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0705-1004 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 5

Quinone ± Annonaceous Acetogenins
993±1005
Á
Â
[14] B. Figadere, J.-C. Harmange, L. X. Hui, A. Cave, Tetrahedron Lett.
[22] The cyclic voltammograms of various quinones and butenolide
samples are given in the Supporting Information.
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Â
Â
[16] P.-E. Sum, L. Weiler, Can. J. Chem. 1978, 56, 2700 ± 2702.
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Kuwabara, H. Iwamura, T. Yagi, Biochemistry 1998, 37, 6436 ± 6445.
[25] Compound 35 was prepared during the total synthesis of mucocin.[6a,b]
Analytical data for 35 are given at the end of the Experimental
Section.
[21] C. R. Lancaster, H. Michel, Structure 1997, 5, 1339 ± 1359.
Received: August 9, 2000 [F2660]
Chem. Eur. J. 2001, 7, No. 5
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0705-1005 $ 17.50+.50/0
1005