Asymmetric syntheses and Wnt signal inhibitory activity of melleumin A and four analogues of melleumins A and B

Article abstract of DOI:10.1002/asia.200800355

The first total synthesis of melleumin A and four analogues of melleumins A and B is described. The N-acyl L-Thr-Gly/β-hydroxy-γ-amino acid coupling/macrolactamization strategy allowed the efficient assembly of the three segments being free of epimerization. While the Jouin-Castro method with minor modification allows a rapid entrance to the key syn-β-hy-droxy-y-amino acid segment, required for the synthesis of melleumin A, an extension of our malimide-based methodology using a changed N-protecting group affords a flexible access to several anti-β-hydroxy-γ-amino acids, and hence analogues of melleumins A and B. Among them, unnatural 4-epi-melleumin B (2a) exhibits a modest inhibitory activity on Wnt signaling. The total synthesis of melleumin A allowed confirmation of its full structure.

Full text of DOI:10.1002/asia.200800355

FULL PAPERS
DOI: 10.1002/asia.200800355
Asymmetric Syntheses and Wnt Signal Inhibitory Activity of Melleumin A
and Four Analogues of Melleumins A and B
Jie-Min Luo,[a] Chao-Feng Dai,[a] Shu-Yong Lin,[b] and Pei-Qiang Huang*[a]
Abstract: The first total synthesis of
melleumin A and four analogues of
melleumins A and B is described. The
droxy-g-amino acid segment, required
for the synthesis of melleumin A, an
extension of our malimide-based meth-
odology using a changed N-protecting
group affords a flexible access to sever-
al anti-b-hydroxy-g-amino acids, and
hence analogues of melleumins A and
B. Among them, unnatural 4-epi-mel-
leumin B (2a) exhibits a modest inhibi-
tory activity on Wnt signaling. The
total synthesis of melleumin A allowed
confirmation of its full structure.
N-acyl
l-Thr-Gly/b-hydroxy-g-amino
acid coupling/macrolactamization strat-
egy allowed the efficient assembly of
the three segments being free of epi-
merization. While the Jouin–Castro
method with minor modification allows
a rapid entrance to the key syn-b-hy-
Keywords: asymmetric synthesis ·
biological activity · natural prod-
ucts · total synthesis · Wnt signal
inhibition
Introduction
studies on the secondary metabolites of the myxomycetes
have so far been limited, more than 100 secondary metabo-
lites have been investigated.[5b]
Natural products are not only important sources for drug
discovery and development, many natural products have
also become indispensable tools for biological studies.[1,2]
Since the emergence of combinatorial chemistry in the
1980s,[3] their importance in drug development has widely
been ignored. However, in recent years there has been a
renaissance of natural products as drug candidates.[4] Among
various sources of natural products, slime molds (myxomy-
cetes), a group of fungus-like organisms usually present in
terrestrial ecosystems, have been shown to be a valuable
source of new biological active metabolites (natural prod-
ucts).[5] The myxomycete life cycle involves two very differ-
ent trophic (feeding) stages, one consisting of uninucleate
amoebae and the other consisting of a distinctive multinu-
cleate structure, the plasmodium.[5b] Although chemical
In 2005, Ishibashi and co-workers reported the isolation
of a novel peptide lactone melleumin A (1) and its seco acid
methyl ester, melleumin B (2) (Figure 1), from the cultured
plasmodium of the myxomycete physarum melleum.[6] In a
subsequent study, through the synthesis of the segments, the
full absolute stereochemistry of melleumin A (1) and mel-
leumin B (2) was determined, jointly by a modification of
Mosherꢀs method and chiral HPLC analysis, as 3S,4S,10S,
and 11R.[7] The total synthesis of melleumin B confirmed
this absolute stereochemistry. Interestingly, while melleumin
B
is inactive, the 10R-, and 3R-epimers, as well as
(3R,4S,10R,11R)-epimer of melleumin B (2) show a moder-
[a] J.-M. Luo, Dr. C.-F. Dai, Prof. Dr. P.-Q. Huang
Department of Chemistry and Key Laboratory for Chemical Biology
of Fujian Province
College of Chemistry and Chemical Engineering, Xiamen University
Xiamen, Fujian 361005 (China)
Fax : (+86)592-2186400
E-mail: pqhuang@xmu.edu.cn
[b] S.-Y. Lin
School of Life Science, Xiamen University
Xiamen, Fujian 361005 (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.200800355.
Figure 1. Structure of melleumin A (1) and B (2) (the stereochemistry at
the C-4 position of melleumin A was confirmed in this study).
328
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Chem. Asian J. 2009, 4, 328 – 335

Table 1. Syn- and anti-b-hydroxy-g-amino acid residues and the parent natural products.
Entry
R
Absolute Configuration
(3S,4S)-statine
(3S,4R)-statine
(3S,4S)-AHPPA
(3S,4S)-ACHPA
(3R,4S)-AHPPA
(2S,3S,4R)-AHMPA
Parent Natural Products
Bioactivity
1
2
3
4
5
6
iBu
iBu
Bn
c-hexCH2
Bn
G
pepstatins[11]
peptide mimetics
potent histone deacetylase inhibitor
peptide mimetics
peptide mimetics
MDR-reversing activity
antitumor antibiotic
E
spiruchostatin[12]
ahpatinins[13]
ACHTUNGTRENNUNG
N
unnatural[14]
T
hapalosin[15]
Me
A
bleomycins 1[16,17]
phleomycins[16]
didemnine B[18]
nordidemnines A–C[19]
dolastatin 10[20]
simplostatin 1[21]
7
8
9
sBu
iPr
sBu
G
antiviral, cytotoxic immunsuppressive
antiviral, cytotoxic immunsuppressive
phase I/II (anticancer)
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
cytotoxicity
ate Wnt signal inhibitory activity.[7,8] Wnt proteins, derived
from the Drosophila Wingless (Wg) and the mouse Int-1
genes, play important roles in embryogenesis and carcino-
genesis.[9] The Wnt signaling pathway has been identified as
a proto-oncogene in mammary tumors with links to tumor-
genesis such as adenomatous polyposis, colon carcinoma,
medulloplastoma, tuberous sclerosis as well as lung cancer.
The study of Wnt and its signaling pathways may open new
avenues for disease treatment.
Figure 2. Syn- and anti-b-hydroxy-g-amino acid residues found in bioac-
Results and Discussion
tive natural products.
In connection with a related program,[10] we now report the
first total syntheses of melleumin A, 4-epi-melleumin A, 4-
epi-melleumin B, 4-epi-deoxymelleumin A, and 4-epi-deoxy-
melleumin B.
an anti-b-hydroxy-g-amino acid segment. The second chal-
lenge was the incorporation of the b-hydroxy-g-amino acid
segment into the target molecule, which might be complicat-
ed by side reactions such as b-elimination,[22] protecting
group migration, g-lactam formation,[12,15] as well as saponifi-
cation of the ester.
Melleumins A and B consist of three amino acid residues,
namely N-acylated l-threonine, glycine, and a hitherto un-
known b-hydroxy-g-amino acid. The key to the synthesis of
these molecules and of their analogues resided on a flexible
approach to the b-hydroxy-g-amino acid residue. At the
time when this work began, the first challenge for synthesis
was that the stereochemistry at C-4 of melleumins A and B
was unknown. Because both syn- and anti-b-hydroxy-g-
amino acids are found in several natural products as rele-
vant substructures (see Figure 2 and Table 1),[11–21] we decid-
ed first to synthesize (3S,4R)-melleumins A and B bearing
Synthesis of (3S,4R)-Melleumin A (1a) and (3S,4R)-
Melleumin B (2a)
As can be seen from the retrosynthetic analysis shown in
Scheme 1, (3S,4R/S)-diastereomers of melleumins A and B
can be synthesized from segment A (3) and segment B (4)
or segment C (5). For the construction of the macrocyclic
Abstract in Chinese:
Scheme 1. Retrosynthetic analysis of (3S,4R/S)-diastereomers of melleu-
mins A and B.
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329

P.-Q. Huang et al.
FULL PAPERS
system, we elected to explore a macrolactamization instead
of a macrolactonization strategy.[12]
The segment A (3) was synthesized from l-Thr by methyl
esterification, N-acylation, saponification, and EDCI/HOBt-
mediated coupling of N-acylated l-Thr 6 with glycine benzyl
ester tosylic acid salt at 08C (Scheme 2).
droxylation of the hemiacetal 8 was assumed to proceed via
the N-acyliminium ion intermediate A.[25] While a working
model was proposed to explain the highly trans-diastereose-
lective reduction of the N-acyliminium ion intermediate sim-
ilar to A,[10d] a computational study is required to fully un-
derstand the origin of the stereoselectivity.
Treatment of lactam 9 with RhCl3 hydrate[23] in ethanol
under reflux for 2 h, followed by treatment of the resulting
enamide with AcOH/H2O under reflux for 20 h produced
the desired lactam 10 with an overall yield of 77%. Reac-
tion of lactam 10 with di-tert-butyl dicarbonate gave imide
11 with a yield of 90%. Catalytic transfer hydrogenolysis of
11 produced the bis-debenzylated product 12 in 85% yield,
which was hydrolyzed (LiOH, THF, H2O) to give 13, and
then to segment B (4) by successive O-silylation and hydrol-
ysis of the concomitantly formed acid silyl ester.
Coupling of segments A (3) and B (4) using Yamaguchiꢀs
reagent[26] furnished the desired product 14 in 70% yield
(Scheme 4). To avoid any complication after the macrolac-
tamization, we decided to first remove the O-protecting
group (TBS), expecting that the nitrogen is more nucleo-
philic than the oxygen, and macrolactamization would domi-
nate over the competing macrolactonization. Indeed, after
desilyation with tetrabutylammonium fluoride (60% yield),
followed by N-deprotection with trifluoroacetic acid, and
catalytic hydrogenolysis of the crude product yielded, the re-
sulting 15 was treated with DPPA (iPr2NEt, DMF)[27] to give
the macrolactamized product (3S,4R)-melleumin A (1a) in
Scheme 2. The synthesis of segment A (3). Reagents and conditions:
a) SOCl2, MeOH, 100%; b) 4-methoxybenzoyl chloride, Et3N, CH2Cl2,
86%; c) LiOH, THF/MeOH/H2O, 100%; d) H-Gly-OBzl·TsOH, EDCI,
HOBt, NMM, DMF, 87%.
The (3S,4R)-b-hydroxy-g-amino acid segment B (4) was
synthesized starting from N-allyl (S)-malimide 7a,[10] in
which an allyl group[23] was selected as the N-protecting
group.[24] The requisite malimide 7a was prepared from (S)-
malic acid in a three-pot manner,[10] which provided mali-
mide 7a with an overall yield of 77% (Scheme 3). Stepwise
reductive alkylation of malimide 7a led, regio- and diaster-
eo-selectively, to lactam 9 with an overall yield of 79%. The
origin of the observed high regioselectivity in the Grignard
addition was revealed by calculation.[10c] The reductive dehy-
Scheme 3. The synthesis of segment B (4). Reagents and conditions: a) p-
BnOC6H4CH2MgCl, THF, 85%; b) Et3SiH, BF3·OEt2, CH2Cl2, ꢀ788C–
RT, 91%; c) RhCl3·nH2O, EtOH, refl. 2 h; AcOH, H2O, refl. 20 h, 77%;
d) Boc2O, Et3N, DMAP, CH2Cl2, 90%; e) 10% Pd/C, HCO2H, MeOH,
85%; f) LiOH, THF, H2O, 100%; g) TBSCl, imid., DMAP, DMF;
K2CO3, MeOH, THF, H2O, 90%.
Scheme 4. Reagents and conditions: a) Cl3C6H2COCl, Et3N, DMAP, 70%
(for 14); 82% (for 14a); b) TBAF, THF, RT, 60% (for 15); 85% (for
15a); c) TFA, CH2Cl2; H2, 10% Pd/C, EtOH; DPPA, iPr2NEt, DMF,
30% (for 1a); 58% (for 1b).
330
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Asymmetric Synthesis and Signal Inhibitory Activity
an overall yield of 30% from 15. The differences between
the 1H NMR and 13C NMR data of (3S,4R)-melleumin A
(1a) and those of the natural melleumin A (1),[6] allowed us
to deduce that this compound is the 4-epi-melleumin A
(1a), namely, the natural product is (3S,4S)-melleumin A
(1).
We then synthesized (3S,4R)-melleumin B (2a). Thus, on
the one hand benzyl ester 3 was cleaved to give the corre-
sponding acid 16 by catalytic hydrogenolysis and on the
other hand, cleavage of Boc in compound 17a (obtained by
cyanide-promoted methanolysis[28] of imide 12) with TFA
gave the b-hydroxy-g-amino acid ester 18a (Scheme 5). Cou-
Scheme 6. Synthesis of segment C (5). Reagents and conditions: a) Mel-
drumꢀs acid, iso-propyl chloroformate, DMAP, CH2Cl2; b) EtOAc, refl.
1 h; c) NaBH4, CH2Cl2, CH3COOH, ꢀ108C, two steps 50%; d) LiOH,
THF, H2O; TBSCl, imid., DMAP, DMF; K2CO3, MeOH, THF, H2O,
85%.
tion of 19 with Meldrumꢀs acid followed by refluxing the
product in ethyl acetate led to the desired tetramic acid 21.
Reduction of 21 with sodium borohydride in the presence of
10% HOAc at ꢀ108C gave cis-22 as the only observable
diastereomer in an overall yield of 50% from 19. Hydrolysis
of the imide 22 under basic conditions (LiOH, THF, H2O),
followed by O-silylation (TBSCl, imid., DMAP, DMF), and
treatment of the resulting silylated product with aqueous
K2CO3 produced the desired segment C (5).
Coupling of segment A (3) with segment C (5) using Ya-
maguchiꢀs reagent[26] produced the desired product 23 in
70% yield (Scheme 7). O-Desilylation with tetrabutylammo-
nium fluoride yielded 24 in 60% yield. N-Deprotection of
24 with trifluoroacetic acid followed by catalytic hydroge-
nolysis and macrolactamization (DPPA, iPr2NEt, DMF)[27]
gave (3S,4S)-melleumin A (1) in an overall yield of 30%
Scheme 5. The synthesis of (3S,4R)-melleumin B (2a) and (3S,4R)-deoxy-
melleumin B (2b). Reagents and conditions: a) H2, 10% Pd/C, EtOH,
80%; b) TFA, CH2Cl2, 08C, 82%; c) EDCI, HOBt, NMM, DMF, 60%
(for 2a); 54% (for 2b).
1
from 24. The H and 13C NMR spectral data of our synthetic
material are identical with those of the natural product.[6]
The optical rotation of synthetic (3S,4S)-melleumin A (1)
shows the same sense as the natural one {½aꢁ2D0 =+43.3 (c=
20
0.15, CH3OH); ½aꢁD20 =+44.1 (c=1.17, CH3OH) lit.[6] ½aꢁD
=
pling of these two fragments (EDCI, HOBt, NMM, DMF)
gave (3S,4R)-melleumin B (2a) with a yield of 60%. The
difference in 1H NMR and 13C NMR spectra of synthetic
(3S,4R)-melleumin B (2a) compared to those of the natural
melleumin B (2)[6] led us to deduce that this compound is
the 4-epi-melleumin B (2a), namely, the natural product is
(3S,4S)-melleumin B (2).
+27 (c=0.15, CH3OH)}. The difference in the values is
likely a result of only a minute amount of the natural prod-
uct (only 1.6 mg) being available for measuring the optical
rotation.
At this point in time, Ishibashi et al. reported the total
synthesis of melleumin B (2),[7] and they deduced the abso-
lute stereochemistry of melleumin A (1) to be (3S,4S). Our
synthesis of (3S,4S)-melleumin A (1) confirmed this assign-
ment.
The study by Ishibashi and co-workers also demonstrated
that while melleumins A (1) and B (2) are inactive, the
10R-,[7] and 3R-epimers, as well as the (3R,4S,10R,11R)-
epimer[8] of melleumin B (2) show moderate Wnt signal in-
hibitory activity. We decided to synthesize the deoxy ana-
logues of (3S,4R)-melleumins A (1b) and B (2b), and test
their Wnt signal inhibitory activity.
Synthesis of Melleumin A (1)
To confirm the stereochemistry at C-4 of melleumin A, we
decided to synthesize (3S,4S)-melleumin A (1). The requi-
site (3S,4S)-syn-b-hydroxy-g-amino acid 5 was synthesized
by the method of Jouin and Castro[29] with minor modifica-
tion. Thus the phenol hydroxyl group of N-Boc-(S)-tyrosine
was first protected as silyl ether 19 (Scheme 6). Condensa-
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P.-Q. Huang et al.
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er gene TOP-Flash,[32] a b-catenin-responsive reporter plas-
mid with multiple TCF-binding sites (CCTTTGATC). As a
control, we used FOP-Flash that has eight mutated TCF-
binding sites (CCTTTGGCC) and has no response to Wnt
signaling, as previously described.[33] Briefly, HEK293T cells
were cultured in 60 mm plates at 60% confluency and each
plate was transfected with 0.5 mg of TOP-Flash luciferase re-
porter plasmid. At 16 h posttransfection, three plates were
treated with 30 mm of each drug; 20 h later, cells were har-
vested and luciferase activity was determined. As shown in
Figure 3, 4-epi-melleumin B (2a) exhibited a moderate in-
hibition on the reporter gene activity, with a reduction of
approximately 23% compared to that from the untreated
cells (Ctrl).
Scheme 7. Reagents and conditions: a) 3, Cl3C6H2COCl, Et3N, DMAP,
70%; b) TBAF, THF, RT, 60%; c) TFA, CH2Cl2; H2, 10% Pd/C, EtOH;
DPPA, iPr2NEt, DMF, 30%.
Figure 3. TOP/FOP-Flash reporter activation ratio of Melleumin A and
four derivatives of Melleumins
A and B. TOPFLASH and FOP-
Synthesis of (3S,4R)-Deoxymelleumin A (1b) and (3S,4R)-
FLASH=two commercial products of affinity purified DNA. TCF=
Transfection grade T cell factor. HEK293T cells were transfected with
Topflash or Fopflash luciferase reporter and three plates were then treat-
ed with 30 mm of each drug for 20 h before harvest. The experiment was
repeated three times. The luciferase activity from the untreated cells
(Ctrl) was defined as 100%.
Deoxymelleumin B (2b)
For the synthesis of (3S,4R)-deoxymelleumins A and B, the
b-hydroxy-g-amino acid segment 4a was synthesized[30] in
the similar way as described for the synthesis of
4
(Scheme 3), except (S)-malimide 7b[10] was used as the
building block, and ceric ammonium nitrate (CAN)[31] was
used to cleave the N-protecting group (PMB). Coupling of
segment 4a with segment B (3) furnished the desired prod-
uct 14a in 82% yield (Scheme 4). O-Desilylation with tetra-
butylammonium fluoride yielded 15a in 85% yield. Cleav-
age of both O- and N-protecting groups (Bn; Boc) was ach-
ieved by successive treatment with trifluoroacetic acid and
catalytic hydrogenolysis, which after a simple filtration to
give the deprotected compound, which was subjected to
DPPA-mediated macrolactamization to give (3S,4R)-deoxy-
melleumin A (1b) with an overall yield of 58% from 15a.
Following the sequence developed for the synthesis of
(3S,4R)-melleumin B (2a), and using (3S,4R)-17a as the b-
hydroxy-g-amino acid segment, (3S,4R)-deoxymelleumin B
(2b) was synthesized with similar efficiency (Scheme 5).
Since few small molecules are known as Wnt signal inhibi-
tors, we believe that these results are interesting for the
identification of Wnt signal inhibitors from natural products.
The novel derivative of the melleumin group may offer a
potential candidate as a small-molecule inhibitor for Wnt
signaling.
Conclusions
In summary, starting from l-tyrosine, we accomplished the
first total synthesis of melleumin A (1) in 8 steps with an
overall yield of 4.6%, which allowed us to confirm the full
absolute configuration of natural melleumin A (1). By using
our malimide-based synthetic methodology, the asymmetric
synthesis of 4-epi-deoxymelleumin A (1b) and 4-epi-deoxy-
melleumin B (2b) were also achieved in 10 and 8 steps from
(S)-malimide 7b with overall yields of 19.1% and 31.2%,
respectively. Extending the scope of this methodology by
Wnt Signal Inhibitory Activity
We next examined the inhibitory effect of the synthesized
compounds on Wnt signaling by using the luciferase report-
332
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Asymmetric Synthesis and Signal Inhibitory Activity
2a: 4-epi-Melleumin B: TFA (0.40 mL) was added dropwise to a cooled
(08C) solution of compound 17a (30 mg, 0.088 mmol) in CH2Cl2
(1.5 mL). After stirring at RT for 2 h, the reaction mixture was concen-
trated under reduced pressure to afford compound 18a, which was used
directly for the next step without further purification. To a cooled
(ꢀ208C) solution of compound 16 (33 mg, 0.106 mmol) in DMF (1 mL)
in the presence of HOBt (20 mg, 0.150 mmol) was added EDCI (19 mg,
0.097 mmol). The resulting mixture was stirred at ꢀ208C for 0.5 h. To the
resulting solution was added dropwise compound 18a in DMF (1 mL) at
08C in the presence of NMM (24 mL). After stirring at 08C for 5 h and
then at RT overnight, the reaction mixture was diluted with ethyl acetate
(30 mL) and washed successively with 1n HCl, 10% Na2CO3 and brine,
dried over Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography (ethyl acetate/metha-
nol 20:1) to give 4-epi-melleumin B (2a) as a colourless oil (16 mg, yield,
60%). ½aꢁ2D0 =+10.0 (c=0.3 in CH3OH); IR (film): n˜ =3339, 2918, 1727,
using the allyl group as imide/amide N-protecting group al-
lowed the asymmetric synthesis of 4-epi-melleumins A (1a)
and B (2a) in 9 and 7 steps from (S)-malimide 7a with over-
all yields of 5% and 14%, respectively. Compared with the
method used for the synthesis of the b-hydroxy-g-amino
acid segment[7,8] and the strategy for the synthesis of melleu-
min B,[7,8] our approaches are both highly diastereoselective
and free of epimerization. The Wnt signal inhibitory activity
exhibited by 4-epi-melleumin B (2a) demonstrates a poten-
tial value of our flexible and epimerization-free, yet highly
diastereoselective, method for developing more active mel-
leumin A and B analogues.
1642, 1595, 1536, 1498, 1258, 1123, 1031 cmꢀ1 1H NMR (400 MHz,
;
[D6]DMSO): d=1.12 (d, J=6.4 Hz, 3H), 2.19 (dd, J=9.6, 16.4 Hz, 1H),
2.44 (dd, J=9.2, 13.6 Hz, 1H), 2.55 (m, 1H), 2.90 (dd, J=2.8, 12.4 Hz,
1H), 3.54 (s, 3H), 3.59 (m, 1H), 3.61 (m, 1H), 3.76 (m, 2H), 3.82 (s, 3H),
4.07 (m, 1H), 4.29 (dd, J=4.8, 7.2 Hz, 1H), 5.04 (d, J=6.4 Hz, 1H), 5.09
(d, J=6.4 Hz, 1H), 6.62 (d, J=8.4 Hz, 2H), 6.97 (d, J=8.4 Hz, 2H), 7.03
(d, J=9.6 Hz, 2H), 7.57 (d, J=8.4 Hz, 1H), 7.89 (d, J=8.8 Hz, 2H), 7.96
(d, J=7.6 Hz, 1H), 8.24 (brt, J=5.6 Hz, 1H), 9.09 ppm (s, 1H);
13C NMR (100 MHz, [D6]DMSO): d=20.0, 34.9, 38.9, 42.2, 51.1, 55.3,
55.4, 60.0, 66.6, 69.8, 113.5, 114.8, 126.1, 129.2, 129.5, 129.9, 155.4, 161.8,
166.4, 168.4, 170.8, 172.0 ppm; MS (ESI): m/z (%): 554 (100) [M+Na+];
HRESIMS calcd for [C26H33N3O9 +H]+: 532.2290; found: 532.2298.
Experimental Section
General
Optical rotations were recorded on a Perkin–Elmer 341 automatic polar-
imeter. 1H NMR and 13C NMR spectra were recorded on a Bruker 400
spectrometer. 1H NMR spectra were registered in CDCl3, and chemical
shifts are expressed in parts per million (d) relative to internal Me4Si. IR
spectra were recorded on a Nicolet Avatar 360 FT-IR spectrophotometer.
Mass spectra were recorded by Bruker Dalton Esquire 3000 plus and Fin-
nigan Mat-LCQ (ESI direct injection), HRFABMS spectra were record-
ed by a Bruker APEX-FTMS apparatus. Elemental analyses were per-
formed using a Vario RL analyzer. Melting points were determined on a
Yanaco MP-500 melting point apparatus and are uncorrected.
22: (4S,5S)-tert-Butyl 5-(4-(tert-Butyldimethylsilyloxy)benzyl)-4-hydroxy-
2-oxopyrrolidine-1-carboxylate: Meldrumꢀs acid (200 mg, 1.40 mmol) and
DMAP (386 mg, 3.16 mmol) were added to a stirred solution of 19
(500 mg, 1.27 mmol) in dry methylene chloride (15 mL) at 08C under ni-
Tetrahydrofuran was distilled prior to use from sodium benzophenone
ketyl. Methylene chloride was distilled from phosphorus pentoxide. Di-
methylformamide was distilled from calcium hydride. Silica gel (Zhifu,
300–400 mesh) from Yantai silica gel factory (China) was used for
column chromatography, eluting (unless otherwise stated) with ethyl ace-
tate/petroleum ether (PE) (60–908C) mixture.
trogen.
A solution of isopropyl chloroformate in toluene (1.8 mL,
1.90 mmol) was then added dropwise over 1 h, and the reaction mixture
was stirred for 3 h at 08C. The mixture was washed twice with 15%
KHSO4 (5 mL), the organic layer was dried over Na2SO4, and the solu-
tion was concentrated to afford the crude acylated Meldrumꢀs acid. This
material was then refluxed in ethyl acetate (15 mL) for 1 h, and the solu-
tion was concentrated to afford the crude product. The crude product
was dissolved in a mixture of CH2Cl2 (20 mL) and AcOH (2.0 mL), then
cooled to ꢀ108C and stirred vigorously while being treated in portions
with NaBH4 (143 mg, 3.8 mmol). The mixture was then stirred for 4 h at
08C. Cooled saturated NaHCO3 (5 mL) was added to the mixture. The
resulting mixture was extracted with CH2Cl2, the organic layer was
washed with brine, dried (Na2SO4), filtered and concentrated in vacuum.
The crude product was purified by chromatography on silica gel (EtOAc/
PE=1:5) to give (4S,5S)-22 (266 mg, 50%) as white crystals. M.p. 1488C;
½aꢁ2D0 =+22.1 (c=1.7 in CHCl3); IR (film): n˜ =3458, 2957, 2930, 2858,
Syntheses
16:
2-((2S,3R)-3-Hydroxy-2-(4-methoxybenzamido)butanamido)acetic
acid: Compound 3 (110 mg, 0.275 mmol) was dissolved in EtOH (6 mL),
and hydrogenated under an atmosphere of H2 with 10% Pd/C (42 mg).
After stirring overnight at RT, the suspension was filtered through a
short pad of Celite. After being concentrated in vacuum, the crude prod-
uct was purified by flash chromatography (EtOAc/PE 4:1, a little acetic
acid was added) to afford 16 as a colourless liquid (70 mg, yield 82%).
½aꢁ2D0 =+16.6 (c=0.5 in CH3OH); IR (film): n˜ =3326, 2972, 1726, 1641,
1606, 1503, 1257, 1181, 1022 cmꢀ1 1H NMR (400 MHz, CDCl3): d=1.14
;
1777, 1510, 1256, 1157 cmꢀ1 1H NMR (400 MHz, CDCl3): d=0.17 (s,
;
(brs, 3H), 2.05 (s, 1H), 3.64 (s, 3H), 3.92 (m, 2H), 4.35 (m, 1H), 4.67 (m,
1H), 6.76 (m, 2H), 7.64–7.86 ppm (m, 4H); 13C NMR (100 MHz, CDCl3):
d=18.7, 41.5, 49.4, 55.4, 67.6, 113.8, 125.2, 129.3, 162.6, 168.2, 171.8,
172.6 ppm; MS (ESI): m/z (%): 333 (100) [M+Na+], 349 (13.5) [M+K+
]; HRESIMS calcd for [C14H18N2O6 +Na]+: 333.1057; found: 333.1059.
6H), 0.96 (s, 9H), 1.51 (s, 9H), 2.35 (dd, J=8.4, 17.2 Hz, 1H), 2.57 (dd,
J=7.6, 17.2 Hz, 1H), 3.07 (d, J=6.0 Hz, 2H), 4.38 (dd, J=6.0, 6.9 Hz,
1H), 4.48 (ddd, J=6.9, 7.6, 8.4 Hz, 1H), 6.76 (d, J=8.4 Hz, 2H),
7.14 ppm (d, J=8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=ꢀ4.5,
18.1, 25.6, 28.0, 33.0, 40.1, 62.6, 65.6, 83.3, 120.1, 130.1, 130.7, 149.8, 154.3,
171.7 ppm; MS (ESI): m/z (%): 422 (100) [M+H+]; elemental analysis:
calcd (%) for C22H35NO5Si: C 62.67, H 8.37, N 3.32; found: C 62.91,
H 8.77, N 3.08.
17a: (3S,4R)-methyl 4-(tert-butoxycarbonylamino)-3-hydroxy-5-(4-hy-
droxyphenyl) pentanoate: THF (5 mL) and MeOH (5 mL) were added
to a mixture of compound 12 (418 mg, 1.36 mmol) and KCN (9 mg,
0.14 mmol). After stirring for 60 h at RT, the volatile was removed under
reduced pressure. The residue was purified by flash chromatography
(EtOAc/PE 1:5) to afford 17a as white crystals (322 mg, yield 70%).
M.p. 1498C; ½aꢁ2D0 =+13.6 (c=1.0 in CH3OH); IR (film): n˜ =3400, 2919,
5:
(3S,4S)-4-(tert-Butoxycarbonyl)-3-(tert-butyldimethylsilyloxy)-5-(4-
(tert-butyldi-methylsilyloxy)phenyl)pentanoic acid: Lithium hydroxide
monohydrate (48 mg, 1.14 mmol) was added to a solution of compound
22 (240 mg, 0.57 mmol) in a mixed solvent (THF/H2O v/v=3:1, 12 mL)
in one portion at 08C. After stirring at the same temperature for 1 h, the
reaction mixture was diluted with ice water (10 mL), then acidified to
pH 2–3 with 1m HCl. The resulting mixture was extracted with EtOAc.
The combined organic layers were washed with brine, dried (Na2SO4), fil-
tered and concentrated in vacuo to give a colorless oil, which was used in
the following reaction without further purification. The crude product,
TBSCl (214 mg, 1.43 mmol), imidazole (155 mg, 2.28 mmol) and DMAP
(10 mg, 0.09 mmol) in DMF (7 mL) was stirred 48 h at RT. The resulting
1
1738, 1651, 1556, 1384, 1253, 1161 cmꢀ1; H NMR (400 MHz, CDCl3): d=
1.37 (s, 9H), 2.50 (dd, J=8.8, 16.4 Hz, 1H), 2.57 (brd, J=15.6 Hz, 1H),
2.74 (dd, J=8.0, 14.0 Hz, 1H), 2.87 (dd, J=4.0, 14.0 Hz, 1H), 3.65 (brs,
1H), 3.71 (s, 3H), 3.81 (brs, 1H), 3.98 (brs, 1H), 4.61 (d, J=8.0 Hz, 1H),
5.83 (brs, 1H), 6.73 (d, J=7.6 Hz, 2H), 7.05 ppm (d, J=8.0 Hz, 2H);
13C NMR (100 MHz, CDCl3): d=28.3, 35.1, 38.0, 52.0, 55.5, 70.1, 79.9,
115.4, 129.2, 130.5, 154.6, 156.0, 173.4 ppm; MS (ESI): m/z (%): 362 (100)
[M+Na+]; elemental analysis: calcd (%) for C17H25NO6: C 60.16, H 7.42,
N 4.13; found: C 60.43, H 7.67, N 3.97.
Chem. Asian J. 2009, 4, 328 – 335
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
333

P.-Q. Huang et al.
FULL PAPERS
mixture was diluted with water (40 mL) and extracted with ether (5ꢂ
20 mL). The combined organic phases were washed with brine (5 mL),
dried over anhydrous Na2SO4 and filtered. After concentration under re-
duced pressure, the residue was dissolved in a mixed solvent (MeOH/
THF v/v=3:1, 12 mL). To the solution K2CO3 (236 mg, 1.71 mmol) was
added in one portion at 08C. After stirring at RT for 30 min, the reaction
mixture was concentrated under reduced pressure, diluted with brine
(15 mL), then acidified to pH 4–5 with 1m KHSO4. The mixture was ex-
tracted with ether (5ꢂ10 mL). The combined organic phases were
washed with brine (2 mL), dried over anhydrous Na2SO4 and filtered.
After concentration under reduced pressure, the residue was purified by
(100 MHz, MeOD): d=17.3, 28.8, 38.1, 40.5, 42.3, 56.0, 57.2, 58.4, 68.0,
69.9, 71.7, 80.2, 114.9, 116.1, 126.9, 129.3, 129.6, 130.6, 131.3, 137.1, 157.0,
164.4, 171.0, 172.6 ppm; MS (ESI): m/z (%): 730 (100) [M+Na+]; HRE-
SIMS calcd for [C37H45N3O11 +H]+: 708.3127; found: 708.3118.
1: Melleumin A: TFA (1.6 mL) was added dropwise to an ice-cold solu-
tion of compound 24 (120 mg, 0.17 mmol) in CH2Cl2 (6 mL). After stir-
ring at 08C for 2 h, the mixture was concentrated under reduced pressure.
The residue was dissolved in EtOH (6 mL), and hydrogenated under an
atmosphere of H2 using 10% Pd/C (120 mg) at RT for 2.5 h. The reaction
mixture was flash-filtered through a short column and the filtrate evapo-
rated under reduced pressure. The residue was dissolved in DMF
(120 mL). To this cooled (08C) solution diphenylphosphoryl azide
(110 mL, 0.51 mmol) and di-iso-propylethylamine (170 mL, 1.02 mmol)
were added dropwise. After stirring at 08C for 5 h and then at RT for 2
d, the reaction mixture was diluted with ethyl acetate (800 mL) washed
with water (5ꢂ100 mL), brine (2ꢂ60 mL), dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The residue was puri-
fied by flash chromatography to give melleumin A (1) (25 mg, yield
flash chromatography on silica gel (EtOAc/PE=1:10) to afford
5
(268 mg, yield 85%) as a pale yellow solid. M.p. 1798C; ½aꢁ2D0 =ꢀ17.8 (c=
1.9 in CHCl3); IR (film): n˜ =3320, 2950, 2930, 1710, 1510, 1408, 1370,
1
1260, 1170, 1100 cmꢀ1; H NMR (400 MHz, CDCl3) arising from the pres-
ence of two rotamers, signals in 1H NMR spectrum were broadened: d=
0.09 (s, 3H), 0.13 (s, 3H), 0.16 (s, 6H), 0.93 (s, 9H), 0.97 (s, 9H), 1.27–
1.35 (m, 9H), 2.47–2.67 (3H, complex), 2.82 (1H, complex), 3.76–4.66
(2H, complex), 5.79 (brs, 1H), 6.75 (d, J=8.3 Hz, 2H), 7.05 ppm (d, J=
8.3 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=ꢀ4.7, ꢀ4.5, ꢀ4.3, 18.1,
18.2, 25.7, 25.9, 28.1, 28.3, 29.7, 36.7, 37.6, 38.9, 40.0, 55.3, 57.6, 70.1, 79.8,
80.3, 120.0, 129.9, 130.1, 130.6, 131.4, 154.1, 156.2, 156.7, 174.9,
175.6 ppm; MS (ESI): m/z (%): 576 (100) [M+Na+]; elemental analysis:
calcd (%) for C28H51NO6Si2: C 60.72, H 9.28, N 2.53; found: C 60.63,
H 9.55, N 2.35.
30%) as
a
pale yellow amorphous solid. ½aꢁ2D0 =+44.1 (c=1.17 in
CH3OH) {lit.[6] ½aꢁD26 =+27 (c=0.15 in CH3OH)}; IR (film): n˜ =3350,
2920, 2855, 1724, 1657, 1615, 1502, 1360, 1255, 1179, 1059 cmꢀ1 1H NMR
;
(400 MHz, [D6]DMSO): d=1.21 (d, J=6.3 Hz, 3H), 2.37 (m, 1H), 2.56
(m, 1H), 2.59 (m, 1H), 2.87 (dd, J=2.1, 14.3 Hz, 1H), 3.48 (m, 2H), 3.75
(m, 1H), 3.82 (s, 3H), 4.13 (m, 1H), 5.01 (dd, J=3.5, 8.9 Hz, 1H), 5.45
(d, J=4.4 Hz, 1H), 5.65 (qd, J=3.6, 6.3 Hz, 1H), 6.20 (d, J=10.0 Hz,
1H), 6.64 (d, J=8.5 Hz, 2H), 6.97 (d, J=8.5 Hz, 2H), 7.01 (d, J=8.8 Hz,
2H), 7.93 (d, J=8.8 Hz, 2H), 8.10 (d, J=8.9 Hz, 1H), 8.52 (brt, J=
5.6 Hz, 1H), 9.16 ppm (brs, 1H); 13C NMR (100 MHz, [D6]DMSO): d=
16.2, 30.8, 38.7, 44.4, 54.8, 54.9, 55.4, 69.6, 71.7, 113.5, 115.0, 126.0, 129.3,
129.4, 129.6, 155.5, 161.8, 166.6, 169.1, 169.2, 170.8 ppm; MS (ESI): m/z
(%): 522 (100) [M+Na+]; HRESIMS calcd for [C25H29N3O8 +H]+:
500.2027; found: 500.2022.
23: (3S,4S)-((2R,3S)-4-(2-(Benzyloxy)-2-oxo-ethylamino)-3-(4-methoxy-
benzamido)-4-oxobutan-2-yl)-4-(tert-butoxycarbonyl)-3-(tert-butyldime-
thylsilyloxy)-5-(4-(tert-butyldimethylsilyloxy)phenyl)pentanoate: Triethyl-
amine (110 mL, 0.79 mmol) and 2,4,6-trichlorobenzoyl chloride (110 mL,
0.66 mmol) were added sequentially to a solution of acid 5 (364 mg,
0.66 mmol) in anhydrous THF (3 mL). After stirring at RT for 40 min, a
solution of compound
3 (369 mg, 0.92 mmol) and DMAP (160 mg,
1.32 mmol) in anhydrous THF (9 mL) was added. The reaction mixture
was stirred at RT for 18 h and then quenched with aqueous NH4Cl. Vola-
tiles were removed under reduced pressure and the remaining aqueous
solution was extracted with EtOAc. The combined organic extracts were
washed with brine, dried over Na2SO4, and concentrated under reduced
pressure. Purification by flash chromatography (EtOAc/PE 1:2) afforded
23 (433 mg, yield 70%) as a colourless oil. ½aꢁ2D0 =ꢀ6.9 (c=1.7 in CHCl3);
IR (film): n˜ =3350, 2950, 2930, 1740, 1690, 1640, 1610, 1509, 1390, 1255,
Acknowledgements
We are grateful to the NSFC (20572088, 20832005) and the program for
Innovative Research Team in Science & Technology (University) in
Fujian Province for financial support. We thank Dr. Sheng-Cai Lin
(School of Life Sciences, Xiamen University) for help with the Wnt re-
porter assays, and Professor G. M. Blackburn for valuable discussion.
1176 cmꢀ1 1H NMR (400 MHz, CDCl3): d=0.09 (s, 3H), 0.10 (s, 3H),
;
0.15 (s, 6H), 0.93 (s, 9H), 0.96 (s, 9H), 1.25 (s, 9H), 1.30 (d, J=6.4 Hz,
3H), 2.34 (dd, J=2.8, 14.0 Hz, 1H), 2.66 (m, 2H), 2.72 (m, 1H), 3.85 (s,
3H), 4.00–4.05 (m, 3H), 4.11 (dd, J=5.4, 18.7 Hz, 1H), 4.77 (brd, J=
10.1 Hz, 1H), 4.90 (m, 1H), 5.14 (s, 2H), 5.50 (brs, 1H), 6.70 (d, J=
8.2 Hz, 2H), 6.86–7.05 (m, 5H), 7.30–7.36 (m, 5H), 7.69–7.88 ppm (m,
3H); 13C NMR (100 MHz, CDCl3): d=ꢀ4.8, ꢀ4.5, ꢀ4.2, 16.2, 18.1, 18.2,
25.7, 25.9, 28.2, 38.6, 40.3, 41.4, 54.6, 55.4, 56.9, 67.0, 70.2, 70.6, 79.4,
113.7, 113.8, 120.1, 125.6, 128.3, 128.4, 128.5, 128.6, 129.5, 129.9, 130.7,
135.2, 154.2, 156.0, 162.5, 167.5, 169.1, 169.4, 169.5 ppm; MS (ESI): m/z
(%): 958 (100) [M+Na+]; HRESIMS calcd for [C49H73N3O11Si2 +Na]+:
958.4676; found: 958.4685.
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20
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1
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15.2 Hz, 1H), 2.57 (dd, J=8.8, 13.7 Hz, 1H), 2.72 (dd, J=6.3, 13.7 Hz,
1H), 3.72 (m, 1H), 3.81 (s, 3H), 3.96 (d, J=8.2 Hz, 2H), 4.25 (m, 1H),
4.79 (d, J=4.9 Hz, 1H), 5.12 (s, 2H), 5.38 (m, 1H), 6.15 (d, J=9.7 Hz,
1H), 6.63 (d, J=8.4 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 6.98 (d, J=8.4 Hz,
2H), 7.25–7.33 (m, 5H), 7.81 ppm (d, J=8.8 Hz, 2H); 13C NMR
334
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ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2009, 4, 328 – 335

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Published online: December 12, 2008
Chem. Asian J. 2009, 4, 328 – 335
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