Mulberry Diels- Alder adducts: Synthesis of chalcomoracin and mulberrofuran C methyl ethers

Article abstract of DOI:10.1021/ol9026705

(Figure Presented) The synthesis of each of the heptamethyl ethers of the mulberry Diels-Alder adducts chalcomoracin (1) and mulberrofuran J (2) is described. The key steps In each approach involved a biomimetic intermolecular [4+2]-cycloaddition between a dehydroprenylphenol diene derived from an Isoprenoid-substituted phenolic compound and an αβ-unsaturated alkene of a chalcone as the dienophlle. Critical to the success of the Diels-Alder reaction was the presence of the free phenol in the 2′-hydroxychalcone.

Full text of DOI:10.1021/ol9026705

ORGANIC
LETTERS
2010
Vol. 12, No. 7
1388-1391
Mulberry Diels-Alder Adducts:
Synthesis of Chalcomoracin and
Mulberrofuran C Methyl Ethers
Christian Gunawan and Mark A. Rizzacasa*
School of Chemistry, The Bio21 Institute, The UniVersity of Melbourne,
Victoria 3010, Australia
masr@unimelb.edu.au
Received November 19, 2009
ABSTRACT
The synthesis of each of the heptamethyl ethers of the mulberry Diels-Alder adducts chalcomoracin (1) and mulberrofuran J (2) is described.
The key steps in each approach involved a biomimetic intermolecular [4+2]-cycloaddition between a dehydroprenylphenol diene derived from
an isoprenoid-substituted phenolic compound and an r,ꢀ-unsaturated alkene of a chalcone as the dienophile. Critical to the success of the
Diels-Alder reaction was the presence of the free phenol in the 2′-hydroxychalcone.
Moraceous plants are a rich source of isoprenoid-substituted
phenolic compounds, in particular the so-called mulberry
Diels-Alder-type adducts isolated from the mulberry tree.1
Common examples of this large class of Diels-Alder adducts
are (+)-chalcomoracin (1)2 and mulberrofuran C (2)3 (Figure
1). Interestingly, Morus alba L. cell cultures produce
compound 1 in yields up to 100 times greater than the intact
plant.4 These naturally occurring cyclohexenes were the first
examples of natural products biosynthesized by an enzyme-
controlled5,6 intermolecular Diels-Alder reaction between
a dehydroprenylphenol diene derived from an isoprenoid-
substituted phenolic compound and an alkene of a chalcone
as the dienophile.1
(1) Nomura, T.; Hano, Y. Nat. Prod. Rep. 1994, 20, 5–218.
(2) Takasugi, M.; Nagao, S.; Masamune, T.; Shirata, A.; Takahashi, K.
Chem. Lett. 1980, 9, 1573–1576.
(3) Nomura, T.; Fukai, T.; Matsumoto, J.; Fukushima, K.; Momose, Y.
Heterocycles 1981, 16, 759–765.
Figure 1. Structures of chalcomoracin (1) and muberrofuran C (2).
(4) Ueda, S.; Nomura, T.; Fukai, T.; Matsumoto, J. Chem. Pharm. Bull.
1982, 30, 3042–3045.
(5) Oikawa, H. Bull. Chem. Soc. Jpn. 2005, 78, 537–554
.
Chalcomoracin (1) exhibits considerable antibacterial
activity against MRSA strains K3 and ST 28 (MIC 0.78 µg/
(6) Stocking, E. M.; Williams, R. M. Angew. Chem., Int. Ed. 2003, 42,
3078–3115
.
10.1021/ol9026705  2010 American Chemical Society
Published on Web 03/02/2010

mL)7 and moderate cytotoxicity against five human cancer
cell lines, with IC50 values ranging from 5.5 to 7.0 µg/mL.8
Mulberrofuran C (2) has been shown to possess hypotensive
activity with intravenous injection of 1 mg kg-1 causing
significant hypotension in rabbits.3 The absolute configuration
of these mulberry Diels-Alder-type adducts was determined
as 3′′S,4′′R,5′′S by a combination of X-ray crystallographic
analysis and CD spectroscopy.9
between synthetic dienes and 2′-hydroxychalcone dienophiles
to afford the heptamethyl ether derivatives 1a and 2a of
mulberry Diels-Alder adducts chalcomoracin (1) and mul-
berrofuran C (2), respectively.
Scheme 2. Synthesis of the 2′-Hydroxychalcone Dienophiles
The enzyme-mediated [4+2]-cycloaddition between a
diene such as the dehydro derivative 3 of phytoalexin
moracin C10 and dienophile chalcone 4 proceeds via the endo
transition state to afford the cis,trans-adduct mulberrofuran
C (2) as one enantiomer (Scheme 1). The alternative exo
transition state would give the trans,trans stereochemistry,
which is found in other Diels-Alder-type metabolites.1
Support for this biosynthetic hypothesis arose from a range
of pyrolysis2 and partial synthesis studies11,12 as well as
elegant feeding experiments.13
Scheme 1. Proposed Biosynthesis of Mulberrofuran C (2)
The synthesis of the requisite Diels-Alder partners began
with the preparation of the chalcone dienophiles 7 and 9 as
shown in Scheme 2. Claisen-Schmidt condensation16 be-
tween ketone 5 and aldehyde 6 proceeded smoothly in the
presence of KOH as base to afford the mulberrofuran
chalcone 717 in excellent yield. For the synthesis of chal-
comoracin precursor, phenol 7 was prenylated under standard
conditions and the resultant prenyl ether 8 was subjected to
a Florisil promoted [1,3]-sigmatropic rearrangement18 to
afford the prenylated chalcone 9. A significant amount of
the corresponding [1,5]-rearranged product was also pro-
duced along with the deprenylated chalcone 7.
Interestingly, a [4+2]-cycloaddition between a 2′-hydroxy-
chalcone14 and dehydroprenylphenol has not been achieved
in vitro.15 We now report a successful [4+2]-cycloaddition
The route to the benzofurandehydroprenyl diene partner
is detailed in Scheme 3. A selective19 Sonogashira coupling20
between the alkyne 1021 and iodide 11 gave the alkyne 12
(7) Fukai, T.; Kaitou, K.; Terada, S. Fitoterapia 2005, 76, 708–711.
(8) Zhang, Q.-J.; Tang, Y.-B.; Chen, R.-Y.; Yu, D.-Q. Chem. BiodiVersity
2007, 4, 1533–1540.
(15) For the confirmation of the structures of mulberry Diels-Alder
adducts kuwanon G and H by partial synthesis [pyrolysis of the octamethyl
ether derivatives (retro-Diels-Alder fragmentation) and reconstruction via
Diels-Alder reaction of the fragments] see ref 11.
(16) Ahmad, S.; Wagner, H.; Razaq, S. Tetrahedron 1978, 34, 1593–
1594.
(9) Hano, Y.; Suzuki, S.; Momura, T.; Iitaka, Y. Heterocycles 1988,
27, 2315–2325.
(10) Takasugi, M.; Mun˜oz, L.; Masamune, T.; Shirata, A.; Takahashi,
K. Chem. Lett. 1978, 1239–1240.
(11) Nomura, T.; Fukai, T.; Narita, T.; Terada, S.; Uzawa, J.; Iitaka,
Y.; Takasugi, M.; Ishikawa, S.-I.; Nagao, S.; Masamune, T. Tetrahedron
(17) Boumendjel, A.; Boccard, J.; Carrupt, P.-A.; Nicolle, E.; Blanc,
M.; Geze, A.; Choisnard, L.; Wouessidjewe, D.; Matera, E.-L.; Dumontet,
C. J. Med. Chem. 2008, 51, 2307–2310.
Lett. 1981, 22, 2195–2198
(12) Nomura, T.; Hano, Y.; Fukai, T. Proc. Jpn. Acad., Ser. B 2009,
85, 391–407
.
.
(18) Talama´s, F. X.; Smith, D. B.; Cervantes, A.; Franco, F.; Cutler,
S. T.; Loughhead, D. G.; Morgans, D. J., Jr.; Weikert, R. J. Tetrahedron
Lett. 1997, 38, 4725–4728.
(13) Hano, Y.; Nomura, T.; Ueda, S. J. Chem. Soc., Chem. Commun.
1990, 611–613.
(14) (a) For Diels-Alder reactions of 2′-hydroxychalcones with o-
benzoquinodimethane see: Brito, C. M.; Pinto, D. C. G. A.; Silva, A. M. S.;
Silva, A. M. G.; Tome´, A. C.; Cavaleiro, J. A. S. Eur. J. Org. Chem. 2006,
2558–2569. (b) For electron transfer-initiated Diels-Alder reactions of 2′-
hydroxychalcones see: Cong, H.; Ledbetter, D.; Rowe, G. T.; Caradonna,
J. P.; Porco, J. A., Jr. J. Am. Chem. Soc. 2008, 130, 9214–9215.
(19) Fu¨rstner, A.; Heilmann, E. K.; Davies, P. W. Angew. Chem., Int.
Ed. 2007, 46, 4760–4763.
(20) Sonogashira, K.; Ohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467–4470.
(21) Prepared from 4-iodo-3,4-dimethoxybenzaldeyde: Kompis, I.; Wick,
A. HelV. Chim. Acta 1977, 60, 3025–34.
Org. Lett., Vol. 12, No. 7, 2010
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version of 7 failed to undergo clean cycloaddition. This
demonstrated that the phenol in chalcone was critical for the
success of the [4+2]-cycloaddition possibly due to the
H-bond to the carbonyl group activating the dienophile.30
The endo-adduct 18 corresponds to hexamethyl mulberro-
furan C while the exo adduct 19 is the hexamethyl ether
derivative of mulberrofuran J.31 Methylation of 18 afforded
mulberrofuran C heptamethyl ether (2a), which had been
reported previously3 but, unfortunately, no NMR data were
quoted so a direct comparison was not possible. Unfortu-
nately, several attempts at deprotection of either 18 or 2a to
give mulberrofuran C (2) only led to incomplete demethy-
lation or decomposition.
Scheme 3. Synthesis of Diene 17
Scheme 4. Synthesis of Mulberrofuran C Heptamethyl Ether (2a)
in good yield. Key to the success of this reaction was the
use of Cs2CO322 rather than amine bases.23 Methanolysis of
the acetate afforded the phenol 13 ready for cyclization;
however, attempts at forming the benzofuran with gold24 or
platinum catalysis25 gave low yields. Fortunately, cyclization
of phenol 13 could be achieved in good yield, using TBAF26
to afford the benzofuran 14. Formation of the dehydroprenyl
diene proved challenging. After extensive experimentation,
it was found that Suzuki-Miyaura coupling27 of iodide 14
and pinacolboronate 16 (Scheme 4),28 prepared by simple
hydroboration of enyne 15 with pinacolborane,29 afforded
the labile diene 17 in excellent yield. This intermediate
proved somewhat unstable and was used immediately after
rapid purification on SiO2. The instability of 17 perhaps
explains why putative biosynthetic precursors such as 3 have
not been isolated.
The assignment of the stereochemistry for each adduct
arose from comparison of key proton NMR data with that
reported for related natural products. Typically, the coupling
constant between H3′′ and H4′′ is of the order of 5 Hz (cis)
in the endo-isomer while in the exo-isomer it is 10 Hz (trans).
In addition, the signal for C3′ and C5′ OMe groups in endo-
The cycloaddition between diene 17 and chalcone 7 failed
to occur in boiling toluene and was not promoted effectively
by Lewis acids. Eventually, we found that the intermolecular
Diels-Alder reaction proceeded at 180 °C in toluene in a
sealed tube giving the endo and exo adducts cis,trans-18 and
trans,trans-19, respectively, in a 1:1 ratio after separation
by preparative HPLC. Interestingly, the fully methylated
Scheme 5. Synthesis of Chalcomoracin Heptamethyl Ether (1a)
(22) Rathwell, D. C. K.; Yang, S.-H.; Tsang, K. Y.; Brimble., M. A.
Angew. Chem., Int. Ed. 2009, 48, 7996–8000.
(23) Miller, M. W.; Johnson, C. R. J. Org. Chem. 1997, 62, 1582–1583.
(24) Zhang, Y.; Xin, Z.-J.; Xue, J.-J.; Li, Y. Chin. J. Chem. 2008, 26,
1461–1464.
(25) Fu¨rstner, A.; Davies, P. W. J. Am. Chem. Soc. 2005, 127, 15024–
15025.
(26) Hiroya, K.; Suzuki, N.; Yasuhara, A.; Egawa, Y.; Kasano, A.;
Sakamoto, T. J. Chem. Soc., Perkin Trans. 2000, 1, 4339–4346.
(27) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457–2483. (b)
Coleman, R. S.; Lu, X.; Modolo, I. J. Am. Chem. Soc. 2007, 129, 3826–
3827.
(28) Vaulter, M.; Truchet, F.; Carboni, B.; Hoffmann, R. W.; Denne, I.
Tetrahedron Lett. 1987, 28, 4169–4172.
(29) Tucker, C. E.; Davidson, J.; Knochel, P. J. Org. Chem. 1992, 57,
3482–3485.
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Org. Lett., Vol. 12, No. 7, 2010

isomer 18 was observed as a broad singlet at δ 3.59 (6H)
and the H2′ and H6′ signals appeared as a broad singlet at
δ 6.95 (2H). On the other hand the C3′ and C5′ OMe signals
where separated at δ 3.71 (3H) and 4.08 (3H) in the exo
isomer 19 and the signals for H2′ and H6′ appeared at δ
6.89 (1H) and 7.09 (1H), indicating that there is significant
restricted rotation about the C3′′-C4′ bond in the exo-isomer
19.
The synthesis of chalcomoracin heptamethyl ether (1a) is
detailed in Scheme 5. Cycloaddition between chalcone 9 and
diene 17 proceeded at 180 °C to give the endo and exo
adducts chalcomoracin hexamethyl ether 20 and mongolicin
F32 hexamethyl ether 21 in a 2:1 ratio favoring endo-isomer
20. Methylation of 20 then afforded chalcomoracin heptam-
ethyl ether (1a). In this case, the data for synthetic 1a could
be matched to the compound obtained by permethylation of
an authentic sample of chalcomoracin (1), thus confirming
the stereochemistry of the endo adduct 20.
In conclusion, we have reported examples of H-bond
accelerated intermolecular [4+2]-cycloadditions between 2′-
hydroxychalcone dienophiles 7 and 9 and labile dehydro-
prenyl diene 17 to afford the methyl ether derivatives 1a
and 2a of the mulberry Diels-Alder adducts chalcomoracin
(1) and mulberrofuran C (2), respectively. Efforts toward
the synthesis of other compounds in this class are underway.
Acknowledgment. This work was funded by the Austra-
lian Research Council Discovery Grants Scheme. We thank
Professor Euis H. Hakim (Institut Teknologi Bandung,
Indonesia) for an authentic sample of chalcomoracin (1).
Supporting Information Available: Experimental details
as well as characterization data and copies of the NMR
spectra of all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
(30) Choy, W.; Reed, L. A., III; Masamune, S. J. Org. Chem. 1983, 48,
1137–1139.
(31) Fukai, T.; Hano, Y.; Hirakura, K.; Nomura, T.; Uzawa, J.;
Fukushima, K. Heterocycles 1984, 22, 1007–1011.
(32) Kang, J.; Chem., R.-Y.; Yu, D.-Q. Planta Med. 2006, 72, 52–59.
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