The first diastereoselective synthesis of cinerins A-C, PAF-antagonistic macrophyllin-type bicyclo[3.2.1]octane neolignans, using a novel Pd-catalysed oxyarylation

Article abstract of DOI:10.1039/b927558d

The first diastereoselective synthesis of PAF-antagonistic cinerins A-C, macrophyllin-type bicyclo[3.2.1]octane neolignans from Pleurothyrium cinereum, has been accomplished using a novel Pd-catalysed oxyarylation to afford a 2,3-dihydrobenzofuran as the key intermediate.

Full text of DOI:10.1039/b927558d

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Organic &
Biomolecular
Chemistry
www.rsc.org/obc
Volume 8 | Number 9 | 7 May 2010 | Pages 1977–2268
ISSN 1477-0520
COMMUNICATION
Ericsson D. Coy B., Luis E. Cuca S. and
Michael Sefkow
The first diastereoselective synthesis
of cinerins A–C, PAF-antagonistic
bicyclo[3.2.1]octane neolignans
EMERGING AREA
Jaskiranjit Kang and Derek Macmillan
Peptide and protein thioester synthesis
1477-0520(2010)8:9;1-B
via NS acyl transfer

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COMMUNICATION
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The first diastereoselective synthesis of cinerins A–C, PAF-antagonistic
macrophyllin-type bicyclo[3.2.1]octane neolignans, using a novel Pd-catalysed
oxyarylation†
Ericsson D. Coy B.,*a Luis E. Cuca S.a and Michael Sefkow*b
Received 8th January 2010, Accepted 2nd February 2010
First published as an Advance Article on the web 12th February 2010
DOI: 10.1039/b927558d
The first diastereoselective synthesis of PAF-antagonistic
cinerins A–C, macrophyllin-type bicyclo[3.2.1]octane neolig-
nans from Pleurothyrium cinereum, has been accomplished
using a novel Pd-catalysed oxyarylation to afford a 2,3-
dihydrobenzofuran as the key intermediate.
both intermediates, the 8,5¢- and 8,3¢-neolignans, were generally
obtained in low yields.
Recently, we have developed a new and efficient synthesis
of trans-2-aryl-2,3-dihydrobenzofurans via a Pd-catalysed oxy-
arylation.7 Obviously this reaction is attractive to develop a
stereoselective synthesis for the cinerins B and C from di-
hydrobenzofuran 3 as precursor, which in turn should be readily
available from isomyristicin (4) and 2-aminophenol 5. The highly
substituted aminophenol 5, though previously unknown and
expected to be very sensitive towards oxidation,8 should be
available from resorcinol 6. We further envisioned that cinerin
C (2) could be prepared from cinerin B (1) by a-methoxylation
of hindered ketones.9 The retrosynthetic analysis of the cinerins is
shown in Scheme 1.
Neolignans containing a bicyclo[3.2.1]octane core belong to an
important class of natural products. These neolignans are further
divided into two subgroups, depending on the connectivity of
the two phenylpropene moieties: the guianin-type neolignans
(8,1¢-connected), and the macrophyllin-type neolignans (8,3¢-
connected).1 Several syntheses of bicyclo[3.2.1]octane neolig-
nans have been developed in the past.2 Although guianin-type
neolignans are the best known, naturally occurring bicyclo-
octanoids, several macrophyllin-type neolignans have been shown
to exhibit important biological activities3 (e.g. PAF-antagonistic
activity), which makes the synthesis of these neolignans partic-
ularly interesting. Very recently, four new macrophyllin-type bi-
cyclo[3.2.1]octane neolignans, the cinerins A–D, were charac-
terised as chemical constituents from Pleurothyrium cinereum
(Lauraceae species).4 Of these, cinerin B (1) and C (2) (Fig. 1)
exhibit good PAF-antagonistic activities.4
Scheme 1 Retrosynthetic analysis for cinerin B (1) and cinerin C (2).
Fig. 1 Macrophyllin-type neolignans cinerin B (1) and C (2).
Our synthesis of dihydrobenzofurans requires a phenylpropene
and an o-diazoniumphenol. The latter reagent is prepared in situ by
treatment of an o-aminophenol and a nitrosonium salt.7 Isomyris-
ticin 4, the readily substituted phenylpropene, was obtained from
myristicin aldehyde and ethylmagnesium bromide followed by
dehydratisation with CuSO4 in 61% yield (E : Z = 14 : 1).10 For the
synthesis of 5 from resorcinol 6 a Claisen rearrangement seemed
obvious as this reaction is well documented for the corresponding
monoallyl ether in diethylaniline.11 In our hands, the best result
was achieved, when the Claisen rearrangement was carried out
Among the reported synthetic approaches, cationic [5+2]-
cycloadditions were commonly employed as a strategy for the
construction of these bicyclic skeletons. Another, rarely applied
route was based on an acid-catalysed rearrangement of 8,3¢-
neolignans.5,6 These intermediates can be readily obtained from
8,5¢-neolignans, comprising a dihydrobenzofuran core.5 However,
aUniversidad Nacional de Colombia, Facultad de Ciencias, Departamento
de Qu´ımica, Laboratorio de Investigacio´n en Productos Naturales Veg-
etales, AA 14490, Cra 30 45-03, Bogota´, D.C., Colombia. E-mail: ed-
coyb@unal.edu.co, lecucas@unal.edu.co
◦
in a sealed flask at 190 C with DMF as solvent. However, only
bUniversita¨t Potsdam/UP Transfer GmbH, Am Neuen Palais 10, 14469
Potsdam, Germany. E-mail: sefkow@uni-potsdam.de
a nearly 1 : 1 mixture of 2- and 4-allylresorcinol was obtained in
78% yield. Raising the steric hindrance for C-2 by silylation of O-1
with TBS-Cl (88% yield) didn’t affect the regioselectivity of the
Claisen rearrangement.12 Thus, the nitro group was introduced
† Electronic supplementary information (ESI) available: Experimental
procedures, full spectroscopic data for all new compounds, and copies
of 1H and 13C NMR spectra. See DOI: 10.1039/b927558d
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The Royal Society of Chemistry 2010
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at the beginning of the synthesis of 5 (e.g. zirconyl nitrate13
63%, or bismuth nitrate14 78%) to examine the influence of
the nitro group in the subsequent reactions. Monoallylation at
O-1 was best achieved with tetrabutylammonium hydrogensulfate
(TBAHS) affording 7 in 79% yield.15,16 Unexpectedly, the Claisen
rearrangement of 7 provided exclusively 2-allyl-4-nitroresorcinol
(8) in 56% yield (Scheme 2).
relative configuration of C-3¢ and only the a-methoxy epimer
is suitable for this reaction. Thus, the protocol provided by
Wang et al. is not sufficient to give the bicyclo[3.2.1]octanes in
reasonable yields. Recently, Felpin described that p-methoxylation
of silyl ether of phenols with PIDA/MeOH gave superior yields
compared to the phenol itself.24 According to Felpin’s modifica-
tion, the oxidative methoxylation of dihydrobenzofuran 11 was
carried out using the corresponding trimethylsilyl ether 3. Indeed,
a- and b-methoxy dienone (12a and 12b) were obtained in better
total yield (86%) and with a preference for 12a (12a : 12b ~1.4 : 1)
(Scheme 4). The change in stereoselectivity might be due to a
change in the mechanism: whereas unprotected phenols (e.g. 11)
react with PIDA at the OH group, the corresponding silyl ether
(e.g. 3) are attacked by this reagent at the carbon para to the
silyl ether.24 As a consequence, cleavage of PIDA-phenol adducts
causes an oxo and then a carbocation, which reacts with MeOH
under thermodynamic control (with a preference for the b-OMe
epimer). On the other hand, the iodonium group in the PIDA-
carbon adducts acts as leaving group in a SN2-like substitution.
Assuming the same preference for the b-isomer of the initial
PIDA-carbon adducts a reverse orientation in favour of the
a-OMe epimer must result.
Scheme 2 Synthesis and Claisen rearrangement of allyl ether 7. (a)
Bi2(NO3)3·5H2O, Me2CO, 50 ◦C, 5 min; (b) 1.1 eq allyl bromide, aq. KOH
50%, TBAHS 1%, Et2O, 0 ◦C, 4 h; (c) DMF, 190 ◦C, 15 h.
Therefore, the Claisen rearrangement of resorcinol monoallyl
ether was not a suitable method to yield 5. Recently, Kimura
et al.17 developed a novel direct C-allylation of arenes, based on
a Pd-catalysed, triethylborane promoted reaction of phenols with
allyl alcohols. With this reaction, 6 was transformed to 4-allyl-
resorcinol (9) in 77% yield. Subsequent nitration using zirconyl
nitrate gave 6-nitro-4-allyl-resorcinol 10 in 64% yield (Scheme 3).
Scheme 3 Synthesis of dihydrobenzofuran 11. (a) 1.2 eq. allyl alcohol,
5 mol% Pd[(Ph3)P]4, 5 eq Et3B, rt, toluene, 3 h; (b) ZrO(NO3)2·xH2O,
Me2CO, rt, 2 h; (c) Zn, CH2Cl2, AcOH, rt, 1 h; (d) 1 eq NOPF6, MeCN,
0
◦C, 2 h; then 1.2 eq 4, 5 mol% Pd2(dba)3, 2 eq ZnCO3, rt, 20 h.
Scheme 4 Synthesis of cinerin B (1). (a) HMDS, CuSO4, CH2Cl2, reflux,
4 h; (b) PIDA, MeOH, r.t. 2 h; (c) TsOH, MeOH, reflux, 2 h; (d) NaBH4,
EtOH, -15 ◦C, 15 min.
With compound 10 in hand, we examined several methods
to reduce the nitro group. The best method to obtain amine 5
was Zn/AcOH–CH2Cl2,18 while other methods, such as NaBH4,19
Na2S2O3,20 Zn/EtOH21 or NH4Cl/ultrasound22 failed to give any
desired product.23 As expected, amine 5 is very unstable and
reacts during/after ordinary workup to give intensively colored
products.8 Thus, 5 was used in the next step without workup or
purification. The amine was immediately treated with one eq. of
The acid-catalysed rearrangement was carried out with dia-
stereoisomerically pure a-methoxy neolignan 12a furnishing the
exo-aryl bicyclodione skeleton 13 in 77% yield, that is in accord
with the reported procedure for analogous substrates.5,6 Diketone
13 was converted to cinerin B (1) in 80% yield by means of a
regioselective and diastereoselective reduction using NaBH4 in
EtOH. The orientation of the 4¢-hydroxy group was determined
by its signal pattern in the 1H NMR spectrum, which is typical for
those structures.25,26
To obtain cinerin C (2), a methoxylation a to the highly hindered
ketones was pursued according to the procedure described by
Abele et al.9 (Scheme 5). However, starting from cinerin B (1)
this reaction was not successful. The only product which could
be characterised was methyl ether 14. To avoid the methylation
of the hydroxy group at C(4¢), diketone intermediate 13 was
used as substrate for the a-methoxylation. Indeed, 3¢-methoxy-
bicyclooctanedione 15, cinerin A,4 was isolated in 21% yield
-
NO+PF6 to give the diazonium salt, which in turn was reacted
with phenylpropene 4 in the presence of 5 mol% Pd2(dba)3 and 2
eq. of ZnCO3 (Scheme 3). Dihydrobenzofuran 11 was obtained in
63% overall yield over three steps (corresponds to an average yield
of 86% for each step).
The synthesis of cinerins proceeds with the oxidation of 11
to methoxy dienone 12. Wang et al.5 reported a procedure
for the conversion of similar substrates using phenyliodonium
diacetate (PIDA) that provided both, the a- and the b-methoxy
epimer at C-3¢ with 20 and 50% yield, respectively. However,
the subsequent acid catalysed rearrangement is controlled by the
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Notes and references
1 R. S. Ward, Nat. Prod. Rep., 1999, 16, 75.
2 M. Sefkow, Synthesis, 2003, 2595.
3 G. Han, Progr. Nat. Sci., 1995, 5, 299.
4 E. D. Coy, L. E. Cuca and M. Sefkow, J. Nat. Prod., 2009, 72, 1245.
5 M. Wang, A. Wu, X. Pan and H. Yang, J. Org. Chem., 2002, 67, 5405.
6 M. A. De Alvarenga, B. U. Brocksom, O. R. Gottlieb, M. Toshida,
R. B. Filho and R. J. Figliuolo, J. Chem. Soc., Chem. Commun., 1978,
831.
7 E. D. Coy, L. Jovanovic and M. Sefkow, submitted for publication.
8 (a) M. Mure and J. P. Klinman, J. Am. Chem. Soc., 1993, 115, 7117;
(b) S. Ma, L. Lin, R. Raghavan, P. Cohenour, P. Y. T. Lin, J. Bennett,
R. J. Lewis, E. L. Enwall, R. Kostrzewa, R. E. Lehr and C. L. Blank,
J. Med. Chem., 1995, 38, 4087.
9 E. Abele, K. Rubina, M. Shymanska and E. Lukevics, Synth. Commun.,
1995, 25, 1371.
10 J. Popławski, B. Łozowicka, A. T. Dubis, B. Lachowska, S. Witkowski,
D. Siluk, J. Petrusewicz, R. Kaliszan, J. Cybulski, M. Strzałkowska and
Z. Chilmonczyk, J. Med. Chem., 2000, 43, 3671.
11 (a) K. D. Kaufman and W. E. Russey, J. Org. Chem., 1965, 30, 1320;
(b) F. C. Gozzo, S. A. Fernandes, D. C. Rodrigues, M. N. Eberlin and
A. J. Marsaioli, J. Org. Chem., 2003, 68, 5493.
Scheme 5 Synthesis of cinerin C (2) and cinerin A (15). (a) CCl4, KOH,
MeI, 18-crown-6, reflux, 9 h; (b) NaBH4, EtOH, -15 ◦C, 15 min.
12 F. Ito, K. Fusegi, T. Kumamoto and T. Ishikawa, Synthesis, 2007, 1785.
13 J. P. Selvam, V. Suresh, K. Rajesh, R. S. Ravinder and Y. Venkateswarlu,
Tetrahedron Lett., 2006, 47, 2507.
14 H.-B. Sun, R. Hua and Y. Yin, J. Org. Chem., 2005, 70, 9071.
15 M.-L. Wang and Z.-F. Lee, J. Mol. Catal. A: Chem., 2007, 264, 119.
16 The monoallyl ether 7 was accompanied by ca. 12% of the correspond-
ing diallyl ether. Other methods, such as phenol allylation with allyl
bromide and KOH in acetone, were less efficient and gave higher yields
of the undesired diallyl ether.
17 M. Kimura, M. Fukasaka and Y. Tamaru, Synthesis, 2006, 3611.
18 H. Gao and J. Kawabata, Bioorg. Med. Chem., 2005, 13, 1661.
19 B. Zeynizadeh and D. Setamdideh, Synth. Commun., 2006, 36, 2699.
20 K. A. Monk, R. Siles, M. B. Hadimani, B. E. Mugabe, J. F. Ackley,
S. W. Studerus, K. Edvardsen, M. L. Trawick, C. M. Garner, M. R.
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42.
from 13. This is an acceptable yield, because the protocol com-
prises three steps–chlorination, hydroxylation and methylation–
in one phase transfer catalysed system.9 Finally, cinerin A (15)
was converted into cinerin C (2) by reduction of the aliphatic
ketone using NaBH4 as described above. The structures 1, 2
and 15 have been unambiguously established by comparison
1
of their H and 13C NMR spectra with those of the authentic
samples.4
In summary, we have developed a straightforward synthesis
of three recently isolated, naturally-occurring macrophyllin-type
bicyclo[3.2.1]octane neolignans from one common precursor. The
key step, a novel Pd-catalysed oxyarylation protocol, recently
developed in our laboratory, provided a dihydrobenzofuran as the
key intermediate from commercially available starting materials.
In addition, our route is attractive because the bicyclooctane
neolignans are available in good yields and diastereoselectivities
and without capricious reaction conditions. The flexibility of our
route allows the use of a variety of substrates to be applied to the
synthesis of a wide-range of this type of neolignans.
23 Interestingly, reduction of 10 with LiAlH4 provided 2-allyl-4-
aminophenol in 67% yield.
24 F.-X. Felpin, Tetrahedron Lett., 2007, 48, 409.
25 G. Q. Han, P. Dai, L. Xu, S. C. Wang and Q. T. Zheng, Chin. Chem.
Lett., 1992, 7, 521.
26 A singlet for the hydrogen at C-4¢ is always observed in bicyclooctanoids
with an OH group oriented towards the aryl group as the angle between
H–C-3¢ and H–C-4¢ is ca. 90◦. The diastereoisomer generally shows a
We thank the Institut fu¨r Chemie at Universita¨t Potsdam for
the analytical support. E.D. Coy acknowledges the DAAD for
financing a research stay at the University of Potsdam.
1
doublet in the H NMR spectrum due to a coupling between H–C-3¢
and H–C-4¢. These results have been independently confirmed by
NOESY spectra.
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 2003–2005 | 2005
©