First synthesis of antimalarial Machaeriols A and B

Article abstract of DOI:10.1016/j.tetlet.2003.12.107

A short and efficient synthesis of the naturally occurring antimalarial compounds, Machaeriols A and B, from commercially available citronellal via hetero-Diels-Alder cycloaddition and Suzuki coupling in 33% overall yield is described.

Full text of DOI:10.1016/j.tetlet.2003.12.107

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1689–1691
First synthesis of antimalarial Machaeriols A and B
Amar G. Chittiboyina, Ch. Raji Reddy, E. Blake Watkins and Mitchell A. Avery*
Department of Medicinal Chemistry, School of Pharmacy, National Center for Natural Products Research,
and Department of Chemistry, University of Mississippi, University, MS 38677, USA
Received 26 November 2003; revised 16 December 2003; accepted 17 December 2003
Abstract—A short and efficient synthesis of the naturally occurring antimalarial compounds, Machaeriols A and B, from com-
mercially available citronellal via hetero-Diels–Alder cycloaddition and Suzuki coupling in 33% overall yield is described.
Ó 2003 Elsevier Ltd. All rights reserved.
Increasing resistance of the malarial parasite Plasmo-
dium falciparum to conventional drugs such as chloro-
quine or mefloquine warrants the development of new
and effective drugs to combat this parasitic disease.
Machaeriol A (1) and Machaeriol B (2) are (+)-trans-
hexahydrodibenzopyran derivatives isolated from
Machaerium multiflorum spruce by Muhammad et al. in
2001 (Fig. 1).1 Machaeriol B showed growth inhibition
of the chloroquine-resistant P. falciparum W-2 clone
(IC50 ¼ 120 ng/mL; SI ¼ >40); while Machaeriol A was
found to be only weakly active. They also reported that
these compounds showed good antibacterial activity
against Staphylococcus aureus and methicillin-resistant
S. aureus, with IC50 values of 5 and 4.5 lg/mL, respec-
tively. Unfortunately, their low natural abundance
(16 mg of each from 500 g of plant material) has limited
further studies. Furthermore, no synthesis of 1 or 2 has
been reported in the literature to date.
In connection with our ongoing efforts to discover novel
natural products for the treatment of malaria, we herein
report the first syntheses of the hexahydrodibenzopyran
derivatives 1 and 2 from commercially available S-())-
citronellal. Our synthetic approach to Machaeriols A
and B involves condensation of protected, lithiated
phloroglucinol with S-citronellal. Upon mild acid
hydrolysis of the protecting groups, a hetero-Diels–
Alder cycloaddition ensues. The resultant diphenol then
undergoes chemoselective Suzuki coupling of the
monotriflate2 with an aryl or alkenyl boronic acid to
afford the natural products.
Murphy et al.3 reported that heating mixtures of phe-
nols and citronellal in the presence of an organic base,
such as quinoline, leads directly to the formation of a
hexahydro dibenzopyran derivative. Phloroglucinol 3
was subjected to hetero-Diels–Alder reaction with (S)-
citronellal in the presence of quinoline as a base under
refluxing conditions, resulting in the formation of an
inseparable diastereomeric mixture (87:13) of hexahydro-
dibenzopyran deriavatives 6 in 45% yield. A major side
product formed in 38% was isopulegol, produced pre-
sumably via Prins reaction.4 Extended reaction times at
elevated temperatures and poor chemoselectivity
prompted us to develop an enantioselective route for the
formation of the tricyclic hexahydrodibenzopyran
derivative 6.
O
HO
HO
O
O
Machaeriol A (1)
Figure 1.
Machaeriol B (2)
Within the literature,5 precedent existed for the con-
densation of (S)-citronellal with an aryl anion, generat-
ing an appropriate benzylic alcohol precursor for our
IMDA approach. Thus, we selected to orthometallate
the tris-(O-methoxymethyl)ether of phloroglucinol (4)6
with n-butyl lithium rather than attempt the generation
of a di- or tri-anion. Hence, on treatment of 4 with
Keywords: Machaeriols; Hetero-Diels-Alder reaction; Suzuki coupling.
* Corresponding author. Tel.: +1-662-915-5879; fax: +1-662-915-5638;
e-mail: mavery@olemiss.edu
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.107

1690
A. G. Chittiboyina et al. / Tetrahedron Letters 45 (2004) 1689–1691
HO
OH
OMOM
OR
RO
a
b
MOMO
OH
OMOM
O
OR
5
6
3, R = H; Phloroglucinol
4, R = CH2OCH3 (MOM)
d
MOMO
OSO2CF3
HO
OSO2CF3
d
c
e
O
O
8
7
MOMO
R
HO
R
f
O
O
9a R = Styryl
9b R = 2-Benzofuryl
1 R = Styryl
2 R = 2-Benzofuryl
Scheme 1. Reagents and conditions: (a) n-BuLi, TMEDA, 0 °C, (S)-citronellal, 30 min, 85%; (b) 4% aqueous HCl in MeOH, rt, 12 h, 65%; (c)
PhNTf2, Et3N, CH2Cl2, 3 h, 74%; (d) NaH, MOMCl, THF, 30 min, 97%; (e) boronic acid (trans-phenylvinyl or 2-benzofuryl) (1.5 equiv), Pd(PPh3)4
(1 mol %)/2 M aq Na2CO3 (1.5 equiv)/MeOH/toluene, reflux, 2 h (9a, 90%; 9b, 86%); (f) 1% aqueous HCl in MeOH, reflux, 30 min (1, 95%; 2, 97%).
1.2 equiv of n-butyl lithium and 1.2 equiv of N,N,N0,N0-
tetramethylethylene diamine (TMEDA) followed by
condensation with (S)-citronellal led to facile formation
of a 1:1 mixture of diasteromers (5) in 85% purified yield
(Scheme 1). Initially, we planned to remove the meth-
oxymethyl (MOM) protecting groups to produce the
triphenol corresponding to 5. Surprisingly, with 4%
aqueous HCl in methanol (v/v) at room temperature, the
product of IMDA reaction, hexahydrodibenzopyran
derivative 6 was produced instead in 65% isolated yield
with >98% diastereoselectivity. Regioselective triflation
In summary, the first syntheses of Machaeriols A (1) and
B (2) have been accomplished efficiently from commer-
cially available phloroglucinol and S-citronellal, giving
natural products ultimately in 33% overall yield (with-
out optimization). This synthetic process lends itself
quite readily to the development of parallel or combi-
natorial libraries. Presently both solid phase and solu-
tion phase chemistries are being investigated to allow
facile construction of such libraries. Of course, these
libraries can then be examined for antimalarial and
other antiinfective activities in vitro and have QSAR
developed. Assessment and understanding of cannabi-
noid activity, if any, of these analogs will be important
eventually in relationship to clinical development.
However, based on known cannabinoid SAR, and a
lack of cannabinoid activity for Machaeriols A and B, it
seems unlikely that this will represent a substantial
obstacle to this research.1
7
of 6 was then readily performed with 1 equiv of PhNTf2
and triethylamine at 0 °C to give the monotriflate 7 in
74% yield. The exclusive formation of monotriflate 7 was
confirmed by 2D NMR experiments. The monotriflate 7,
when further subjected to methoxymethylation8 (NaH,
MOMCl) gave the MOM-protected triflate 8 in 97%
yield. Introduction of the requisite styryl or benzofuran
moieties of the Machaeriols into the MOM-triflate 8 was
readily accomplished by Suzuki coupling.
Studies are underway using gene microarrays to under-
stand potential mechanisms of action of this exciting
and novel class of antiinfective natural products.
Using 1.5 equiv of the appropriate boronic acid with
1 mol % tetrakis(triphenylphosphine) palladium in a 2 M
aqueous solution of Na2CO3 (1.5 equiv) together with
toluene–methanol (8:1) at 100 °C, lead to the coupled
products 9a or 9b in 90% or 86% yields, respectively.
Finally removal of the MOM group was achieved by
mild acid treatment9 to provide 1 and 2 in 95% and 97%
yields, respectively. The spectral10 and physical proper-
ties of 1 and 2 were in agreement with those of natural 1
and 2, confirming the earlier absolute stereochemical
assignment.1
Acknowledgements
We wish to thank Dr. Larry Walker and colleagues of
the National Center for Natural Products Research for
the discovery of this class of compounds and for
bringing them to our attention during regular meetings.

A. G. Chittiboyina et al. / Tetrahedron Letters 45 (2004) 1689–1691
1691
2H); 1.08 (s, 3H); 0.97 (d, 3H, J ¼ 6.5 Hz); 0.78 (dd, 1H,
J ¼ 11.5, 24.5 Hz). 13C NMR (CDCl3, 100 MHz): 156.0,
155.8, 148.0, 117.1, 113.5, 103.2, 100.6, 78.3, 48.7, 38.4,
35.3(2), 32.8, 27.9, 27.5, 22.5, 19.0. HRMS (ESI): calcd for
C17H21F3O5S: 395.1140 [M+H]þ, found: 395.1146.
We also are deeply indebted to the CDC for funding
under cooperative agreement UR3/CCU418652.
1
8: H NMR (CDCl3, 400 MHz): 6.55 (d, 1H, J ¼ 2.0 Hz);
6.40 (d, 1H, J ¼ 1.9 Hz); 5.17 (dd, 2H, J ¼ 21 Hz); 3.49 (s,
3H); 2.95 (br d, 1H, J ¼ 12.0 Hz); 2.43 (ddd, 1H, J ¼ 2.5,
11.0, 14.2 Hz); 1.85 (m, 2H); 1.63 (m, 1H); 1.46 (m, 1H);
1.37 (s, 3H); 1.10 (m, 2H); 1.05 (s, 3H); 0.94 (d, 3H,
J ¼ 6.4 Hz); 0.74 (dd, 1H, J ¼ 11.5, 23.5 Hz). 13C NMR
(CDCl3, 100 MHz): 157.3, 155.4, 148.4, 117.1, 115.3,
104.3, 99.5, 94.6, 78.0, 56.4, 48.8, 38.8, 35.6, 35.3, 32.9,
27.9, 27.5, 22.6, 18.9. HRMS (ESI): calcd for
C19H25F3O6S: 477.0961 [M+K]þ, found: 477.0974.
References and notes
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Khan, I. A. J. Nat. Prod. 2001, 64, 1322.
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M. J. Chem. Soc., Perkin Trans. 1 1992, 3397; (b) Murphy,
S. M.; Tuladhar, S. M.; Duffy, B. J. Chem. Soc., Perkin
Trans. 1 1992, 605; (c) Casiraghi, G.; Cornia, M.; Canati,
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Commun. 1986, 271, and references cited therein.
4. Arnold, R. T.; Veeravagu, P. J. Am. Chem. Soc. 1960, 82,
5411.
9a: 1H NMR (CDCl3, 400 MHz): 7.50 (d, 2H, J ¼ 7.6 Hz);
7.36 (t, 2H, J ¼ 7.6, 7.2 Hz) 7.26 (t, 1H, J ¼ 7.2 Hz); 7.06
(d, 1H, J ¼ 16.4 Hz); 6.99 (d, 1H, J ¼ 16.4 Hz); 6.80 (d, 1H,
J ¼ 1.7 Hz); 6.71 (d, 1H, J ¼ 1.9 Hz); 5.26 (dd, 2H,
J ¼ 20.6 Hz); 3.55 (s, 3H); 3.05 (br d, 1H, J ¼ 12.4 Hz);
2.51 (ddd, 1H, J ¼ 2.5, 11.5, 14.0 Hz); 1.89 (m, 2H); 1.67
(m, 1H); 1.47 (m, 1H); 1.42 (s, 3H); 1.16 (m, 2H); 1.10 (s,
3H); 0.95 (d, 3H, J ¼ 6.4 Hz); 0.83 (dd, 1H, J ¼ 12,
24.5 Hz). 13C NMR (CDCl3, 100 MHz): 157.0, 154.9,
137.4, 136.7, 128.6(2), 128.5, 128.4, 127.5, 126.5, 126.0,
115.2, 109.4, 104.4, 94.4, 77.1, 56.3, 49.2, 39.3, 36.0, 35.5,
33.0, 28.1, 27.7, 22.7, 19.0. HRMS (ESI): calcd for
C26H32O3: 393.2430 [M+H]þ, found: 393.2425.
9b: 1H NMR (CDCl3, 400 MHz): 7.60 (d, 1H, J ¼ 7.2 Hz);
7.55 (d, 1H, J ¼ 7.6 Hz); 7.29 (m, 2H); 7.19 (d, 1H,
J ¼ 1.2 Hz); 7.08 (d, 1H, J ¼ 1.2 Hz); 7.00 (s, 1H); 5.34 (dd,
2H, J ¼ 20.8 Hz); 3.60 (s, 3H); 3.11 (br d, 1H, J ¼ 12.4 Hz);
2.57 (ddd, 1H, J ¼ 2.5, 11.5, 14.0 Hz); 1.92 (m, 2H); 1.70
(m, 1H); 1.58 (m, 1H); 1.46 (s, 3H); 1.15 (m, 2H); 1.15 (s,
3H); 1.02 (d, 3H, J ¼ 6.4 Hz); 0.9 (dd, 1H, J ¼ 12, 24 Hz).
13C NMR (CDCl3, 100 MHz): 157.2, 155.9, 155.1, 154.8,
129.6, 129.3, 124.1, 122.8, 120.8, 116.1, 111.2, 108.2, 102.5,
101.2, 94.6, 77.3, 56.4, 49.2, 39.2, 36.1, 35.5, 33.0, 28.1,
27.7, 22.7, 19.0. HRMS (ESI): calcd for C26H30O4:
407.2222 [M+H]þ, found: 407.2242.
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Synthesis; Wiley: New York, 1996; Vol. 3, p 4096; (b)
Hendrickson, J. B.; Bergeron, R. Tetrahedron Lett. 1973,
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P.; Keck, G. E.; Gras, J.-L. J. Am. Chem. Soc. 1978, 100,
8031.
9. Yardley, J. P.; Fletcher, H. III. Synthesis 1976, 244.
10. Spectral data for new compounds:
1
7: H NMR (CDCl3, 500 MHz): 6.35 (d, 1H, J ¼ 2.5 Hz);
6.25 (d, 1H, J ¼ 2.5 Hz); 5.42 (br s, 1H); 3.00 (br d, 1H,
J ¼ 12.5 Hz); 2.46 (ddd, 1H, J ¼ 2.5, 11.5, 14.0 Hz); 1.88
(m, 2H); 1.62 (m, 1H); 1.46 (m, 1H); 1.39 (s, 3H); 1.17 (m,