A short total synthesis for biologically interesting (+)- and (-)-machaeriol A

Article abstract of DOI:10.1055/s-2008-1078487

This paper describes a new and efficient synthetic approach for biologically interesting natural (+)-machaeriol A and its unnatural enantiomer (-)-machaeriol A. The key strategies involve stilbene formation through a Horner-Wadsworth-Emmons reaction and t

Full text of DOI:10.1055/s-2008-1078487

LETTER
1643
A Short Total Synthesis for Biologically Interesting (+)- and (–)-Machaeriol A
Total
S
ynthesis
i
of (+)-
k
and
(
–)-Mac
a
haeriol
A
i Xia, Yong Rok Lee*
School of Chemical Engineering and Technology, Yeungnam University, Gyeongsan 712-749, Korea
Fax +82(53)8104631; E-mail: yrlee@ynu.ac.kr
Received 6 March 2008
mg/mL; 3: 0.65 mg/mL; 4: 20 mg/mL) and methicillin-re-
Abstract: This paper describes a new and efficient synthetic ap-
proach for biologically interesting natural (+)-machaeriol A and its
unnatural enantiomer (–)-machaeriol A. The key strategies involve
stilbene formation through a Horner–Wadsworth–Emmons reaction
sistant S. aureus (IC50, 1: 10 mg/mL; 2: 4.5 mg/mL; 3: 0.7
mg/mL; 4: 30 mg/mL).7 They also showed potent in vitro
antimalarial activity against Plasmodium falciparum W-2
and trans-hexahydrodibenzopyran formation through a tandem al- clone (IC50, 1: 6.0 mg/mL; 2: 1.2 mg/mL; 3: 3.0 mg/mL).7
dol–hetero-Diels–Alder reaction.
These important biological activities have led to the de-
velopment of synthetic approaches. The first synthesis of
machaeriol A (1) and machaeriol B (2) was reported by
Avery starting from phloroglucinol through hetero-Diels–
Alder cyclization and Suzuki coupling reaction as the key
steps in 34% (7 steps) and 32% (7 steps) overall yields, re-
spectively.8 However, in these synthetic routes, there was
no reported data on the specific rotation for the optically
pure natural products 1 and 2. Recently, another total syn-
thesis of (+)-machaeriol A (1) was accomplished starting
from synthesized enol silyl ether of a,b-epoxycyclohex-
anone through a SN2¢ reaction to aryl cyanocuprate as the
key step in overall 26% yield (10 steps).9 (+)-Machaeriol
D (4) was also synthesized starting from 4-bromo-2,4-di-
hydroxybenxzoic acid in 12% overall yield (17 steps).10
Although a few synthetic approaches to (+)-machaeriol A
(1), B (2), and D (4) have been reported, these synthetic
routes have many reaction steps and low yield. In particu-
lar, the synthesis of enantiomers of these natural products
has not been reported.
Key words: cannabinoid analogues, hetero-Diels–Alder reaction,
(+)-machaeriol A, (–)-machaeriol A
Cannabinoids are widely distributed in nature, and have
been isolated from Indian hemp, Cannabis sativa, which
have been used as both a medicine and a psychotomimetic
drug since ancient times.1 These compounds have been
shown to have analgetic, antiemetic, psychotropic, and
anti-inflammatory properties.2 They also have potential
therapeutic utility for the treatment of asthma and glauco-
ma.3 The medical use of cannabinoids as therapeutic
agents has been limited by their psychotropic properties.4
However, the discovery of the two cannabinoid receptors,
CB1 and CB2, has ushered in a new era in research into
the development of drugs.5 Currently, D9-tetrahydrocan-
nabinol (D9-THC) and its derivative have been used as a
medicine, Marinol® and Cesamet®, for treating patients
with chemotherapy-induced nausea and vomiting
(CINV), who have failed to respond adequately to con-
ventional antiemetic treatments.6
Recently, we developed a new and useful methodology
for preparing a variety of benzopyrans using ethylenedi-
amine diacetate (EDDA)-catalyzed reactions of resorci-
nols to a,b-unsaturated aldehydes (Scheme 1).11
Interestingly, structurally related machaeriols A (1), B (2),
C (3), and D (4) with cannabinoid analogues were recently
isolated from the bark of Machaerium multiflorum spruce
(Figure 1), which is located in Loreto and Peru.7
These reactions involve a formal [3+3] cycloaddition
through 6p-electrocyclization.12 This methodology pro-
vides a rapid route for the synthesis of benzopyran deriv-
atives with a variety of substituents on the pyranyl ring.13
Machaeriols A (1), B (2), C (3), and D (4) have been re-
ported to have potent in vitro antimicrobial activity
against Straphylococcus aureus (IC50, 1: 15 mg/mL; 2: 5.0
R
OH
OH
OH
H
H
H
R
H
H
H
O
O
O
O
R = H: (+)-machaeriol A (1)
R = OH: (+)-machaeriol C (3)
(–)-machaeriol A (5)
R = H: (+)-machaeriol B (2)
R = OH: (+)-machaeriol D (4)
Figure 1 Natural products 1–4 isolated from Machaerium multiflorum and unnatural enantiomer 5
SYNLETT 2008, No. 11, pp 1643–1646
x
x
.x
x
.2
0
0
8
Advanced online publication: 11.06.2008
DOI: 10.1055/s-2008-1078487; Art ID: U01408ST
© Georg Thieme Verlag Stuttgart · New York

1644
L. Xia, Y. R. Lee
LETTER
O
H
Scheme 3 shows the efficient and concise synthetic ap-
proach to natural (+)-machaeriol A (1). First, a reaction of
3,5-dimethoxybenzaldehyde (6) and diethyl benzylphos-
phonate (7) in the presence of potassium tert-butoxide in
THF gave 3,5-dimethoxy-trans-stilbene (8) in 90%
yield.14 Treatment of compound 8 with pyridine hydro-
chloride at 190 °C for four hours afforded pinosylvin (9,
85%),14 which was isolated from pine leaf of Pinus densi-
flora and the heartwood of Pinus sylvestries.15 Interesting-
ly, pinosylvin (9) with a stilbenoid showed antibacterial,
antimicrobial, antifungal, and antioxidant activities.16 It
was also reported to have potent inhibitory effects on ty-
rosinase and prostaglandin E2 production in lipopolysac-
charide-induced mouse macrophage cells.17 A reaction of
compound 9 with (S)-(–)-citronellal (10a, [a]D –15.0,
neat) in the presence of ethylenediamine diacetate (20
mol%) and triethylamine (2 mL) as a cocatalyst in reflux-
ing xylene for 24 hours gave (+)-machaeriol A (1) in 75%
yield.18 The specific rotation of synthetic material 1 was
[a]D +112.0 (c 0.16, MeOH), whereas the reported data is
[a]D +115.4 (c 0.39, MeOH).7b The spectroscopic data of
the synthetic material 1 is in good agreement with those
reported data.7b
R2
R4
O
OH
O
R
OH
R2
R3
R4
R3
R
EDDA
(10 mol%)
R1
O
R1
OH
Scheme 1 Benzopyran formation by [3+3] cycloaddition
This reaction for the formation of benzopyrans appears to
be an ideal method for synthesizing enantiomerically pure
molecules with the cannabinoid moiety. As a part of an
ongoing study into the synthetic efficacy of this method-
ology, we report the efficient and concise synthesis of bi-
ologically interesting (+)-machaeriol A (1) and its
unnatural isomer, (–)-machaeriol A (5), using hetero-
Diels–Alder cycloaddition as a key step.
Scheme 2 shows the retrosynthetic analysis. (+)-
Machaeriol A (1) can be prepared from reaction of pino-
sylvin (9) and (S)-(–)-citronellal (10a) through a hetero-
Diels–Alder reaction.
Pinosylvin (9) can be generated from a Horner–Wads-
worth–Emmons reaction between commercially available
diethyl 3,5-dimethoxybenzaldehyde (6) and benzylphos-
phonate (7) followed by methyl ether cleavage of the
dimethoxy groups.
Scheme 4 shows the mechanism for the formation and ste-
reostructure of (+)-machaeriol A (1). Aldehyde 10a was
first protonated by EDDA to give a protonated aldehyde,
OH
OH
OHC
OH
H
+
OH
10a
H
O
9
O
12
1
OMe
OEt
+
P
O
EtO
OHC
OMe
6
7
Scheme 2 Retrosynthetic analysis of natural (+)-machaeriol A (1)
OEt
OH
P
OMe
OMe
O
EtO
7
pyridine hydrochloride
OH
KOt-Bu
THF
90%
190 °C
85%
OHC
OMe
OMe
9
6
8
OHC
OH
H
10a
H
EDDA, Et3N
xylene
O
reflux
75%
1
Scheme 3 Total synthesis of natural (+)-machaeriol A (1)
Synlett 2008, No. 11, 1643–1646 © Thieme Stuttgart · New York

LETTER
Total Synthesis of (+)- and (–)-Machaeriol A
1645
OH OH
OH
H
10a
H
9
OH
O
– H2O
EDDA, Et3N
O
H
11
12
1
O
H
Scheme 4 The mechanism for the formation and stereochemistry of (+)-machaeriol A (1)
which was then attacked by pinosylvin (9) to yield inter- expected to be widely used in the synthesis of other natu-
mediate 11.
ral products including cannabinoid analogues.
Such a process for producing aldol-type products by a
Ca(OH)2-mediated reaction of resorcinol to enals was al-
ready suggested by Shigemasa.19 The dehydration of
compound 11 in the presence of EDDA and Et3N af-
fords o-quinone methide 12. The stereospecificity of
product 1 might be explained by a pseudoequatorial con-
formation of o-quinone methide 12 for the coplanar struc-
ture adopted by the methyl group in the chairlike
transition state.20 In the process of the hetero-Diels–Alder
reaction of o-quinone methide 12, the exo transition state
must have been more energetically favorable than the
endo transition state. This is in good agreement with Mari-
no, who reported the synthesis of hexahydrocannabinol
using intramolecular hetero-Diels–Alder cycloaddition of
o-quinone methide.21
Acknowledgment
This work was supported by grant No. RTI04-01-04 from the Re-
gional Technology Innovation Program of the Ministry of Commer-
ce Industry and Energy (MOCIE).
References and Notes
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Next, the synthesis of unnatural (–)-machaeriol A (5) was
attempted using pinosylvin (9), as shown in Scheme 5.
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OHC
OH
OH
H
10b
OH
H
9
EDDA, Et3N
xylene
O
5
reflux
76%
Scheme 5 Synthesis of unnatural (–)-machaeriol A (5)
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Pan, X. Angew. Chem. Int. Ed. 2006, 45, 3651.
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[a]D +12.5, neat) in the presence of ethylenediamine diac-
etate (20 mol%) and triethylamine (2 mL) in refluxing xy-
lene for 24 hours gave (–)-machaeriol A (5) in 76% yield.
The specific rotation value of synthetic compound 5 was
[a]D –99.8 (c 0.30, MeOH).
In conclusion, a new and concise synthetic route for bio-
logically interesting natural (+)-machaeriol A (1) and its
enantiomer (–)-machaeriol A (5) was developed starting
from 3,5-dimethoxybenzaldehyde (6) and diethyl ben-
zylphosphonate (7). The key strategies involved stilbene
formation through a Horner–Wadsworth–Emmons reac-
tion and trans-hexahydrodibenzopyran formation through
hetero-Diels–Alder cycloaddition. This synthetic route is
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Synlett 2008, No. 11, 1643–1646 © Thieme Stuttgart · New York

1646
L. Xia, Y. R. Lee
LETTER
Akao, Y.; Nazawa, Y. Biochem. Biophys. Res. Commun.
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J = 12.6 Hz), 2.52 (1 H, ddd, J = 13.4, 11.1, 2.4 Hz), 1.90–
1.87 (2 H, m), 1.68–1.64 (1 H, m), 1.52 (1 H, ddd, J = 11.4,
11.1, 2.1 Hz), 1.43 (3 H, s), 1.17–1.12 (2 H, m), 1.12 (3 H,
s), 0.98 (3 H, d, J = 6.6 Hz), 0.81 (1 H, J = 13.4, 12.6 Hz).
13C NMR (75 MHz, CDCl3): d = 155.8, 155.6, 137.7, 137.1,
129.0, 128.9, 128.5, 127.9, 126.9, 113.5, 108.8, 106.0, 77.8,
49.5, 39.3, 36.1, 35.9, 33.3, 28.5, 28.1, 23.0, 19.5. IR (neat):
3382, 3026, 2922, 2868, 1615, 1568, 1510, 1451, 1422,
1356, 1265, 1138, 1041, 961, 906, 878, 822, 737, 694 cm–1.
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(18) Spectral Data for Compound 1
1H NMR (300 MHz, CDCl3): d = 7.48 (2 H, d, J = 7.3 Hz),
7.36 (2 H, dd, J = 7.7, 7.3 Hz), 7.27 (1 H, t, J = 7.7 Hz), 7.01
(1 H, d, J = 16.3 Hz), 6.93 (1 H, d, J = 16.3 Hz), 6.63 (1 H,
d, J = 1.3 Hz), 6.44 (1 H, d, J = 1.3 Hz), 3.10 (1 H, br d,
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Synlett 2008, No. 11, 1643–1646 © Thieme Stuttgart · New York