A concise asymmetric synthesis of (-)-virolin, (-)-surinamensin,(-)- raphidecursinol B and (-)-polysphorin

Article abstract of DOI:10.1055/s-0031-1290678

Highly concise and general asymmetric syntheses of biologically important natural (-)-8,4-oxyneolignans [(-)-virolin, (-)-surinamensin, (-)-raphidecursinol B, and (-)-polysphorin] are reported. The key step in the synthesis is the Evan's syn-aldol reaction to achieve the adducts with the desired stereochemistry. The four biologically important plant metabolites were synthesized using two common intermediates. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290678

LETTER
▌1485
lAetteCr oncise Asymmetric Synthesis of (–)-Virolin, (–)-Surinamensin,
(–)-Raphidecursinol B and (–)-Polysphorin
Synthesis of (–)-Virolin
Manda Nagaraju, Rajesh Chandra, Bhimrao B. Gawali*
Organic Chemistry Division-II, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 706, India
Fax +91(40)27193382; E-mail: gawalibb@yahoo.co.in
Received: 14.03.2012; Accepted: 03.04.2012
OH
OH
Abstract: Highly concise and general asymmetric syntheses of
9
2
OMe
OMe
OMe
OMe
3
8
1
biologically important natural (–)-8,4′-oxyneolignans [(–)-virolin,
(–)-surinamensin, (–)-raphidecursinol B, and (–)-polysphorin] are
reported. The key step in the synthesis is the Evan’s syn-aldol reac-
tion to achieve the adducts with the desired stereochemistry. The
four biologically important plant metabolites were synthesized us-
ing two common intermediates.
7
6'
4
O
O
6
5'
4'
1'
2'
5
OMe
7'
OMe
OMe
3'
8'
9'
(–)-virolin (I)
antischistosomal
antioxidant
(–)-surinamensin (II)
Key words: asymmetric synthesis, chiral auxiliary, aldol reaction,
natural products, oxyneolignans
antischistosomal
antileukemic
antifungal
antifungal
OH
OH
Virolin (I), surinamensin (II), raphidecursinol B (III), and
polysphorin(IV) are members of the 8,4′-oxyneolignan
family1 and exhibit rich and diverse biological properties.
These compounds, whose common structural feature is
the presence of 1-aryl-2-aryloxypropanol moiety, occur in
Myristicaceae and other primitive plant families in neo-
tropical regions and are often isolated in racemic forms.2
While raphidecursinol B (III) and polysphorin (IV) show
antimalarial activity,2c,3 virolin (I) and surinamensin (II)
exhibit activity against leishmaniasis.2b,4 They are also
reported to possess antifungal,5 antioxidant,6 and
antischistosomal7 activities (Figure 1). The pharmaceuti-
cally important biological profiles coupled with the scarce
availability from natural sources prompted many groups
to attempt the laboratory synthesis of this compound
class,2a,b,8–11 often as racemates. Synthetic methods also
provide the opportunity to expand the diversity by gener-
ating non-natural congeners. Usually the aromatic rings of
these compounds are highly oxygenated, containing hy-
droxyl, methoxy, or methylenedioxy groups. One of the
rings also carries an alkenyl – either an (E)-propenyl or al-
lyl – pendent group.
OMe
OMe
OMe
OMe
OMe
O
OMe
O
OMe
OMe
OMe
OMe
(–)-polysphorin (IV)
antimalarial
(–)-raphidecursinol B (III)
antimalarial
Figure 1 Structures of (–)-virolin (I), (–)-surinamensin (II), (–)-raph-
idecursinol B (III), and (–)-polysphorin (IV)
which is complementary to the drugs targeting the eryth-
rocytic stages.3 The preliminary results of our research en-
deavors form the subject matter of the present
communication, wherein we report the asymmetric syn-
thesis of (–)-virolin (I), (–)-surinamensin (II), (–)-raphi-
decursinol B (III), and (–)-polysphorin (IV) employing
Evans syn-aldol reaction as the common strategy.
Our strategy is depicted retrosynthetically in Scheme 1. It
was envisaged that the reductive deoxygenation of the pri-
mary hydroxyl group resulting from the auxiliary-assisted
aldol reaction of suitable substrates would afford the 1-
aryl-2-aryloxypropanol moiety in the required stereo-
chemistry. The auxiliary-linked chiral precursor could
easily be generated from aryloxyacetic acid, which in turn
could be readily prepared from commercially available
starting materials. A closer look at the target structures re-
veals that all the four natural compounds could be arrived
at using only two different aryloxyacetic acids as virolin
and surinamensin share the same B-ring motif while a
simple isomerization of the B-ring double bond in raphi-
decursinol B would afford polysphorin.
The first asymmetric route to (–)-polysphorin and ana-
logues was reported by Prof. Ley’s group making use of
polymer-supported reagents, catalysts, and scavengers.9
Subsequently Curti et al. described another asymmetric
route employing (S)- or (R)-methyl lactate as the chiral
sources.10 We have been pursuing antimalarial drug can-
didates, because of the re-emergence of the disease with
strains resistant to traditionally administered quinoline
class of drugs, most notably chloroquine. Polysphorin and
structurally related compounds emerged attractive as they
target the pathogen in the hepatic stages of the infection,
The B-ring precursor for virolin and surinamensin was as-
sembled starting from vanillin (1). The alkylation of the
phenolic group with ethylbromoacetate afforded the α-
aryloxy ester derivative (Scheme 2). The introduction of
the propenyl group under Wittig conditions resulted in a
SYNLETT 2012, 23, 1485–1488
Advanced online publication: 29.05.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290678; Art ID: ST-2012-D0241-L
© Georg Thieme Verlag Stuttgart · New York

1486
M. Nagaraju et al.
LETTER
O
OH
O
R3
R3
R1
AUX
R1
B
A
O
O
OMe
OMe
R2
OMe
OMe
OMe
R2
OMe
O
R1
N
O
OH
AUX =
Ph
Ph
R2
OMe
B-ring precursors
OH
A-ring precursors
O
O
OMe
OMe
OMe
OH
OMe
OMe
OMe
12
virolin
OMe
O
OMe
13
1
4
virolin
surinamensin
raphidecursinol B
polysphorin
polysphorin
raphidecursinol B
surinamensin
Scheme 1 Retrosynthetic strategy and the building blocks
mixture of E- and Z-isomers 2,12 which was converted into the corresponding aryloxyacetic acid derivative 6 (92%
the exclusive E-form using (MeCN)2PdCl2 in methanol at for four steps).
room temperature.13 Subsequent hydrolysis of the ester
With both the A- and B-ring counterparts at our disposal,
we proceeded to the crucial auxiliary-assisted aldol reac-
tion. A thorough literature scouting of the prior art con-
vinced us the use of valine-based chiral oxazolidinone 7
as the auxiliary since it affords the aldol adducts in consis-
tently high yields and enantioselection. It could also be
moiety yielded the requisite aryloxyacetic acid 3.14 The
yield of the four-step procedure is 92%. For the generation
of B-ring building block of polysphorin and raphide-
cursinol B, 2,6-dimethoxyphenol (4) was initially allylat-
ed, and the resultant allylaryl ether was subjected to
Claisen rearrangement to afford 4-allylphenol derivative
readily prepared from inexpensive starting materials.16
5 (Scheme 2).15 Alkylation of the phenol derivative with
ethyl bromoacetate followed by the hydrolysis provided
i) BrCH2CO2Et
OMe
OMe
K2CO3, acetone
reflux, 4 h, 98%
O
O
CO2Et
OH
ii) Ph3PCHMe
K2CO3, 1,4-dioxane
reflux, 4 h
OHC
2
1
OMe
i) (MeCN)2PdCl2, MeOH, r.t., 24 h
97% (2 steps)
CO2H
ii) NaOH, MeOH–CH2Cl2, r.t., 3 h, 97%
3
OMe
i) allyl bromide, K2CO3
acetone, reflux
6 h, 99%
OMe
OH
OH
ii) Bi(OTf)3, MeCN
reflux, 4 h, 97%
OMe
OMe
5
4
OMe
i) BrCH2CO2Et, K2CO3, acetone
reflux, 5 h, 99%
O
CO2H
ii) NaOH, MeOH–CH2Cl2, r.t., 3 h, 97%
OMe
6
Scheme 2 Preparation of intermediates 3 and 6
Synlett 2012, 23, 1485–1488
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of (–)-Virolin
1487
Ph
Ph
O
O
i) n-BuLi, THF, 0 °C
ii) 8 or 9, THF, 0 °C to r.t.
Ph
Ph
O
O
MeO
R2
N
NH
MeO
O
R2
Cl
O
R1
O
O
10 R1 = H, R2 = (E)-propenyl; 92%
11 R1 = OMe, R2 = allyl; 92%
7
R1
8 R1 = H, R2 = (E)-propenyl
9 R1 = OMe, R2 = allyl
R3
OMe
Ph
Ph
OH
O
O
i) n-Bu2BOTf, DIPEA
CH2Cl2, 0 °C to r.t.
LAH, Et2O, r.t., 2 h
N
OMe
OMe
ii) 12 or 13, –78 °C to r.t.
O
R3
O
R1
OMe
OMe
O
R2
12 R3 = H
14 R1 = H, R2 = (E)-propenyl, R3 = H; 86%
15 R1 = H, R2 = (E)-propenyl, R3 = OMe; 87%
16 R1 = OMe, R2 = allyl, R3 = OMe; 87%
13 R3 = OMe
OH
OH OH
R3
R3
R1
R1
i) TsCl, cat. DMAP, Et3N
O
CH2Cl2, 0 °C to r.t., 3 h
O
OMe
OMe
ii) LAH, Et2O
r.t., 2 h
OMe
OMe
R2
I
R1 = H, R2 = (E)-propenyl, R3 = H; 98%
OMe
R2
OMe
17 R1 = H, R2 = (E)-propenyl, R3 = H; 97%
18 R1 = H, R2 = (E)-propenyl, R3 = OMe; 98%
19 R1 = OMe, R2 = allyl, R3 = OMe; 96%
II R1 = H, R2 = (E)-propenyl, R3 = OMe; 98%
III R1 = OMe, R2 = allyl, R3 = OMe; 98%
Scheme 3 Synthesis (–)-virolin (I), (–)-surinamensin (II), and (–)-raphidecursinol B (III)
Aryloxyacetic acid derivatives 3 and 6, prepared as de- ductive removal of the auxiliary afforded the diols 17, 18,
tailed earlier, were attached to the auxiliary following the and 19 in near quantitative yields.16 The last step in our
literature reported procedures.16 Thus the reaction of lith- synthetic sequence is the deoxygenation of the primary
ium salt of the auxiliary with aryloxyacid chlorides, pre- hydroxyl group from the diols 17, 18, and 19. This is
pared from 3 and 6, afforded the corresponding N-acyl- achieved by the tosylation of the primary OH group fol-
imidazolidinone derivatives 10 and 11 in excellent yields lowed by the reductive removal of the tosylate moiety to
(Scheme 3). The aldol reaction of the boron enolates, gen- afford (–)-virolin (I), (–)-surinamensin (II), and (–)-raph-
erated from imidazolinones 10 and 11 by treating with n- idecursinol B (III). The spectral characteristics of the nat-
dibutylborontriflate in the presence of Hünig’s base17 af- ural products prepared compare favorably with the
forded only a single diastereomer (the 1H NMR spectra of literature-reported spectral data (see Supporting Informa-
the crude reaction samples show signals corresponding to tion). Structural integrity of I, II, and III was further con-
only one diastereomer with a de >99%).17–19 Further NMR firmed by the specific rotation analysis, which matched
analysis of the isolated, pure sample confirmed the diaste- well with literature-reported values. Employing this pro-
reomer to be the syn-aldol adduct. The coupling constants tocol, the overall yields achieved for the final compounds
(Jα,β of the methyne protons of the newly formed bond) of (–)-virolin, (–)-surinamensin, and (–)-raphidecursinol B
the aldol adducts 14, 15, and 16 were found to be 3.77, are 70%, 75%, and 67%, respectively, starting from 1 and
3.96, and 6.00 Hz, respectively, which falls within the 4.
range 2–6 Hz reported for syn-aldol adducts.18,19 The re-
OH
OH
OMe
OMe
OMe
OMe
OMe
OMe
PdCl2, MeOH
r.t., 6 h, 97%
O
O
OMe
OMe
OMe
OMe
(–)-raphidecursinol B (III)
(–)-polysphorin (IV)
Scheme 4 Synthesis of (–)-polysphorin (IV)
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1485–1488

1488
M. Nagaraju et al.
LETTER
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Finally, the synthesis of (–)-polysphorin (IV) was
achieved by the isomerization of the double bond in (–)-
raphidecursinol B (III, 97%). The double-bond isomeri-
zation, carried out in the presence of catalytic PdCl2 in
MeOH,10 afforded only the E-isomer as reported in the lit-
erature (Scheme 4).
In conclusion, we have achieved an efficient and concise
asymmetric total synthesis of biologically important plant
metabolites (–)-virolin, (–)-surinamensin, (–)-raphide-
cursinol B, and (–)-polysphorin using two common inter-
mediates, beginning from readily available starting
materials. These structurally very similar compounds dif-
fer in their biological properties depending on the degree
of oxygenation of phenyl rings as well as the nature of the
alkene chain present. This augers well for the develop-
ment of novel drug candidates employing structure–activ-
ity relationship (SAR) studies, especially since these
compounds exhibit useful biological properties. Synthesis
of non-natural congeners of the compounds with a view to
obtaining molecules with better biological profiles, using
the synthetic strategy presented in this communication, is
currently being pursued.
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Acknowledgment
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MN thank CSIR-New Delhi for the award of research fellowship.
We are grateful to Dr. J. S. Yadav, Director IICT, Hyderabad for
support.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
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