Concise access toward chiral hydroxy phenylpropanoids: formal synthesis of virolongin B; kigelin; kurasoin A; 4-hydroxysattabacin, and actinopolymorphol A

Article abstract of DOI:10.1016/j.tetlet.2016.06.070

A simple, two step strategy consisting of Sharpless asymmetric dihydroxylation followed by regioselective breaking of [Formula presented] bond is utilized to target key chiral intermediates of natural products virolongin B, kigelin, kurasoin A, 4-hydroxy-sattabacin, and actinopolymorphol A. Derivatives of enantiopure hydroxy phenyl propanoids and α-hydroxy Weinreb amides are synthesized. The reductive cleavage of [Formula presented] bond in a regioselective manner is obtained using Pd/C in methanol.

Full text of DOI:10.1016/j.tetlet.2016.06.070

Tetrahedron Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Concise access toward chiral hydroxy phenylpropanoids: formal
synthesis of virolongin B; kigelin; kurasoin A; 4-hydroxysattabacin,
and actinopolymorphol A
⇑
Sagar N. Patil, Santosh G. Tilve
Department of Chemistry, Goa University, Taleigao Plateau 403206, Goa, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple, two step strategy consisting of Sharpless asymmetric dihydroxylation followed by regioselec-
tive breaking of CAO bond is utilized to target key chiral intermediates of natural products virolongin B,
kigelin, kurasoin A, 4-hydroxy-sattabacin, and actinopolymorphol A. Derivatives of enantiopure hydroxy
Received 30 May 2016
Revised 14 June 2016
Accepted 16 June 2016
Available online xxxx
phenyl propanoids and
a-hydroxy Weinreb amides are synthesized. The reductive cleavage of CAO bond
in a regioselective manner is obtained using Pd/C in methanol.
Ó 2016 Published by Elsevier Ltd.
Keywords:
Sharpless dihydroxylation
CAO bond breaking
Regioselectivity
Phenylpropanoids
Formal synthesis
b-Hydroxy phenyl propanoid unit is ubiquitous in many potent
bioactive natural products. Such functionally rich phenyl propa-
noid units have close resemblance to monolignols and are impor-
tant to biosynthesis of clinically important lignans, neolignans,
and various heterolignans.1 For example, neolignan virolongin B
(1) was isolated from Licaria aurea, Aristolochia birostris etc. the
extracts of which are known for their pronounced abortifacient,
narcotic, and therapeutic properties.2 Isocoumarin, kigelin (2) is a
b-hydroxy propanoid unit containing natural compound showing
significant activity against human pathogenic fungi (dermato-
phytes), Microsporum canis and Trichophyton longifusus.3 Protein
farnesyl transferase inhibitor, kurasoin A (3) was isolated from fer-
mentation broth of Paecilomyces sp. FO-3684.4
4-Hydroxysattabacin (4) isolated from soil bacteria Bacillus sp.
exhibits potent antiviral properties most notably against herpes
simplex viruses type HSV 1and HSV 2.5 Estrogen receptor dimeriz-
ing, actinopolymorphol A (5) was isolated from Actinopolymorpha
rutilus (YIM 45725).6 Neocarazostatin B (6) was originally discov-
ered from the culture of Streptomyces sp. GP 38.7 This bacterial car-
bazole can act as a free radical scavenger. It exhibits potent
neuronal cell-protecting activity in case of free radical induced
lipid peroxidation in rat brain cells. Lomatin (7) is a naturally
occurring pyranocoumarin, isolated from Lomatium nutalli
(Fig. 1).8 All these b-hydroxy phenyl propanoid derived bioactive
natural frameworks inspire synthetic chemists to develop
approaches for such units in a concise and efficient manner. Study-
ing the asymmetric synthesis of hydroxy propanoids has tremen-
dous scope in natural product synthesis. Synthesis of such
molecules requires construction of asymmetric CAO bond, which
has always been of great importance in the field of synthetic
organic chemistry.9 Chiral hydroxy moieties and related deriva-
tives form a wide range of natural compounds which prompts che-
mists to constantly study CAO bond forming reactions. Many
literature methods are available to form CAO bond enantioselec-
tively (Fig. 2).10 Chiral pool and enzymatic resolution are much
established methods but have their own limitations of substrate
scope.10k,l Organocatalytic hydroxylation or use of chiral hydroxy-
lating agents are recent enantioselective methods10o–q and are yet
to be fully explored for natural product synthesis. Nucleophilic
addition of an organo metallic reagent in the presence of a chiral
ligand is a nascent and very promising method in synthesizing
key building blocks of bioactive compounds10g,h (Fig. 2). Chiral
epoxidation and asymmetric dihydroxylation (AD) are the well-
documented methods for natural product synthesis10i,j (Fig. 2).
Hence, we chose the AD and further regioselective CAO bond
breaking strategy for the synthesis of natural products 1–5. Though
regioselective CAO bond breaking has good potential and scope it
has been very less explored in natural product synthesis. CAO
bond breaking methodologies have recently gained much attention
in various other disciplines of organic chemistry. For example,
⇑
Corresponding author.
E-mail address: stilve@unigoa.ac.in (S.G. Tilve).
http://dx.doi.org/10.1016/j.tetlet.2016.06.070
0040-4039/Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Patil, S. N.; Tilve, S. G. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.06.070

2
S. N. Patil, S. G. Tilve / Tetrahedron Letters xxx (2016) xxx–xxx
O
MeO
MeO
O
OMe
OH
O
Ph
O
MeO
MeO
O
OH
OH
HO
OMe
HO
MeO
4-Hydroxy Sattabacin (4)
Kurasoin A (3)
Kigelin (2)
HO
Virolongin B (1)
OMe
CH3
OH
O
O
O
OH
N
OAc
H
HO
O
Lomatin (7)
Neocarazostatin B (6)
Actinopolymorphol A (5)
Figure 1. Representative examples of homobenzyl hydroxyl group containing chiral natural compounds.
(Stereoselective reduction)10a, b
sis of key compound 13 we needed to synthesise isoelemicine 11
which was synthesized as reported in the literature.14 Synthetic
procedure commenced with the allyation of phenol 8a to get com-
pound 9 which on Claisen rearrangement gave the phenolic com-
pound 10. PdCl2 mediated isomerisation of 10 and further
methylation gave the required iso-elemicin 11. Compound 11
was also synthesized by Grignard addition of ethyl magnesium
bromide to 3,4,5-trmethoxy benzaldehyde followed by dehydra-
tion in two steps. Subsequently under the UpJohn dihydroxyla-
tion15 conditions compound 11 afforded racemic diol 12. Having
synthesized diol compound 12 the stage was set to study the
regioselective cleavage of benzylic hydroxyl group and obtain
hydroxyphenyl propanoids of further synthetic application.
Hydrogenolysis is always a tricky reaction and selectivity depends
on the substrate reactivity hence different combination of catalysts
and conditions are reported.16 Initially we studied racemic com-
pound 12 (Scheme 1) to study the regioselective CAO bond break-
ing under different conditions (Table 1).
R
Ar
o
o
CHO
Ar
R
Ar
(enantioselective
(enantioselctive hydroxylation
hydroxylation)10o, p, q
followed by reduction)10c, d
OH
R
R
R
Ar
Ar
Ar
OAc
OH
(Dynamic resolution)10m, n
OH
O
(C-O bond breaking)10e, f,
R
Ar-MX/ R-MX
Ar
(Organometallic asymmetric
NH2
reaction)10g, h
Ar
(chiral pool)10k, l
R
(epoxide opening)10i, j
Figure 2. Enantioselective CAO bond forming reactions.
First we tried microwave assisted hydrogenolysis using Pd(OH)2
/C and ammonium formate in ethylene glycol.17 This always gave a
complex mixture. Refluxing the reaction mixture with a strong
hydride donor, lithium aluminum hydride (LAH) also failed to deli-
ver the product (entry 2, Table 1).18 Pressure hydrogenation condi-
tions using different supported palladium catalysts such as Pd
(OH)2/C; Pd/C(10%) their combinations in ethanol failed to break
regioselective CAO bond.19 Acidic additives such as perchloric acid
and acetic acid etc. also failed to give promising results (entry 4,
Table 1).20
selective hydrogenolysis of CAO bonds of lignin (a polymeric mate-
rial/ biomass derived from plants) to get smaller fragments/ mole-
cules having tremendous demands in their usage as lignocellulosic
biofuels.11 Novel synthesis of chemical frameworks via targeted
CAO bond scission is yet another recently explored topic in the
field of synthetic organic chemistry.12 Many catalytic systems are
being optimized to selectively cleave CAO bonds in a molecule
demonstrating not only the efficacy of catalytic systems but also
highlighting the importance of the CAO bond breaking strategy.13
To realize the synthesis of the natural compound, kigelin, (2) we
targeted synthesis of key chiral intermediate 13 and for the synthe-
Finally changing the solvent to dry methanol and under pres-
sure hydrogenation condition (4.5 atm), in the presence of Pd/C
MeO
MeO
MeO
CHO
HO
8a
8b
OMe
OMe
d
Br
a
OH
MeO
MeO
MeO
MeO
MeO
MeO
b
c
e
OH
O
HO
(+/-)
OMe
OMe
11
OMe
f
OMe
10
12
9
OH O
MeO
MeO
MeO
MeO
O
OH
(+/-) Kigelin (2)
(+/-)
OMe
13
Scheme 1. Reagents and conditions: (a) K2CO3, acetone reflux, 6 h, 98%; (b) DCB, reflux,16 h, 88%; (c) (i) PdCl2 (0.1 equiv), MeOH, rt, argon, 24 h, 85%; (ii) (CH3)2SO4, K2CO3,
acetonitrile, 8 h, rt, 98%; (d) EtMgBr, 0 °C to rt, 2 h then PTSA toluene, heat, 55%; (e) Upjohn conditions, acetone–H2O (1:1), OsO4 (0.02 equiv), NMO (3 equiv), 18 h, rt, 95%; (f)
10% Pd/C (60%), H2 (4.5 atm), MeOH, 72 h, rt, 85%.
Please cite this article in press as: Patil, S. N.; Tilve, S. G. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.06.070

S. N. Patil, S. G. Tilve / Tetrahedron Letters xxx (2016) xxx–xxx
3
26.6 = À12.09 (c 1.8, CHCl3) as chiral dihydroxy compounds using
Table 1
[
a
]
Regioselective CAO bond breaking and optimization studies of model structure (12)
Sharpless ligands (DHQ)2PHAL and (DHQD)2PHAL respectively
(Scheme 2). Regioselective CAO bond breaking of chiral diols under
Entry Reaction conditions
Remarks
optimized conditions resulted in synthesis of both the enantiomers
1
Microwave; Ammonium formate 10% Pd/C (W/W); Mix. of
24.4
ethylene glycol
compoundsa
of hydroxy phenyl propanoid derivative 13a, 84% ee, [
a]
=
a
a
2
3
4
LAH, THF/Dioxane reflux
Pd(OH)2/C; EtOH, H2 (4 atm)
EtOH, HClO4, Pd/C, H2 (4 atm)
—
—
+11.38 (c 0.9, CHCl3); matching with the reported optical rotation
[
a
]
20 = +20.8 (c 0.8, CHCl3) and 13b, 84% ee, [
a
]
26.6 = À11.14 (c
Mix. of
0.8, CHCl3). 1H, 13C NMR, and optical rotations were in well accor-
dance to the compound reported in the literature. Compound 13
constitutes a formal access to synthesis of dihydroisocoumarin
based natural compound kigelin, an active ingredient of skin
creams and lotions.22 Asymmetric synthesis of the same can be
accomplished using chiral intermediate 13b and from chiral com-
pound 13a synthesis of a neolignan, virolongin B, (1) natural com-
pound exhibiting wide range of bioactivity and other pharmaco-
properties is known in the literature.23
compoundsb
50% of 13a
85% of 13
85% of 13
5
6
7
MeOH, Pd/C (0.2 W/W), H2 (4.5 atm)
MeOH, Pd/C (0.6 W/W), H2 (4.5 atm)
MeOH, Pd/C (1 equiv W/W), H2 (4.5–6 atm)
a
The starting material was recovered.
EtOAc, dioxane, acetic acid as solvents were also tried.
b
as a catalyst could dramatically improve the outcome without
usage of strong acidic conditions giving us 50% of the expected
compound. NMR data of the compound obtained after purification
was exactly matching with the literature reports.21 With these ini-
tial results we further optimized the conditions and noted that
increasing loading of catalyst increased the yield to 80–85%.
Increasing the catalyst loading further neither could accelerate
the reaction nor improve the yield of the expected compound
(entry 7, Table 1). With these encouraging results for the regiose-
lective CAO bond breaking method, we decided to complete the
asymmetric version of the same sequence. Simply traversing the
dihydroxylation reaction under Sharpless asymmetric conditions
Scope of the method was then successfully extended to more
challenging and tricky scaffolds,
a,b unsaturated Weinreb amide
derivatives to synthesize chiral
a
-hydroxy Weinreb amides
(Scheme 3). Synthesis commenced with commercially available
p-coumaric acid which was converted to Weinreb amide 14 by
EDC coupling followed by UpJohn dihydroxylation to get a water
soluble phenolic dihydroxy compound 15 which upon regioselec-
tive CAO bond breaking yielded 16 in racemic form. However,
the phenolic Weinreb amide 14 failed to give the corresponding
chiral diols under Sharpless conditions and we attributed this out-
come to the fact that phenolic core of the compound may be fol-
lowing unwanted oxidation reactions in the presence of K3Fe
yielded both alpha, [
a]
26.7 = +11.47 (c 1.9, CHCl3); 90% ee and beta,
MeO
a, c
OH
MeO
MeO
MeO
one step
OMe
MeO
O
OMe 13a
Lit. method
OMe
84%ee
MeO
MeO
(11)
(-) Virolongin B (1)
OMe
MeO
MeO
b, c
OH
13b
OMe
84%ee
Scheme 2. Reagents and conditions: (a) (DHQ)2PHAL (0.05 equiv), OsO4 (0.02 equiv; (2% aq), K3Fe(CN)6 (3 equiv), K2CO3 (3 equiv), tButanol–H2O (1:1), 18 h, rt, 90%.; (b)
t
(DHQD)2PHAL (0.05 equiv), OsO4 (0.02 equiv), K3Fe(CN)6 (3 equiv), K2CO3 (3 equiv), Butanol–H2O (1:1), 18 h, rt, 90%; (c) 10% Pd/C (60%), H2 (4.5 atm), MeOH, 72 h, rt, 85%.
O
O
O
O
O
OH
N
N
a
HO
TBDMSO
OTBDMS
17
HO
14
P-Coumaric acid
(+/-)
b
d
O
O
OH
O
O
N
O
O
Sharpless asymmetric
dihydroxylation conditions
N
N
c
OH
OH
HO
HO
14
HO
(+/-)
16
(+/-)
15
h
O
OH
O
O
O
O
O
N
N
OH
OH
g
f
e
OH
20
O
O
O
HO
19
18
P-Coumaric acid
Ph
Ph
Ph
Scheme 3. Reagents and condition: (a) EDCÁHCl (1.1 equiv), N,O-dimethyl hydrochloride (1.3 equiv), Hunig’s base (3.5 equiv), HOBT (1.1 equiv), DMF, 48 h, rt, 70%; (b) Upjohn
conditions, acetone–H2O (1:1), OsO4 (0.02 equiv), NMO (3 equiv), 72 h, rt, 80%; (c) 10% Pd/C (60%), H2 (4.5 atm), MeOH, 110 h, rt, 65%.; (d) TBDMSCl (2.1 equiv), imidazole
(2.5 equiv), DMF, 18 h, rt, 90%; (e) Benzyl bromide (2.1 equiv), NaOH (5 equiv), EtOH–H2O (1:1), reflux, 36 h, followed by acidic-work-up, 95%; (f) EDCÁHCl (1.1 equiv), N,O-
dimethylhydroxylamine hydrochloride (1.3 equiv), Hunig base (3.5 equiv), HOBT (1.1 equiv), DMF, 56 h, rt, 85%; (g) Upjohn conditions, acetone–H2O (1:1), OsO4 (0.02 equiv),
NMO (3 equiv), 48 h, rt, 90%; (h) 10% Pd/C (60%), H2 (4.5 atm), MeOH, 110 h, rt, 75%.
Please cite this article in press as: Patil, S. N.; Tilve, S. G. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.06.070

4
S. N. Patil, S. G. Tilve / Tetrahedron Letters xxx (2016) xxx–xxx
O
O
N
O
O
O
TBDMSO
OTBDMS
N
N
d
17a
17b
a, c
b, c
OH
16a
O
HO
HO
90%ee
O
N
O
O
O
O
N
19
d
Ph
OH
16b
TBDMSO
OTBDMS
94%ee
Scheme 4. Reagents and conditions: (a) (DHQ)2PHAL (0.05 equiv), OsO4 (0.02 equiv), K3Fe(CN)6 (3 equiv), K2CO3 (3 equiv), THF–tButanol–H2O (1:2:2), 18 h, rt, 90%; (b)
(DHQD)2PHAL (0.05 equiv), OsO4 (0.02 equiv), K3Fe(CN)6 (3 equiv), K2CO3 (3 equiv), THF–tButanol–H2O (1:2:2), 18 h, rt, 90%; (c) 10% Pd/C (60%), H2 (4.5 atm), MeOH, 110 h, rt,
75%.; (d) TBDMSCl (2.1 equiv), imidazole (2.5 equiv), DMF, 18 h, rt, 90%.
(CN)6 which is used as an oxidizing agent in the reaction. Therefore
we decided to protect the phenolic hydroxyl of Weinreb amide
compound 14 by a benzyl group which could be later knocked
under the optimized late stage hydrogenolysis step (CAO bond
breaking) along with the targeted benzylic hydroxyl group to give
compound 16 in one step. After protection and EDC mediated cou-
this article can be found, in the online version, at http://dx.doi.
org/10.1016/j.tetlet.2016.06.070.
References and notes
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25 = À1.8 (c 0.8, MeOH) and beta
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In conclusion, a simple and effective regioselective CAO bond
breaking method is studied for its application in the field of syn-
thesis of b-hydroxy phenyl propanoid containing natural products.
We have synthesized key chiral intermediates derivatives of chiral
hydroxy phenyl propanoids and also
a-hydroxy Weinreb amide
derivatives to formally access five different bioactive natural com-
pounds. We envision that the scope of the present regioselective
CAO bond breaking method can also be extended to other compet-
itive aromatic scaffolds, such as chromans and carbazole deriva-
tives to target enantioselective synthesis of lomatin and
neocarazostatin B (Fig 1) respectively.
Acknowledgments
We thank the CSIR New Delhi for financial support and S.N.P.
acknowledges CSIR-New Delhi for senior research fellowship.
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