Total syntheses of (±)-vestitol and bolusanthin III using a wittig strategy

Article abstract of DOI:10.1055/s-0030-1260783

An intramolecular Wittig olefination was utilized to -produce the key isoflav-3-ene intermediate needed to prepare (±)-vestitol and bolusanthin III in ca. 30% and 20% respective yields after eight steps. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0030-1260783

LETTER
1605
Total Syntheses of ( )-Vestitol and Bolusanthin III Using a Wittig Strategy
Total
Syntheses
(
m
)-Vestitol and
B
olu
a
santhin II
I
rjit Luniwal, Paul W. Erhardt*
Department of Medicinal and Biological Chemistry, Center for Drug Design and Development,
College of Pharmacy and Pharmaceutical Sciences, University of Toledo, 2801 W. Bancroft Street, Toledo, Ohio 43606, USA
Fax +1(419)5307946; E-mail: paul.erhardt@utoledo.edu
Received 28 January 2011
HO
O
HO
O
Abstract: An intramolecular Wittig olefination was utilized to
produce the key isoflav-3-ene intermediate needed to prepare ( )-
vestitol and bolusanthin III in ca. 30% and 20% respective yields af-
ter eight steps.
HO
OMe
HO
OMe
1
2
Key words: vestitol, bolusanthin III, total syntheses, intramolecu-
lar Wittig olefination
HO
HO
Often displaying phytoestrogenic and antioxidant proper-
ties, polyphenolic isoflavans remain of interest for poten-
tial use as selective estrogen receptor modulators (SERM)
and as cancer preventative agents.1 Within this structural
theme, vestitol and bolusanthin III (1 and 2 in Figure 1, re-
spectively) are a closely-related pair of isoflavonoids that
differ in their degree of conformational rigidity and extent
of conjugation between two similarly appended phenolic
hydroxyl groups. The levorotatory2 and dextrorotatory3
enantiomers of isoflavan 1 have been isolated from vari-
ous sources, as has its achiral isoflavene relative 2.4 Both
(–)-1 and 2 are present in the common licorice Glycyrrhi-
za pallidiflora.5 Vestitol, in particular, has been found to
have significant activity against antibiotic resistant H. py-
lori while licorice extracts, in general, are considered to
be potentially useful as chemopreventatives for peptic ul-
cer and gastric cancer.6 Given their structural similarity to
human estrogen receptor ligands, such as estradiol and di-
ethylstilbestrol (3 and 4 in Figure 1, respectively), we
have undertaken a multistep, total synthesis of racemic 1
and 2 in order to generate quantities that can be deployed
to further scope their potential anticancer profile and to
ascertain if they have demonstrable phytoestrogenic prop-
erties. Although 1 has been synthesized previously,1a,2d,7
to our knowledge this is the first report of a total synthesis
for 2.
OH
OH
3
4
Figure 1 Target compounds ( )-vestitol [1, depicted as the (–)-en-
antiomer obtained from licorice] and bolusanthin III (2), and their
structural similarities to human estrogen receptor ligands estradiol (3)
and diethylstilbestrol (4)
or copper oxide9 to provide intermediate 5.10 As we have
done previously, selective benzylation of 2,4-dihydroxy-
benzaldehyde at the para position was followed by reduc-
tion with sodium borohydride to provide the salicyl
alcohol intermediate 6.8c,d Coupling of 5 and 6 was ac-
complished by a nucleophilic substitution reaction11 to
form ether 7.12 The latter was converted to a Wittig salt by
treatment with triphenylphosphine hydrobromide13 and
used in an intramolecular olefination reaction8c,d–i to ob-
tain the key, penultimate intermediate 8.14 A total synthe-
sis of racemic vestitol was then achieved in eight steps
upon catalytic hydrogenation5 which simultaneously re-
duced the olefin while cleaving the two benzyl-protecting
groups. The overall yield was 29%.15
Alternatively, to produce bolusanthin III, we first attempt-
ed to remove the benzyl groups in 8 by treatment with
pentamethylbenzene/trifluoroacetic acid (PMB/TFA)16
and with boron tribromide (BBr3).17 However, both re-
agents proved too harsh and resulted in degradation of 8
to multiple side products without providing detectable
levels of desired material (TLC). A possible mechanism
for this ready decomposition could involve the allylic
ether either becoming protonated in the case of TFA or
chelated with the Lewis acid in the case of BBr3. Either
species can collapse to a benzyl carbocation that leads to
multiple decomposition pathways. Ultimately, the synthe-
sis of 2 was achieved by treating 8 with BCl3 in the pres-
ence of PMB at –78 °C.18 An eight-step procedure leading
to 2 was thus accomplished in 21% overall yield.19 Unlike
the previous isolations of 2 from natural sources, the syn-
thesized product can be obtained conveniently as a free-
Drawing from our evolving studies pertaining to the syn-
theses of various pterocarpan phytoalexins,8a–d we imag-
ined that an intramolecular Wittig reaction could be used
to form the isoflav-3-ene system in 2. Reduction of the lat-
ter can readily yield ( )-1.5 This synthetic strategy is
shown in Scheme 1.
4-Methoxy-2-hydroxyacetophenone was protected with a
benzyl group under mildly basic conditions and then sub-
jected to selective a-iodination using either Selectfluor8c
SYNLETT 2011, No. 11, pp 1605–1607
x
x
.x
x
.2
0
1
1
Advanced online publication: 10.06.2011
DOI: 10.1055/s-0030-1260783; Art ID: S01011ST
© Georg Thieme Verlag Stuttgart · New York

1606
A. Luniwal, P. W. Erhardt
LETTER
(3) (a) Kurosawa, K.; Ollis, W. D.; Redman, B. T.; Sutherland,
I. O. Chem. Commun. 1968, 1263. (b) Abreu-Matos, F. J.;
Gottlieb, O. R.; Souza-Andrade, C. H. Phytochemistry
(Elsevier) 1975, 825.
(4) Erasto, P.; Bojase-Moleta, G.; Majinda, R. T.
Phytochemistry (Elsevier) 2004, 65, 875.
(5) Kajiyama, K.; Hiraga, Y.; Takahashi, K.; Hirata, S.;
Kobayashi, S.; Sankawa, U.; Kinoshita, T. Biochem. Syst.
Ecol. 1993, 21, 785.
(6) Fukai, T.; Marumo, A.; Kaitou, K.; Kanda, T.; Terada, S.;
Nomura, T. Life Sci. 2002, 71, 1449.
O
O
I
a,b
HO
HO
OMe
BnO
OMe
OH
5
6
e
OH
H
BnO
c,d
O
OH
(7) Rohwer, M. B.; Heerden, P. S.; Brandt, E. V.;
Bezuidenhoudt, B. C. B.; Ferreira, D. J. Chem. Soc., Perkin
Trans. 1 1999, 3367.
O
OBn
BnO
O
f
(8) (a) Khupse, R. S.; Erhardt, P. W. J. Nat. Prod. 2007, 70,
1507. (b) Khupse, R. S.; Erhardt, P. W. J. Nat. Prod. 2008,
71, 275. (c) Khupse, R. S.; Erhardt, P. W. Org. Lett. 2008,
10, 5007. (d) Luniwal, A.; Khupse, R. S.; Reese, M. D.;
Fang, L.; Erhardt, P. W. J. Nat. Prod. 2009, 72, 2072.
(e) Burali, C.; Desideri, N.; Stein, M. L.; Conti, C.; Orsi, N.
Eur. J. Med. Chem. 1987, 119. (f) Kinder, F. R.; Jarosiniski,
M. A.; Anderson, W. K. J. Org. Chem. 1991, 56, 6475.
(g) Kumar, P.; Bodas, M. S. Org. Lett. 2000, 2, 3821.
(h) Evans, L. A.; Griffiths, K. E.; Guthmann, H.; Murphy,
P. J. Tetrahedron Lett. 2002, 43, 299. (i)Yuan, Y.; Men, H.;
Lee, C. J. Am. Chem. Soc. 2004, 126, 14720.
OMe
OH
7
BnO
O
HO
O
OBn
OH
g
OMe
OMe
8
( )-1
h
(9) Yin, G.; Gao, M.; She, N.; Hu, S.; Wu, A.; Pan, Y. Synthesis
2007, 3113.
HO
O
OH
(10) 1-(2¢-Benzyloxy-4-methoxyphenyl)ethanone
To a solution of 4-methoxy-2-hydroxyacetophenone (5.0 g,
30 mmol) in MeCN (80 mL), K2CO3 (5.0 g, 36 mmol) and
benzyl bromide (5.0 g, 29 mmol) were added. The reaction
mixture was stirred under reflux while progress was
followed by TLC and 1H NMR. After 24 h solvent was
evaporated under vacuum. The off-white residue was
dissolved in EtOAc and washed with 2 M NaOH, 0.1 M HCl,
H2O, and brine. After drying over anhyd Na2SO4 and then
filtration, the volatiles were evaporated under vacuum to
obtain the desired ketone (7.4 g, 28.8 mmol, 96%) as a white
solid; mp 84–88 °C. TLC: Rf = 0.40 (EtOAc–hexanes = 1:3).
1H NMR (600 MHz, CDCl3): d = 7.85 (1 H, d, J = 8.4 Hz),
7.40 (5 H, m), 6.53 (2 H, m), 5.13 (2 H, s), 3.83 (3 H, s), 2.56
(3 H, s). 13C NMR (150 MHz, CDCl3): d = 197.8, 164.3,
160.1, 135.9, 132.7, 128.7, 128.2, 127.6, 121.4, 105.3, 99.4,
70.6, 55.5, 32.2
OMe
2
Scheme 1 Synthesis of racemic vestitol and bolusanthin III.
Reagents and conditions: (a) BnBr, K2CO3, MeCN, reflux, 24 h, 96%;
(b) Selectfluor, I2, CH2Cl2–MeOH (1:5), r.t., 20 h, 84%; (c) BnBr,
KHCO3, MeCN, reflux, 15 h, 85%; (d) NaBH4, EtOH, 0 °C 1 h, r.t.,
10 h, 58%; (e) K2CO3, Me2CO, reflux, 16 h, 78%; (f) (i) Ph3P·HBr,
MeCN, r.t., 1 h; (ii) KOt-Bu, MeOH, reflux, 24 h, 70% across two
steps; (g) 10% Pd/C, EtOAc, H2 (2.4 bar), r.t., 14 h, 84%; (h) BCl3,
PMB, CH2Cl2, –78 °C, 15 min, 61%.
flowing powder that displays a discernable melting point.
This constitutes the first published report20 for the total
synthesis of bolusanthin III.
Compound 5
To a solution of protected ketone from the previous step
(22.7 g, 88.6 mmol) in anhyd CH2Cl2 (100mL) and anhyd
MeOH (500 mL), SelectfluorTM (18.9 g, 53.3 mmol) was
added followed by addition of elemental iodine (11.25 g,
44.3 mmol). The reaction mixture was stirred for 20 h.
Progress was monitored by TLC and 1H NMR. After
completion, the reaction mixture was filtered and the
precipitate was washed with CH2Cl2. The combined filtrate
was evaporated under vacuum, and the solid residue was
dissolved in CH2Cl2 (200 mL) and washed with freshly
prepared 10% Na2S2O3 solution (3 × 125 mL). The organic
layer was dried over anhyd Na2SO4, filtered, and evaporated
to dryness. The solid residue was purified by recrystall-
ization from Me2CO–MeOH (1:10, 100 mL) to obtain 5
(28.4 g, 74.3 mmol, 84%) as yellowish crystals; mp 96–
100 °C. TLC: Rf = 0.54 (EtOAc–hexanes = 1:3). 1H NMR
(600 MHz, CDCl3): d = 7.91 (1 H, d, J = 9.0 Hz), 7.44 (5 H,
m), 6.57 (1 H, dd, J = 9.0 Hz), 6.53 (1 H, d, J = 2.4 Hz), 5.17
(2 H, s), 4.40 (2 H, s), 3.84 (3 H, s). 13C NMR (150 MHz,
CDCl3): d = 165.1, 159.7, 135.5, 134.1, 128.8, 128.5, 127.9,
117.4, 106.0, 99.3, 71.0, 55.6, 9.9. Anal. Calcd (%) for
Acknowledgment
We are thankful to the USDA ARS SRRC for financial support.
References and Notes
(1) (a) Gharpure, S. J.; Sathiyanarayanan, A. M.; Jonnalagadda,
P. Tetrahedron Lett. 2008, 49, 2974. (b) Khupse, R. S.;
Sarver, J. G.; Trendel, J. A.; Ellis, N. R.; Reese, M. D.;
Wiese, T. E.; Boue, S. M.; Burrow, M. E.; Cleveland, T. E.;
Bhatnagar, D.; Erhardt, P. W. J. Med. Chem. 2011,
submitted.
(2) (a) Pschorr, R.; Knoffler, G. Ann. Chem. 1911, 382, 50.
(b) Bonde, M. R.; Millar, R. L.; Ingham, J. L.
Phytochemistry (Elsevier) 1973, 12, 2957. (c) Donnelly,
D. M. X.; Kavanagh, P. J. Phytochemistry (Elsevier) 1974,
13, 2587. (d) Gottlieb, O. R.; Oliveira, A. B.; Machado-
Goncalves, T. M.; Oliveira, G. G.; Pereira, S. A.
Phytochemistry (Elsevier) 1975, 14, 2495.
Synlett 2011, No. 11, 1605–1607 © Thieme Stuttgart · New York

LETTER
C16H15IO3·0.5H2O: C, 49.13; H, 4.12. Found: C, 48.82; H,
Total Syntheses ( )-Vestitol and Bolusanthin III
1607
68.9, 55.6. Anal. Calcd (%)for C30H26O4·0.5H2O: C, 78.41;
H, 5.92. Found: C, 78.30; H, 5.69.
3.78.
(11) Kraus, G. A.; Kim, I. Org. Lett. 2003, 5, 1191.
(12) Compound 7
(15) Racemic vestitol [( )-1]
To a solution of 8 (50 mg, 0.11 mmol) in EtOAc (15 mL) at
0 °C, 10% w/w Pd/C (15–20 mg) was added. The mixture
was stirred at r.t. under hydrogen atmosphere (2.4 bar).
Progress was followed by TLC. After completion, the
reaction mixture was passed through a pad of Celite. Solvent
was evaporated under vacuum, and the residue further
purified using flash column chromatography (EtOAc–
hexanes = 1:1) to obtain ( )-1 (25 mg, 90 mmol, 84%) as an
off-white powder; mp 172–179 °C (lit.2d 171–173 °C). TLC:
Rf = 0.44 (EtOAc–hexanes = 1:1). 1H NMR [600 MHz,
(CD3)2CO]: d = 8.52 (1 H, br), 8.10 (1 H, br), 7.05 (1 H, d,
J = 8.4 Hz), 6.88 (1 H, d, J = 8.4 Hz), 6.50 (1 H, d, J = 2.4
Hz), 6.42 (1 H, dd, J = 2.4, 8.4 Hz), 6.35 (1 H, dd, J = 2.4,
8.4 Hz), 6.27 (1 H, d, J = 2.4 Hz), 4.23 (1 H, m), 3.97 (1 H,
t, J = 10.2 Hz), 3.71 (3 H, s), 3.47 (1 H, m), 2.96 (1 H, m),
2.79 (1 H, m). 13C NMR [100 MHz, (CD3)2CO]: d = 160.3,
157.4, 156.6, 156.0, 130.9, 128.6, 120.8, 114.2, 108.6,
105.5, 103.4, 102.4, 70.4, 55.2, 32.5, 30.9. Anal. Calcd (%)
for C16H16O4: C, 70.57; H, 5.92. Found: C, 70.22; H, 5.98.
(16) Yoshino, H.; Tsuchiya, Y.; Saito, I.; Tsujii, M. Chem.
Pharm. Bull. 1987, 35, 3438.
To a solution of salicyl alcohol 6 (0.19 g, 0.82 mmol) and
a-iodo ketone 5 (0.28 g, 0.74 mmol) in Me2CO (15 mL),
K2CO3 (0.14 g, 0.98 mmol) was added under a flow of N2.
The reaction mixture was refluxed for 16–18 h. Progress was
followed by TLC. After completion, the solvent was
evaporated under reduced pressure. The solid residue was
dissolved in EtOAc (120 mL) and washed with 1 M NaOH,
H2O, brine, dried over anhyd Na2SO4, and evaporated to
dryness under vacuum. The solid residue was purified using
flash column chromatography to obtain 7 (0.28 g, 0.57
mmol, 78%) as off-white solid; mp 150–153 °C. TLC:
Rf = 0.17 (EtOAc–hexanes = 1:2). 1H NMR [600 MHz,
(CD3)2CO)]: d = 7.89 (1 H, d, J = 8.4 Hz), 7.45 (10 H, m),
7.22 (1 H, d, J = 9.0 Hz), 6.83 (1 H, d, J = 2.4 Hz), 6.68 (1
H, dd, J = 2.4, 9.0 Hz), 6.56 (1 H, dd, J = 2.4, 8.4 Hz), 6.26
(1 H, d, J = 2.4 Hz), 5.33 (2 H, s), 5.21 (2 H, s), 4.99 (2 H,
s), 4.57 (2 H, d, J = 6.6 Hz), 4.15 (1 H, t, J = 6.6 Hz), 3.90 (3
H, s). 13C NMR [100 MHz, (CD3)2CO): d = 193.7, 161.7,
160.1, 158.0, 138.2, 137.0, 133.2, 129.6, 129.5, 129.3,
129.2, 129.1, 128.6, 107.5, 106.0, 101.0, 99.8, 74.6, 71.7,
70.5, 60.9, 56.1. Anal. Calcd (%) for C30H28O6·0.25H2O:
C, 73.68; H, 5.87. Found: C, 73.33; H, 5.71.
(17) Ward, D. E.; Gai, Y.; Kaller, B. F. J. Org. Chem. 1995, 60,
7830.
(13) Yaun, Y.; Men, H.; Lee, C. J. Am. Chem. Soc. 2004, 126,
14720.
(18) Okano, K.; Okuyama, K.-I.; Fukuyama, T.; Tokuyama, H.
Synlett 2008, 1977.
(14) Compound 8
(19) Bolusanthin III (2)
To a suspension of 7 (97 mg, 0.2 mmol) in anhyd MeCN (4
mL), Ph3P·HBr (70 mg, 0.2 mmol) was added under a flow
of N2. The reaction mixture was stirred at r.t. and followed
by TLC. After completion, solvent was evaporated under
vacuum to obtain an off-white residue which was directly
used in the next step without further purification.
To a solution of 8 (0.45 g, 1 mmol) and pentamethylbenzene
(1.48 g, 10 mmol) in anhyd CH2Cl2 (30 mL) at –78 °C, BCl3
(0.2 mmol) was added dropwise under N2. The mixture was
stirred at –78 °C, and after 15–20 min the reaction was
quenched with a CHCl3–MeOH (10:1, 20 mL) mixture. The
resulting mixture was warmed to r.t. The organic solvent was
evaporated under vacuum. The residue was purified by
column chromatography [silica gel 35 mm dia, 8 inch thick,
EtOAc–hexanes (1:2)] to obtain 2 (0.17 g, 0.61 mmol, 61%)
as a brownish solid; mp 150–154 °C (lit. reports an amor-
phous material5 or a brown paste4 after isolation from natural
sources). TLC: Rf = 0.48 (EtOAc–hexanes = (1:2). 1H NMR
(600 MHz, CD3OD): d = 7.14 (1 H, d, J = 8.4 Hz), 6.88 (1
H, d, J = 8.4 Hz), 6.53 (1 H, s), 6.42 (1 H, dd, J = 2.4, 8.4
Hz), 6.37 (1 H, d, J = 2.4 Hz), 6.33 (1 H, dd, J = 2.4, 8.4 Hz),
6.24 (1 H, d, J = 1.8 Hz), 4.94 (2 H, s), 3.74 (3 H, s).
13C NMR (150 MHz, CD3OD): d = 161.8, 159.1, 157.3,
155.9, 130.1, 130.0, 128.4, 121.4, 119.9, 117.6, 109.4,
106.1, 103.4, 102.4, 69.2, 55.6. Anal. Calcd (%) for
C16H14O4·0.1H2O: C, 70.63; H, 5.26. Found: C, 70.42; H,
5.20.
To a solution of the above phosphonium salt in anhyd MeOH
(15 mL), KOt-Bu (45 mg, 0.4 mmol) was added under a flow
of N2. The reaction mixture was refluxed for 16–20 h.
Progress was monitored by TLC. After completion, the
mixture was reduced to one-third of original volume under
vacuum and then filtered. The precipitate was dissolved in
CH2Cl2 (30 mL). The organic phase was washed with H2O,
brine, dried over anhyd Na2SO4, and evaporated to dryness
under vacuum to obtain 8 (50 mg, 0.11 mmol, 70% over 2
steps) as an off-white solid; mp 119–122 °C. TLC: Rf = 0.65
(EtOAc–hexanes = 1:2). 1H NMR [600 MHz, (CD3)2CO]:
d = 7.41 (10 H, m), 7.28 (1 H, d, J = 8.4 Hz), 7.01 (1 H, d,
J = 7.8 Hz), 6.70 (1 H, d, J = 2.4 Hz), 6.60 (1 H, s), 6.57 (2
H, m), 6.46 (1 H, d, J = 1.8 Hz), 5.16 (2 H, s), 5.10 (2 H, s),
4.93 (2 H, s), 3.80 (3 H, s). 13C NMR [150 MHz, (CD3)2CO]:
d = 161.7, 160.3, 158.2, 155.5, 138.2, 137.8, 130.0, 129.9,
129.3, 129.4, 129.23, 128.7, 128.6, 128.5, 128.3, 128.2,
121.5, 121.4, 118.1, 108.9, 106.3, 102.8, 100.5, 71.0, 70.4,
(20) Portions of this work were described previously as a poster
presentation at the 239th American Chemical Society
meeting in San Francisco during March, 2010. The
published abstract was denoted as ORGN-941.
Synlett 2011, No. 11, 1605–1607 © Thieme Stuttgart · New York