A Formal Total Synthesis of (±)-Rishitinol

Full text of DOI:10.1080/00304948.2020.1780887

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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A Formal Total Synthesis of (±)-Rishitinol
Kelly P. Marrugo , Alexis Maldonado , Ajoy K. Banerjee & Elvia V. Cabrera
To cite this article: Kelly P. Marrugo , Alexis Maldonado , Ajoy K. Banerjee & Elvia V. Cabrera
(2020): A Formal Total Synthesis of (±)-Rishitinol, Organic Preparations and Procedures
International, DOI: 10.1080/00304948.2020.1780887
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Published online: 08 Sep 2020.
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ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
https://doi.org/10.1080/00304948.2020.1780887
OPPI BRIEF
A Formal Total Synthesis of ( )-Rishitinol
Kelly P. Marrugoa, Alexis Maldonadob, Ajoy K. Banerjeeb , and Elvia V. Cabrerac
a
ꢀ
ꢀ
Department of Organic Chemistry, Faculty of Chemical Sciences, University of Concepcion, Concepcion,
b
c
Chile; Chemistry Center, Venezuelan Institute of Scientific Research (IVIC), Caracas, Venezuela; Faculty
of Chemical Engineering, Central University of Ecuador, Quito, Ecuador
ARTICLE HISTORY Received 6 January 2020; Accepted 18 April 2020
Rishitinol (Scheme 1, 5), a phytoalexin sesquiterpene, is produced in stressed white
potato (Solanum tuberosum) as a response to infection by Phytophtora infestans fun-
gus.1,2 It was isolated from diseased tuber slices of the Rishiri variety of potato, along
with rishitin (6).3,4 The latter is the most abundant terpeniod phytoalexin;5 it exhibits
antifungical6 activity and also has nematicidal7 properties. It is hoped that compound 5
will exhibit both of these desirable properties. There is reason for these aspirations,
since aromatization of the A ring and hydroxylation of rishitin at the isopropenyl group
have not diminished biological activities in related compounds.8,9 The ethyl-5,8-
dimethyl-1-oxo-tetralin-3-carboxylate (4), a potential intermediate for rishitinol 5, was
synthesized2 in six steps with an overall yield of 6%. In relation to our studies on the
synthesis10,11 of sesquiterpene alcohols, a concise approach was sought for the synthesis
of tetralone
4 (Scheme 1) to improve its yield. The synthetic details are
described below.
Stobbe condensation12 of the commercially available aldehyde 1 with dimethylsucci-
nate (DMS) was accomplished in toluene and sodium hydride at reflux. The resulting
compound, on hydrolysis with hydrochloric acid (5%) and catalytic hydrogenation with
palladium on carbon (10%) in ethanol, afforded the diacid 2 in 65% yield. The cycliza-
tion of the acid 2 with sulfuric acid (98%) at room temperature afforded the tetralone 3
in 24% yield.
Heating the tetralone 3 with 5% ethanolic hydrochloric acid yielded the ester 4 in
78% (overall yield 12%) which was superior to the reported2 overall yield (6%). As the
conversion of the ester 4 to rishitinol 5 was already accomplished in two steps, an alter-
native synthesis of the ester 4 constitutes a formal total synthesis of rishitinol.
In conclusion, we have developed a four-step synthesis of the ester 4 with an overall
yield of 12%. In addition the experimental procedure of the present report is very sim-
ple compared with the published method.2 The present synthesis of the ester 4 is
attractive due to the brevity and convenience of the steps. It is worthwhile to mention
that ester 4 could also be a potential intermediate for the synthesis of the sesquiterpene
alcohols emmotin-F,13 emmotin-G,14 and occidol.15
CONTACT Ajoy K. Banerjee
aabanerje@gmail.com
Chemistry Center, Venezuelan Institute of Scientific Research
(IVIC), Caracas-1020A, Venezuela.
ß 2020 Taylor & Francis Group, LLC

2
K. P. MARRUGO ET AL.
Scheme 1. Preparation of rishitinol.
Experimental section
Reagents were obtained from commercial sources and used without purification.
Solvents were dried by distillation from appropriate drying agents immediately prior to
use. For work-up, all organic extracts were dried over anhydrous MgSO4, filtered and
the solvent evaporated in vacuo. Flash column chromatography was performed on silica
gel (0.04-0.63 mm) using the solvent systems indicated. Unless otherwise stated, all melt-
ing points are uncorrected and were determined on an Electrothermal melting point
apparatus. IR spectra were taken on a Nicolet Fourier-transform (FT) instrument. Mass
spectra were recorded on a Thermo Scientific TSQ Quantum Ultra AM Triple
Quadruple mass spectrometer. NMR spectra were recorded on a Bruker AVANCE-500
spectrometer in a suitable deuterated solvent, as noted. Chemical shifts (d) are expressed
in ppm and were noted in the range of d 0-10 ppm. Elemental analyses were performed
on a Carlo-Erba 1108 Elemental Analyser.
2,5-Dimethylbenzylsuccinic acid (2)
To a stirring suspension of NaH (268 mg, 6.71 mmol) in toluene (5 mL), heated at reflux
for 15 min, was added very slowly a mixture of DMS (399 mg, 0.3 mL, 2.73 mmol) and
aldehyde 1 (305 mg, 2.28 mmol) dissolved in toluene (10 mL). The mixture was stirred
for 20 h at refluxing temperature, cooled, diluted with water and extracted with ether.
The aqueous phase was cooled, acidified with aqueous HCl (5%) and extracted with
ether. The combined organic extracts were dried and evaporated to obtain amber col-
ored material (380 mg) which was dissolved in EtOH (10 mL), Pd/C (10%, 389 mg)
added and the mixture stirred under hydrogen for 24 h. The reaction mixture was fil-
tered and evaporated under reduced pressure to give a solid, which on chromatographic
purification (hexane:ether 4:6) afforded the diacid 2 (351 mg, 65%); mp. 140-141 ꢀC

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
3
(lit.2 mp unspecified); IR (cmꢁ1): 3407 (OH), 1726 (CO), 1704 (CO); MS (m/z): 105
(Mþ- CH2-CH(COOH)-CH2-COOH); 1H NMR (acetone-d6): d 10.65 (bs, 2H, 2-
COOH), 7.03 (d, 1H, J¼ 7.65 Hz, H-4’), 6.99 (s, 1H, H-6’), 6.92 (d, 1H, J¼ 7.65 Hz, H-
3’), 3.07-3.01 (m, 2H, H-2, H-5), 2.73 (dd, 1H, J¼ 15.50 Hz, 10.50 Hz, H-5), 2.66 (dd,
1H, J¼ 17.00 Hz, 9.00 Hz, H-3), 2.40 (dd, 1H, J ¼ 17.00, 4.50 Hz, H-3), 2.29 (s, 3H, 2’-
Me), 2.24 (s, 3H, 5’-Me); 13C NMR (Acetone-d6): d: 175.83 (C-1), 173.30 (C-4), 137.78
(C-2’), 135.83 (C-5’), 133.92 (C-1’), 131.38 (C-6’), 131.15 (C-4’), 128.09 (C-3’), 42.52 (C-
2), 35.63 (C-5), 35.44 (C-3), 20.93 (2’-Me), 18.93 (5’-Me).
Anal. Calcd for C13H16O4: C, 66.08; H, 6.83. Found: C, 66.31; H, 6.99.
5,8-Dimethyl-1-tetralone-3-carboxylic acid (3)
To the diacid 2 (100.3 mg, 0.43 mmol) was added H2SO4 (98%, 2 mL, 0.037 mmol) and
the mixture was stirred at room temperature for 12 hr. To the resulting material was
added very carefully several chips of ice and the result was extracted with dichlorome-
thane. The organic extract was washed with brine, dried and evaporated to obtain a
dense yellow liquid which on chromatographic purification (hexane:ether 1:1) yielded
the tetralone 3 (24.2 mg, 24%) as a white solid; mp.129-131 ꢀC (lit.2 135-137 ꢀC); IR
1
(cmꢁ1): 3441 (OH), 1726 (CO), 1662 (CO); MS (m/z): 218 (Mþ), 173 (Mþ -COOH);
H NMR (CDCl3): d 7.22 (d, 1H, J ¼ 7.50 Hz, H-6) , 7.02 (d, 1H, J¼ 7.50 Hz, H-7), 3.23-
3.13 (m, 2H, H-4, H-3), 3.01 (dd, 1H, J¼ 16.01 Hz, 9.50 Hz, H-4), 2.92 (ddd, 1H,
J ¼ 16.51 Hz, 5.50 Hz, 1.50 Hz, H-2), 2.81 (dd, 1H, J¼ 16.51 Hz, 11.15 Hz, 1.50 Hz, H-2),
2.58 (s, 3H, 8-Me), 2.29 (s, 3H. 5-Me); 13C NMR (CDCl3): 197.88 (C-1), 179.05
(COOH), 140.68 (C-5), 139.22 (C-8), 134.44 (C-6), 133.97 (C-10), 130.58 (C-9), 130.49
(C-7), 41.66 (C-2), 39.11 (C-3), 29.43 (C-4), 23.17 (8-Me), 19.68 (5-Me).
Anal. Calcd for C13H14O3: C, 71.54; H, 6.47. Found: C, 71.77; H, 6.62.
Ethyl-5,8-dimethyl-1-tetralone-3-carboxylate (4)
The tetralone 3 (35.9 mg, 0.164 mmol) dissolved in a solution of HCl in EtOH (5%,
5 mL) was heated under reflux for 5 h. The solution was cooled, diluted with water and
extracted with dichloromethane. The organic extract was washed with an aqueous solu-
tion of sodium bicarbonate (5%), brine and dried. The resulting material was chromato-
graphed (hexane:ether 8:2) to yield the ester 4 as a pale yellow solid (32 mg, 78%); mp:
73-74 ꢀC (from hexane: ethyl acetate) (lit.2 74-76 ꢀC); IR (cm-l): 1740 (CO), 1673 (CO);
1
MS (m/z): 247 (M þ H); H NMR (CDCl3): d 7.20 (d, 1H, J ¼ 7.80, H-6), 7.01 (d, 1H,
J¼ 7.80, H-7), 4.16 (q, 2H, J ¼ 7.20 Hz, H-1’), 3.15 (ddd, 1H, J¼ 16.80 Hz, 10.20 Hz, H-
4), 3.09-3.05 (m, 1H, H-3), 2.97 (dd, 1H, J¼ dd, 1H, J¼ 16.80 Hz, 10.20 Hz, H-4), 2.87
(ddd, 1H, J¼ 16.20 Hz, 4.20 Hz, 1.21 Hz, H-2), 2.78 (dd, 1H, J ¼ 16,21 Hz, 11.40 Hz, H-
2), 2.57 (s, 3H, 8-Me), 2.28 (s, 3H, 5-Me), 1.23 (t, 3H, J ¼ 7.21 Hz, H-2’); 13C NMR
(CDCl3): 198.19 (C-1), 173.48 (COOEt), 140.01 (C-5), 139.02 (C-8), 134.29 (C-6),
133.95 (C-10), 130.68 (C-9), 130.35 (C-7), 61.02 (C-1’), 42.17 (C-2), 39.41 (C-3), 29.72
(C-4), 23.17 (8-Me), 19.68 (5-Me), 14.16 (C-2’).
Anal. Calcd for C15H18O3: C, 73.14; H, 7.37. Found: C, 73.35; H, 7.42.

4
K. P. MARRUGO ET AL.
Acknowledgments
The authors gratefully acknowledge Mr. Jose Gregorio, of the library of IVIC, for searching many
references for the manuscript and Marniev Luiggi, Chemistry Center, IVIC, for reading
the manuscript.
ORCID
Ajoy K. Banerjee
http://orcid.org/0000-0002-5586-002X
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