Squaric acid ester-based total synthesis of echinochrome A

Article abstract of DOI:10.1021/jo016034m

The total synthesis of echinochrome A is described. Both key intermediates 5 and 8 were efficiently prepared from diisopropyl squarate 7. Nucleophilic addition of aryllithium 8 to 5, followed by thermal ring-expansion/cyclization of the 1,2-adduct 4, furnished hydroquinone 3. Oxidation and full deprotection of 3 gave the title compound.

Full text of DOI:10.1021/jo016034m

J . Org. Chem. 2002, 67, 1689-1691
1689
Squ a r ic Acid Ester -Ba sed Tota l Syn th esis
of Ech in och r om e A
Eduardo Pen˜a-Cabrera*
Facultad de Quı´mica, Universidad de Guanajuato. Col.
Noria Alta S/ N. Guanajuato, Gto. 36050, Mexico
F igu r e 1. Structure of echinochrome A.
Lanny S. Liebeskind
6. The crude material smoothly rearranged to 5 in 66%
overall yield upon treatment with a catalytic amount of
concentrated HCl at 25 °C.
Emory University, Department of Chemistry, 1515 Pierce
Drive, Atlanta, Georgia 30322
Vinyl-substituted cyclobutenone 10, the precursor of
aryllithium 8, was prepared in 64% yield by addition of
vinylmagnesium bromide to 7 followed by an aqueous
NH4Cl quench (Scheme 3). Compound 10 was then
thermolyzed to produce the corresponding hydroquinone
which, due to its high tendency to oxidize in air, was
directly methylated with MeI/KOH in DMSO6 to give 9
in 87% overall yield from 10.
Aryllithium 8 was generated from 9 with s-BuLi in the
presence of TMEDA; 1,2-addition at the more electro-
philic carbonyl group of 53 took place uneventfully to
produce adduct 4 in 59% overall yield (Scheme 4). Adduct
4 thermally rearranged at 160 °C to produce hydro-
quinone 3. The crude hydroquinone was immediately
oxidized with ceric ammonium nitrate in ether/water to
naphthoquinone 2, which, on exposure to air, hydrolyzed
to naphthoquinone 11 in 95% yield from 4. This observa-
tions did not affect the synthetic plan since the last step
involved the complete deprotection of the hydroxyl groups.
Toward this end, exposure of 11 to an excess of TMSI7
in either CCl4 or HBr8 in acetic acid only gave mixtures
of partially demethylated products. We then attempted
to achieve the deprotection using BBr3 in dichloro-
methane.9 Full deprotection took place in 41% yield only
when an excess of BBr3 (10-fold) was used (eq 1). If a
lesser amount of BBr3 was used, a complex mixture of
partially demethylated products was observed.
eduardop@quijote.ugto.mx
Received August 15, 2001
Abstr a ct: The total synthesis of echinochrome A is de-
scribed. Both key intermediates 5 and 8 were efficiently
prepared from diisopropyl squarate 7. Nucleophilic addition
of aryllithium 8 to 5, followed by thermal ring-expansion/
cyclization of the 1,2-adduct 4, furnished hydroquinone 3.
Oxidation and full deprotection of 3 gave the title compound.
Echinochrome A 1 (Figure 1) is a highly oxygenated
component of the pigments derived from sea urchins. It
was first unambiguously identified by Moore and co-
workers1 in a mixture of ca. 30 compounds obtained from
calcareous fragments of two Echinothrix species, i.e., E.
diadema Linn and E. calamaris Pallis.
Echinochrome A possesses antibacterial properties
against both Gram-positive and Gram-negative marine
bacteria, particularly Pseudomonas strain No. 111 and
Vibrio fisheri (NCMB 1281).2 Echinochrome A was first
synthesized by Wallenfels and Gauhe in 1943, albeit in
very low overall yield (1.5-2%).3 Herein is reported a
successful total synthesis of the title compound utilizing
the chemistry of squaric acid developed by Moore and
Liebeskind.4
The total synthesis of echinochrome A was conceived
as depicted in Scheme 1. The main feature of the
proposed retrosynthetic analysis relies on the fact that
both intermediates 5 and 8 can be synthesized from
diisopropylsquarate 7, a common and readily available
starting material.
The synthesis was begun with the preparation of
4-ethyl-3-isopropoxycyclobutene-1,2-dione 5 by a previ-
ously developed method (Scheme 2).5 Diisopropylsquarate
7 was treated with EtMgBr at -78 °C and then quenched
at low temperature to give the corresponding 1,2-adduct
In conclusion, a simple and efficient convergent total
synthesis of echinochrome A starting from squaric acid
esters was achieved.
* To whom correspondence should be addressed. E-mail: (L.S.L.)
chemLL1@emory.edu.
Exp er im en ta l Section
(1) Moore, R. E.; Singh, H.; Scheuer, P. J . J . Org. Chem. 1966, 31,
3645.
(2) Service, M.; Wardlaw, A. C. Comp. Biochem. Physiol. 1984, 79B,
161.
Gen er a l Meth od s. 1H NMR spectra were recorded on a
Varian Gemini 200 (200 MHz) spectrometer in deuteriochloro-
form (CDCl3) with either tetramethylsilane (TMS) (0.0 ppm) or
chloroform (7.26 ppm) as internal reference unless otherwise
indicated. Data are reported in the following order: chemical
shift in ppm (δ), multiplicities (br (broadened), s (singlet), d
(3) Wallenfels, K.; Gauhe, A. Ber. 1943, 76, 325.
(4) (a) Moore, H. W.; Yerxa, B. R. In Synthetic Utility of Cyclobu-
tendiones; Halton, B., Ed.; J AI Press: Greenwich, CT, 1995; Vol. 4, pp
81-162. (b) Liebeskind, L. S. Tetrahedron Symp. Print 1989, 45, 3053-
3060. (c) Koo, S.; Liebeskind, L. S. J . Am. Chem. Soc. 1995, 117, 3389-
3404. (d) Sun, L.; Liebeskind, L. S. J . Am. Chem. Soc. 1996, 118, 12473
e) Paquette, L. A.; Doussot, P. Res. Chem. Intermed. 1996, 22, 767-
780. (f) Ohno, M.; Yamamoto, Y.; Eguchi, S. Synlett 1998, 1167.
(5) (a) Liebeskind, L. S. Tetrahedron 1989, 45, 3053, (b) Liebeskind,
L. S.; Fengl, R. W.; Wirtz, K. R.; Shawe, T. T. J . Org. Chem. 1988, 53,
2482.
(6) Syper, L.; Kloc, K.; Mlochowski, J . Tetrahedron 1980, 36, 123.
(7) Rosen, B. I.; Weber, W. P. J . Org. Chem. 1977, 42, 3463.
(8) Kawasaki, I.; Matsuda, K.; Kaneko, T. Bull. Chem. Soc. J pn.
1971, 44, 1986.
(9) McOmie, J . F. W.; West, D. E. Organic Syntheses; Wiley: New
York, 1973; Collect. Vol. V, p 412.
10.1021/jo016034m CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/05/2002

1690 J . Org. Chem., Vol. 67, No. 5, 2002
Notes
Sch em e 1
Exp er im en ta l P r oced u r es. 3-Eth yl-4-isop r op oxycyclo-
Sch em e 2
bu ten -1,2-d ion e (5). Ethylmagnesium bromide (5.60 mL, 3.00
M, 16.800 mmol, 1.11 equiv) was added via syringe to a cold
(-78 °C) THF (40 mL) solution of 2,3-diisopropyl squarate (3.00
g, 15.14 mmol, 1.00 equiv). The reaction mixture was slowly
allowed to reach 25 °C, and then it was stirred for 8 h at that
temperature. After that period of time, the dark solution was
cooled to -78 °C and quenched with a saturated NH4Cl solution.
After the mixture warmed to 25 °C, it was extracted with ether
(3 × 20 mL), and the organic extracts were combined and dried
over anhyd MgSO4. The mixture was filtered, and the solvent
was removed under reduced pressure to give a yellow oil. The
oil was taken up in dichloromethane (20 mL) and treated with
4 drops of concentrated HCl. After ca. 4 h, all of the starting
material had reacted. The dark solution was washed with water
(1 × 20 mL), dried over anhyd MgSO4, and filtered. The solvent
was removed under reduced pressure to give a yellow oil (1.4 g,
8.30 mmol, 55%). TLC (silica gel, 20% ethyl acetate/hexanes, Rf
) 0.36); chromatographic purification (Baeckstro¨m column, silica
gel, 1.5 × 10 cm, ethyl acetate/hexanes gradient); IR (CH2Cl2,
KCl, cm-1) 2986 (m), 2940 (m), 1792 (s), 1759 (s), 1593 (s); 1H
NMR (CDCl3, 300 MHz) δ 5.28 (sept, J ) 6.2 Hz, 1 H), 2.51 (q,
J ) 7.6 Hz, 2 H), 1.34 (d, J ) 6.1 Hz, 6 H), 1.17 (t, J ) 7.6 Hz,
3 H); 13C NMR (CDCl3, 75.5 MHz) δ 197.6, 195.0, 194.1, 185.0,
78.7, 22.4, 18.3, 9.7; HRMS(EI) calcd for C9H12O4 168.0786, found
168.0771.
Sch em e 3
1,2-Diisop r op yl-3-h yd r oxy-3-vin ylcyclobu ten on e (10). To
a
cold (-78 °C, dry ice/acetone) THF (20 mL) solution of
diisopropylsquarate (3.0 g, 15.10 mmol) was added vinylmag-
nesium bromide (18.74 mmol, 15.6 mL, 1.00 M) dropwise. After
4 h, the reaction was quenched at -78 °C with aq NH4Cl (20
mL). The crude mixture was allowed to reach 25 °C and then
extracted with ether (3 × 20 mL), and the organic extracts were
combined and dried over anhyd MgSO4. The mixture was
filtered, and the solvent was removed under reduced pressure.
The product (2.20 g, 64%) was obtained as a yellow oil. TLC
(silica gel, 20% ethyl acetate/hexanes, Rf ) 0.26); chromato-
graphic purification (Baeckstro¨m column, silica gel, 1.5 × 10 cm,
ethyl acetate/hexanes gradient); IR (NaCl, cm-1) 3384 (s), 2975
(s), 2935 (s), 2875 (m), 1650 (s), 1540 (m); 1H NMR (CDCl3, 200
MHz) δ 5.95 (dd, J ) 17.3, 10.6 Hz, 1 H), 5.50 (dd, J ) 17.3, 1.0
Hz, 1 H), 5.31 (dd, J ) 10.6, 1.0 Hz, 1 H), 4.85 (two overlapping
multiplets, J ) 6.2 Hz, 2 H), 3.37 (bs, 1 H), 1.39 (d, J ) 6.2 Hz,
3 H), 1.36 (d, J ) 6.2 Hz, 3 H), 1.29 (d, J ) 6.1 Hz, 3 H), 1.26 (d,
J ) 6.1 Hz, 3H); 13C NMR (CDCl3, 75.5 MHz) δ 184.2, 166.1,
134.6, 132.4, 118.0, 86.6, 77.3, 73.6, 22.7, 22.5, 22.4; HRMS (EI)
calcd for C12H8O4 226.1205, found 226.1196.
(doublet), t (triplet), q (quartet), sex (sextet), hep (heptet), m
(multiplet), exch (exchangeable), app (apparent)), coupling con-
stants, J (Hz), and integration. Infrared spectra were recorded
on a Perkin-Elmer FTIR 1600 series spectrophotometer. Peaks
are reported (cm-1) with the following relative intensities: s
(strong, 67-100%), m (medium 40-67%), and w (weak 20-40%).
Analytical thin-layer chromatography was performed on
Merck silica gel plates with F-254 indicator. Acid-pretreated
silica gel plates were used to monitor the final deprotection of
2. Visualization was accomplished by UV light, iodine, or
p-anisaldehyde solution. Medium-pressure liquid chromatogra-
phy (MPLC) was performed as described by Baeckstro¨m et al.10
using gradient solutions with the indicated solvent systems.
Purification of 1 was carried out using acid-pretreated silica gel.
THF was dried over activated 4 Å molecular sieves. TMEDA was
distilled from sodium and stored over activated 4 Å molecular
sieves. All reactions were performed under a dry N2 atmosphere
in oven- and or flame-dried glassware.
Com m er cia l Ch em ica ls. The following materials were
obtained from commercial sources: s-BuLi, EtMgBr, MeI, ceric
ammonium nitrate, TMSI, HBr in acetic acid, and BBr3.
1,4-Dim eth oxy-2,3-d iisop r op oxyben zen e (9). Cyclobuten-
one 10 (2.26 g, 10.0 mmol) was immersed into a preheated oil
bath at 160 °C for 15 min. The hydroquinone thus formed (Rf )
0.5, 20% EtOAc/hexanes) was taken up in DMSO (10 mL), and
ground KOH (4.56 g, 80 mmol) was added followed by MeI (2.84
(10) Baeckstro¨m, P.; Stridh, K.; Li, L.; Norin, T. Acta Chem. Scand.
1987, B41, 442.

Notes
J . Org. Chem., Vol. 67, No. 5, 2002 1691
Sch em e 4
g, 20 mmol). After 2 h, the mixture was poured into water (100
mL). The mixture was extracted with ether (3 × 10 mL), and
the organic extracts were combined and dried over anhyd
MgSO4. The mixture was filtered, and the solvent was removed
under reduced pressure. The product (2.20 g, 87%) was obtained
as a yellow oil after purification: TLC (silica gel, 20% ethyl
acetate/hexanes, Rf ) 0.8); chromatographic purification (Baeck-
stro¨m column, silica gel, 1.5 cm × 10 cm, ethyl acetate/hexanes
gradient); IR (NaCl, cm-1) 3512 (w), 2975 (s), 2973 (s), 2931 (s),
filtered, and the solvent was removed under reduced pressure
to give a bright red oil (silica gel, 20% ethyl acetate/hexanes, Rf
) 0.68), which on 7 h exposure to air hydrolyzed to hydrox-
ynaphthoquinone 11 (0.35 g, 91%); TLC (silica gel, 20% ethyl
acetate/hexanes, Rf ) 0.40); chromatographic purification (Baeck-
stro¨m column, silica gel, 1.5 × 10 cm, ethyl acetate/hexanes
gradient); IR (neat, cm-1) 3350 (m), 2975 (s), 2935 (s), 2875 (m),
1650 (s), 1540 (m); 1H NMR (CDCl3, 200 MHz) δ 7.45 (bs, 1 H),
4.72 (m, J ) 6.1 Hz, 1 H), 4.68 (m, J ) 6.1 Hz, 1 H), 3.91 (s, 3
H), 3.89 (s, 3 H), 2.53 (q, J ) 7.5 Hz, 2 H), 1.33 (d, J ) 6.2 Hz,
6 H), 1.15 (t, J ) 7.5 Hz, 3 H); 13C NMR (CDCl3, 75.5 MHz) δ
183.8, 179.8, 153.8, 152.7, 152.3, 151.8, 150.5, 125.0, 121.8, 118.2,
76.9, 76.6, 61.2, 22.7, 22.6, 16.7, 12.6; HRMS (FAB+) calcd for
C20H26O7 379.1757, found 379.1746.
1
1594 (w), 1488 (s); H NMR (CDCl3, 300 MHz) δ 6.55 (s, 2 H),
4.47 (m, J ) 6.2 Hz, 2 H), 3.78 (s, 6 H), 1.29 (d, J ) 6.1, 12 H);
13C NMR (CDCl3, 75.5 MHz) δ 148.4, 141.7, 105.6, 75.1, 55.9,
22.4; HRMS (EI) calcd for C14H22O4 254.1518, found 254.1530.
2-Eth yl-3-isop r op oxy-4-h yd r oxy-4-(2′,5’-d im eth oxy-3′,4′-
d iisop r op oxyp h en yl)-2-cyclobu ten -1-on e (4). To a cold (-78
°C) mixture of TMEDA (0.23 g, 1.97 mmol) and sec-butyllithium
(1.5 mL, 1.3 M, 1.97 mmol) was added dropwise a THF (5 mL)
solution of 1,4-dimethoxy-2,3-diisopropoxybenzene 9 (0.5 g, 1.97
mmol) via cannula. At this point, the solution turned bright
yellow. The mixture was stirred at -78 °C for 2 h and at 25 °C
for 1 h. It was then cooled to -78 °C and cannulated into a cold
(-78 °C) THF (7 mL) solution of 3-ethyl-4-isopropoxycyclobuten-
1,2-dione 5 (0.3 g, 1.97 mmol). After 2 h, the reaction was
quenched at -78 °C with water. The mixture was warmed to
25 °C and extracted with ether (3 × 20 mL). The organic extracts
were combined and dried over anhyd MgSO4. The mixture was
filtered, and the solvent was removed under reduced pressure
to give a yellow oil (0.49 g, 59%): TLC (silica gel, 20% ethyl
acetate/hexanes, Rf ) 0.16); chromatographic purification (Baeck-
stro¨m column, silica gel, 1.5 × 10 cm, ethyl acetate/hexanes
gradient); IR (KCl, cm-1) 3387 (w), 2975 (w), 2931 (w), 1791 (s),
1748 (s), 1617 (s); 1H NMR (CDCl3, 200 MHz) δ 6.45 (s, 1 H),
5.26 (br s, 1 H), 4.79 (m, J ) 6.2 Hz, 1 H), 4.50 (m, J ) 6.2 Hz,
1H), 4.41 (m, J ) 6.0 Hz, 1H), 3.99 (s, 3 H), 3.76 (s, 3 H), 2.23
(q, J ) 7.5 Hz, 2 H), 1.44 (d, J ) 6.3 Hz, 3 H), 1.36 (d, J ) 6.3
Hz, 3 H), 1.3-1.2 (m, 6H), 1.18 (t, J ) 7.6 Hz, 3 H); 13C NMR
(CDCl3, 75.5 MHz) δ 190.4, 178.8, 150.1, 146.3, 145.8, 141.8,
129.0, 123.8, 104.2, 93.4, 77.2 (s), 77.3, 60.8 (s), 75.6, 75.4, 62.2,
55.9, 22.7, 22.5, 22.4, 22.3, 15.9, 11.9; HRMS (FAB+) calcd for
C23H34O7 422.2305, found 422.2313.
Ech in och r om e A. To a cold (-78 °C) dichloromethane (3 mL)
solution of naphthoquinone 11 (230 mg, 0.6 mmol) was added
dropwise a dichloromethane solution of BBr3 (6.1 mL, 1.00 M,
6.1 mmol, 10 equiv). The initially pale yellow solution turned
red as the addition proceeds. After the addition was complete,
the cooling bath was removed and the mixture was stirred at
25 °C for 24 h. After that time, the reaction was quenched with
water (30 mL) at -78 °C. The mixture was warmed to 25 °C
and stirred at that temperature for 24 h to ensure a complete
hydrolysis. The organic phase was then separated, and the
aqueous phase was extracted with ethyl acetate (4 × 15 mL).
The organic extracts were combined and dried over anhyd
MgSO4. The mixture was filtered, and the solvent was removed
under reduced pressure to give a bright red solid. The product
(65 mg, 41%) was obtained as a bright-red solid after chroma-
tography purification): TLC (H+-pretreated silica gel, 40% ethyl
acetate/hexanes, Rf ) 0.34); chromatographic purification (Baeck-
stro¨m column, H+-pretreated silica gel, 1.5 × 10 cm, ethyl
acetate/hexanes); mp 215-216 °C (lit.1 mp 222-223 from
chloroform) (ethyl acetate/hexanes, 1:4); IR (KBr pellet, cm-1
)
3308 (s), 2975 (m), 2930 (m), 2880 (m), 1584 (s), 1465 (m), 1422
(s), 1280 (s); 1H NMR (300 MHz) δ 2.74 (q, J ) 7.5 Hz, 2 H),
1.17 (t, J ) 7.6 Hz, 3 H); 13C NMR (75.5 MHz) δ 179.6, 177.9,
165.1, 163.5, 155.0, 143.1, 140.9, 126.8, 108.3, 103.7, 17.4, 13.3;
HRMS (EI) calcd for C12H10O7 266.0427, found 266.0430.
Ack n ow led gm en t. E.P.-C. wishes to thank Profes-
sor Cecilio Alvarez-Toledano for performing spectral
analyses on some of the derivatives prepared, as well
as Mr. Oracio Serrano and Mr. Marco A. Ramirez for
their contribution to this project. Financial support from
CONACyT (Mexico) No. 27600-E is gratefully acknowl-
edged.
2-Eth yl-3-h yd r oxy-6,7-d iisop r op oxy-5,8-d im eth oxy-1,4-
n a p h th oqu in on e (11). Cyclobutenone 4 (0.43 g, 1.0 mmol) was
placed into a round-bottomed flask fitted with a condenser. The
system was purged several times with nitrogen and then
immersed into an oil bath at 150 °C. After 20 min, the reaction
had gone to completion as indicated by TLC (silica gel, 20% ethyl
acetate/hexanes, Rf ) 0.67). The yellow oil was taken up in ether
(5 mL), and water (3 mL) was added. To this mixture was
gradually added solid ceric ammonium nitrate until the hydro-
quinone was completely oxidized to the naphthoquinone 2. The
organic phase was then separated, and the aqueous phase was
extracted with ether (3 × 10 mL). The organic extracts were
combined and dried over anhyd MgSO4. The mixture was
Su p p or tin g In for m a tion Ava ila ble: NMR spectra for
obtained compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O016034M