A synthesis of puraquinonic acid

Article abstract of DOI:10.1016/S0040-4039(01)00144-7

2-Methyl-1,4-benzenediol (10) was acylated with α-chloroisobutyroyl chloride and converted by treatment with AlCl₃ into the indanone derivative 12, which was elaborated into the substituted indane acid 24. Oxidation then afforded racemic puraqu

Full text of DOI:10.1016/S0040-4039(01)00144-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2253–2255
A synthesis of puraquinonic acid
Soleiman Hisaindee and Derrick L. J. Clive*
Chemistry Department, University of Alberta, Edmonton, Alberta, Canada T6G 2G2
Received 11 December 2000; revised 19 January 2001; accepted 22 January 2001
Abstract—2-Methyl-1,4-benzenediol (10) was acylated with a-chloroisobutyroyl chloride and converted by treatment with AlCl3
into the indanone derivative 12, which was elaborated into the substituted indane acid 24. Oxidation then afforded racemic
puraquinonic acid. © 2001 Elsevier Science Ltd. All rights reserved.
The fungal metabolite puraquinonic acid (1)1 has the
noteworthy property of inducing differentiation in HL-
60 cells, and its structure may therefore offer some
guidance for the design of antileukemia drugs.2 The
absolute configuration of 1, which has [h]2D2 +1 (c 1.0,
CHCl3), is not known. Compounds 2 and 3, which are
structurally related to puraquinonic acid, have been
isolated3 from injured fruit bodies of the fungus Russula
indanone 6, which was acylated (6“7) and converted
into puraquinonic acid. In this route (4“5“6“7“1,
Scheme 1), the C(2%) oxygen had to be protected in the
form of the heterocycle shown, in order to avoid cycliza-
tion of the type 8“95 during the Nazarov cyclization
(Scheme 2). We have now bypassed this inconvenient
requirement, and report (Scheme 3) a much shorter
route to 1 (15 steps versus 28).
delica, but no evaluation of the biological properties of
these metabolites has been reported. Recent work in this
laboratory has resulted in a synthetic route to ( )-1,4
starting from 2,5-dimethoxybenzoic acid (4), which was
first elaborated into 5. Then, Nazarov cyclization (5“6,
concentrated H2SO4, 84%) served to generate the
Acylation of 10 with a-chloroisobutyroyl chloride gave
the diester 11 (88%), which is reported (no yield is
given) in the patent literature6 to undergo rearrange-
ment and cyclization (11“12) on heating with AlCl3. In
our hands this transformation is easily accomplished
(43%), and methylation (MeI, K2CO3, DMF) gave the
Scheme 1.
Keywords: antileukemia compound; Claisen rearrangement; quinone; oxidation; differentiation inducer.
* Corresponding author. E-mail: derrick.clive@ualberta.ca
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00144-7

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S. Hisaindee, D. L. J. Cli6e / Tetrahedron Letters 42 (2001) 2253–2255
appropriate functionality for conversion into
puraquinonic acid.
Reduction of the ketone carbonyl (NaBH4, MeOH,
91%) and radical deoxygenation (19“20“21, 80%
overall) took the route to a stage where the 2%,3% double
bond had to be cleaved. This seemingly straightforward
operation was initially troublesome, as ozonolysis
resulted in destruction of the starting material, and
Scheme 2.
treatment
with
OsO4–NaIO4
under
standard
conditions8 gave the required aldehyde 22 in low yield
(ca. 22%). However, use of OsO4–LiIO4 in an aqueous
phosphate buffer at pH 6.69 afforded 22 in 98% yield,
and NaBH4 reduction (96%) led to alcohol 23. Simple
hydrolysis (LiOH, aqueous THF, 93%) liberated the
parent acid 24,4 which we had previously4 oxidized
[Ce(NH4)2(NO3)6, 2,6-pyridinedicarboxylic acid N-
oxide,10 77%] to racemic puraquinonic acid.
corresponding bis-methyl ether 13 (64%). Selective
demethylation, directed by the carbonyl group, was
then achieved on treatment with BCl3 (−78°C to room
temperature, 97%).7 From that point, O-allylation
(14“15, NaH, allyl bromide, DMF, 96%, or 99% after
correction for recovered 14), Claisen rearrangement
(15“16, 200°C, 8 h, 67%, or 75% after correction for
recovered 15), and O-methylation (MeI, K2CO3, DMF,
93%) gave the highly substituted indanone derivative
17; acylation with Mander’s reagent [LDA,
MeOC(O)CN, 88%] then provided ketoester 18, which
contains all the required skeletal carbons and the
In the present route, formation of the five-membered
ring at an early stage avoids complications engendered
by the presence of the (2%-oxyethyl) side chain, and a
considerable shortening of the synthesis results. Our
Scheme 3. (a) a-Chloroisobutyroyl chloride, pyridine, 88%; (b) AlCl3, 25°C for 20 min, then 190°C for 10 min, 43%; (c) MeI,
K2CO3, DMF, 5 h, 64%; (d) BCl3, −78°C to room temperature, 5 h, 97%; (e) NaH, allyl bromide, DMF, 0°C to room
temperature, 1.5 h, 96%, or 99% after correction for recovered 14; (f) degassed decalin, 200°C, 8 h, 67%, or 75% after correction
for recovered 15; (g) MeI, K2CO3, DMF, 12 h, 93%; (h) LDA, THF, −78°C, MeOC(O)CN, 88%; (i) NaBH4, MeOH, 0°C, 40 min,
91%; (j) Im2CꢀS, DMAP, ClCH2CH2Cl, room temperature, 12 h, 97%; (k) Bu3SnH, AIBN, PhMe, 1.5 h, reflux, 83%; (l) EtOAc,
LiIO4–Li3PO4–buffer, pH 6.6, 1% aqueous OsO4, 17 h, 98%; (m) NaBH4, MeOH, 0°C, 1 h, 97%; (n) LiOH·H2O, 1:1
dioxane–water, room temperature, 3 h, 93%; (o) Ce(NH4)2(NO3)6, 2,6-pyridinedicarboxylic acid N-oxide, 77%.

S. Hisaindee, D. L. J. Cli6e / Tetrahedron Letters 42 (2001) 2253–2255
2255
attempts to effect oxidative cleavage of the allyl side
chain of 21 illustrate the significant improvement that
can be achieved in the Lemieux–Johnson oxidation by
controlling the pH.
J=5.8, 1.6 Hz, 2H), 3.78 (s, 3H), 3.91 (s, 3H), 4.90 (dq,
J=17.1, 1.8 Hz, 1H), 5.00 (dq, J=10.2, 1.7 Hz, 1H),
5.85–5.96 (m, 1H); 13C NMR (CDCl3, 125 MHz) l 12.8
(q%), 16.5 (q%), 30.5 (t%), 31.6 (t%), 42.4 (q%), 60.1 (q% or d%),
62.3 (d% or q%), 115.1 (t%), 126.8 (s%), 132.0 (s%), 136.0 (d%),
139.2 (s%), 144.6 (s%), 151.2 (s%), 152.5 (s%), 206.0 (s%); exact
mass m/z calcd for C16H20O3 260.1412, found 260.1407.
All new compounds were characterized spectroscopi-
cally, including accurate mass measurements.11
18: FTIR (CDCl3 cast) 1745, 1707 cm−1 1H NMR
;
(CDCl3, 400 MHz) l 1.52 (s, 3H), 2.30 (s, 3H), 2.94 (d,
J=17.3 Hz, 1H), 3.47 (dq, J=5.8, 1.6 Hz, 2H), 3.64 (d,
J=17.3 Hz, 1H), 3.70 (s, 3H), 3.79 (s, 3H), 3.91 (s, 3H),
4.90 (dq, J=17.2, 1.6 Hz, 1H), 5.03 (dq, J=10.2, 1.6 Hz,
1H), 5.86–5.96 (m, 1H); 13C NMR (CDCl3, 125 MHz) l
12.8 (q%), 21.2 (q%), 30.6 (t%), 36.6 (t%), 52.6 (q%), 56.4 (s%),
60.2 (q%), 62.3 (q%), 115.3 (t%), 125.1 (s%), 132.6 (s%), 135.8
(d%), 140.2 (s%), 143.6 (s%), 151.1 (s%), 153.2 (s%), 172.6 (s%),
200.0 (s%); exact mass m/z calcd for C18H22O5 318.1467,
Acknowledgements
Acknowledgment is made to the Natural Sciences and
Engineering Research Council of Canada and to
AnorMED (Langley, BC) for financial support.
References
found 318.1466. 21: FTIR (CHCl3 cast) 1733 cm−1 1H
;
NMR (CDCl3, 360 MHz) l 1.36 (s, 3H), 2.16 (s, 3H),
2.88 (dd, J=16.0, 2.2 Hz, 2H), 3.38–3.50 [m containing
dd at l 3.46 (J=15.8, 4.7 Hz), 4H in all], 3.70 (s, 3H),
3.72 (s, 3H), 3.73 (s, 3H), 4.91 (dq, J=17.1, 1.9 Hz, 1H),
5.00 (dq, J=10.0, 1.8 Hz, 1H), 5.89–5.97 (m, 1H); 13C
NMR (CDCl3, 50.3 MHz) l 11.8 (q%), 25.2 (q%), 31.0 (t%),
41.2 (t%), 41.4 (t%), 50.0 (s%), 52.1 (q%), 59.9 (q%), 60.4 (q%),
114.7 (t%), 129.1 (s%), 130.3 (s%), 131.4 (s%), 132.5 (s%), 136.7
(d%), 151.0 (s%), 177.9 (s%), two signals overlap in this
spectrum; exact mass m/z calcd for C18H24O4 304.1675,
1. Becker, U.; Erkel, G.; Anke, T.; Sterner, O. Nat. Prod.
Lett. 1997, 9, 229–236.
2. (a) Degos, L. Leukemia Res. 1990, 14, 717–719; (b) Suh,
N.; Luyengi, L.; Fong, H. H. S.; Kinghorn, A. D.;
Pezzuto, J. M. Anticancer Res. 1995, 15, 233–240; (c)
Mason, M. D. In Molecular Biology for Oncologists;
Yarnold, J. R.; Stratton, M. R.; McMillan, T. J., Eds.;
Chapman and Hall: London, 1996; pp. 112–121.
3. Clericuzio, M.; Han, F.; Pan, F.; Pang, Z.; Sterner, O.
Acta Chem. Scand. 1998, 52, 1333–1337.
found 304.1679. 22: FTIR (CDCl3 cast) 1727 cm−1 1H
;
4. Clive, D. L. J.; Sannigrahi, M.; Hisaindee, S. J. Org.
NMR (CDCl3, 360 MHz) l 1.37 (s, 3H), 2.12 (s, 3H),
2.89 (dd, J=15.9, 3.3 Hz, 2H), 3.47 (d, J=15.8 Hz, 1H),
3.50 (d, J=15.8 Hz, 1H), 3.71 (overlapping singlets, 6H
in all), 3.72 (t, J=2.0 Hz, 2H), 3.74 (s, 3H), 9.68 (t,
J=2.0 Hz, 1H); 13C NMR (CDCl3, 125 MHz) l 12.6 (q%),
25.1 (q%), 30.9 (q%), 41.2 (t%), 41.6 (t%), 42.5 (t%), 50.1 (s%),
52.2 (q%), 60.0 (q%), 123.5 (s%), 129.5 (s%), 131.1 (s%), 134.3
(s%), 151.0 (s%), 151.2 (s%), 177.7 (s%), 199.6 (d%); exact m/z
calcd for C17H22O5 306.1467, found 306.1472. 23: FTIR
Chem. 2001, 66, 954–961.
5. Attempts to open the heterocycle (BBr3 or Me3SiI) gave
unidentifiable products.
6. Kundiger, D. G.; Ovist, E. B. W. US Patent 2,881,218,
1959.
7. Dean, F. M.; Goodchild, J.; Houghton, L. E.; Martin, J.
A.; Morton, R. B.; Parton, B.; Proce, A. W.; Somvichien,
N. Tetrahedron Lett. 1966, 4153–4159.
8. Clive, D. L. J.; Bo, Y.; Tao, Y.; Daigneault, S.; Wu,
Y.-J.; Meignan, G. J. Am. Chem. Soc. 1998, 120, 10332–
10349.
9. Falling, S. N.; Rapoport, H. J. Org. Chem. 1980, 45,
1260–1270.
(CDCl3 cast) 3427, 1731 cm−1 1H NMR (CDCl3, 360
;
MHz) l 1.36 (s, 3H) 1.90 (br s, 1H), 2.21 (s, 3H),
2.84–2.97 [m containing a dd at l 2.87 ppm (J=16.1, 3.3
Hz) and a t at l 2.92 (J=6.8 Hz), 4H in all), 3.44 (d,
J=15.9 Hz, 1H), 3.48 (d, J=15.8 Hz, 1H), 3.70 (s, 3H),
3.73–3.79 (m, containing two singlets at l 3.73 and l
3.76, 8H in all); 13C NMR (CDCl3, 125 MHz) l 12.2 (q%),
25.3 (q%), 30.6 (t%), 41.2 (t%), 41.6 (t%), 50.1 (s%), 52.2 (q%),
60.0 (q%), 60.1 (q%), 62.8 (t%), 128.9 (two overlapping s%),
131.0 (s%), 132.9 (s%), 150.98 (s%), 151.09 (s%), 177.6 (s%);
exact mass m/z calcd for C17H24O5 308.1624, found
308.1619.
10. Syper, L.; Kloc, K.; Mlochowski, J.; Szulc, Z. Synthesis
1979, 521–522.
11. Characterization data for key compounds: The symbols
s%, d%, t% and q% in 13C spectra refer to 0, 1, 2, and 3
attached protons, respectively. 17: FTIR (CHCl3 cast)
1707 cm−1; 1H NMR (CDCl3, 360 MHz) l 1.29 (d, J=7.3
Hz, 3 H), 2.28 (s, 3 H), 2.62–2.72 [m containing d at l
2.64 (J=4.2 Hz), 2H in all], 3.32–3.40 (m, 1H), 3.46 (dt,
.
.