Synthesis of (+)-puraquinonic acid.

Article abstract of DOI:10.1039/b205487f

(+)-Puraquinonic acid (1a) was synthesized, using a route based on ring-closing metathesis and radical cyclization, the chirality of the quaternary carbon being controlled by a temporary adjacent asymmetric center.

Full text of DOI:10.1039/b205487f

Synthesis of (+)-puraquinonic acid
Derrick L. J. Clive* and Maolin Yu
Chemistry Department, University of Alberta, Edmonton, Alberta, Canada T6G 2G2
Received (in Corvallis, OR, USA) 3rd June 2002, Accepted 29th August 2002
First published as an Advance Article on the web 19th September 2002
(+)-Puraquinonic acid (1a) was synthesized, using a route
based on ring-closing metathesis and radical cyclization, the
chirality of the quaternary carbon being controlled by a
temporary adjacent asymmetric center.
membered ring of puraquinonic acid. Treatment of 17 with
Bu4NF in THF effected desilylation (17 ? 18, 95%), and
heating with tricyclohexylphosphine[1,3-bis(2,4,6-trimethyl-
phenyl)-4,5-dihydroimidazol-2-ylidene][benzylidene]rutheniu-
m(IV) dichloride19 in CH2Cl2 gave the optically active allylic
alcohol 19 in 88% yield.† Examination of the alcohol by HPLC
[CHIRALPACK AS, hexane] and comparison with a racemic
sample showed that 19 had ee > 98%. The alcohol was readily
converted into the Stork bromo acetals (19? 20, ethyl vinyl
ether, Br2, 2,6-lutidine, 91%), and these underwent radical
cyclization when treated with Bu3SnH and AIBN in refluxing
PhMe. Best results (85% yield) were obtained when the
stannane and initiator were added in one portion. The
cyclization must occur with cis ring fusion,7b,8 and so the
stereochemistry of 21 is assigned as shown.
Puraquinonic acid (1b), shown in the present work to have most
probably the 2R-configuration, is a fungal metabolite1,2 that
induces differentiation in HL-60 cells.1 This property is relevant
to the design of antileukemia drugs.3 The absolute configuration
of natural 1 was previously unknown, and recent publications
from this laboratory4,5 describe syntheses of the racemic
compound. Making optically active 1 is a more demanding task
because the features responsible for its chirality are far removed
from C(2).6
The tetrahydrofuran ring was now degraded to remove the
C(3) oxygen (see 21) and generate the carboxy at C(2). Acid
hydrolysis (1+4 AcOH–water, 91%) gave lactols 22, and
mesylation (MsCl, Et3N, THF, 75%) afforded the sensitive
elimination product 23, which should be used immediately.
Selective cleavage of the vinyl ether double bond was best done
with the OsO4–NaIO4 combination, rather than with O3, and
gave 24. Oxidation of the CHO group (NaClO2, NaH2PO4,
2-methyl-2-butene), titration with CH2N2 and treatment of the
Our approach is based on the use of a temporary asymmetric
center at C(3) (see 19, Scheme 2), and on the fact that radical
cyclization of the derived Stork bromo acetals7 20 must give a
cis-fused7b,8 product (20 ? 21), thereby forming the quaternary
center at C(2) with a configuration determined by that of the
starting alcohol 19.
O-Allylation of phenolic aldehyde 29–12 (2 ?3, NaH, allyl
bromide, 79%) and thermal Claisen rearrangement (decalin,
200 °C, 66%) gave 4. Introduction of a second oxygen (see 6)
was initially troublesome, until we found that sequential
oxidation to a quinone ketal13 [4 ? 5, PhI(OAc)2, MeOH,
83%], Zn-mediated reduction14 (5 ? 6, Zn–AcOH, 70%), and
methylation (MeI, K2CO3, 92%) gave the requisite p-dimethoxy
compound 7 (Scheme 1). The aldehyde was protected as its
dimethyl acetal [(MeO)3CH, TsOH.H2O, 4 Å sieves, 97%)],
and the side chain olefin was degraded (8 ? 10) by double bond
cleavage (OsO4, NaIO4, 95%), reduction (NaBH4, MeOH,
95%), and benzylation (NaH, Bu4NI, THF, BnBr, 92%). Acetal
hydrolysis (10 ? 11, Amberlite IR-120, aqueous acetone, 95%)
and Stille coupling with tributylvinyltin [CuI, Pd(PPh3)4, 66%]
gave the key intermediate 12.
Asymmetric aldol condensation15 of 12 with (S)-4-isopropyl-
3-propionyl-2-oxazolidinone, using Bu2BOSO2CF3 to generate
the intermediate enol, gave 13 (78%) (Scheme 2), whose
stereochemistry we assign on the basis of precedent,15,16 the
coupling constant for the C(1A)H (J = 9.3 Hz) indicating16a an
anti relationship for the substituents at C(1A) and C(2A). This is
an uncommon stereochemical outcome, but one for which there
is precedent with aromatic aldehydes.16a The hydroxy was
silylated (t-BuMe2SiOSO2CF3, 2,6-lutidine, 95%) and the
chiral auxiliary was replaced by a benzyloxy group (BnOLi,17
THF, 89%) (13 ? 14). Reduction (DIBAL-H, 89%) then
afforded primary alcohol 15. Replacement of the hydroxy by an
o-nitrophenylseleno group (15 ? 16, o-(NO2)C6H4SeCN,
Bu3P),18 and selenoxide elimination (30% H2O2, 81% from 15)
served to generate a double bond (15 ? 16 ? 17) and set the
stage for a ring-closing metathesis that would form the five-
a
Scheme 1 R = OMe. Reagents and conditions: (i) NaH, allyl bromide,
DMF, 2 h, 79%; (ii) degassed trans-decalin, reflux, 7 h, 66%; (iii)
PhI(OAc)2, MeOH, 12 h, 83%; (iv) Zn powder, AcOH, 7 h, 70%; (v) MeI,
K2CO3, DMF, 12 h, 92%; (vi) (MeO)3CH, TsOH·H2O, MeOH, reflux, 12 h,
97%; (vii) OsO4 (catalytic), NaIO4, 5+2+2 CCl4–water–t-BuOH, 1.5 h,
95%; (viii) NaBH4, MeOH, 0 °C, 1.5 h, 95%; (ix) NaH, BnBr, THF, 12 h,
92%; (x) 1+1 acetone–water, Amberlite IR-120, 12 h, 95%; (xi)
Bu3(CH2NCH)Sn, CuI, Pd(PPh3)4, PhMe, reflux, 40 h, 66%.
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crude product with methanolic K2CO3 [to hydrolyze the C(3)
formate] afforded hydroxy ester 25 (54% overall from 23). The
C(3) hydroxy was now removed by Barton–McCombie deox-
ygenation5,20 (25 ? 26, Im2CS, DMAP, ca. 96%; 26 ? 27,
Bu3SnH, AIBN, PhMe, 73–77%). Hydrogenolysis (H2, Pd/C,
96%) released the sidechain hydroxy and the ester was
hydrolyzed with LiOH (LiOH·H2O, dioxane, water, 95%).
Finally, treatment with Ce(NH4)2(NO3)6 in the presence of
2,6-pyridinedicarboxylic acid N-oxide4,21 gave synthetic pur-
[a]D22 + 1° (c 1.0 CHCl3), but HPLC comparison [CHIRACEL
OD-RH, 1+1 i-PrOH–water] showed that the natural and
synthetic compounds are enantiomeric, and remeasurement of
22
the specific rotation of the natural material gave [a]D 22.2° (c
22
0.55 CHCl3), [a]D 21.3° (c 0.6 CH2Cl2). Therefore, natural
(2)-puraquinonic acid has the 2R configuration, based on our
stereochemical assignment to C(1A) in 13.
All new compounds were characterized spectroscopically
except for 16, 24 and 26, which were used crude.
22
aquinonic acid (81%) with [a]D22 +3.2° (c 0.3 CHCl3), [a]D
Acknowledgement is made to NSERC and to AnorMED for
financial support. We thank Dr M. Sannigrahi, S. Hisaindee, X.
Gao, J. Kennedy, Dr X. Lu, and A. Ondrus for assistance,
Professor O. Sterner for helpful correspondence, and Professor
T. Anke for a sample of 1b. M.Y. holds a University of Alberta
Graduate Research Assistantship.
+3.1° (c 0.7 CH2Cl2). The natural product is reported1 to have
Notes and references
† Ring-closing metathesis did not work with 17.
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Scheme 2 Reagents and conditions: (i) t-BuMe2SiOSO2CF3, 2,6-lutidine,
CH2Cl2, 1 h, 95%; (ii) BnOLi, THF, 0 °C, 6 h, 89%; (iii) DIBAL-H,
CH2Cl2, 0 °C, 1 h, 89%; (iv) o-(NO2)C6H4SeCN, Bu3P, THF, 12 h; (v) 30%
H2O2, THF, 5 h, 81% from 15; (vi) Bu4NF, THF, 36 h, 95%; (vii)
tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimida-
zol-2-ylidene][benzylidene]ruthenium(IV) dichloride, CH2Cl2, reflux, 20 h,
88%; (viii) ethyl vinyl ether, Br2, CH2Cl2, 2,6-lutidine, 20 h, 91%; (ix)
Bu3SnH and AIBN (both added in one portion), PhMe, reflux, 1.5 h, 85%;
(x) 1+4 AcOH–water, THF, reflux, 12 h, 91%; (xi) MsCl, Et3N, THF, 2 h,
then reflux, 1 h, 75%; (xii) OsO4 (catalytic), NaIO4, 5+2+2 CCl4–water–t-
BuOH, 9 h; (xiii) NaClO2, 2-methyl-2-butene, NaH2PO4, t-BuOH, 3 h; (xiv)
CH2N2, Et2O, then MeOH, K2CO3, 54% from 23; (xv) Im2CS, DMAP,
CH2Cl2, reflux, 19 h, ca. 96%; (xvi) Bu3SnH, AIBN, PhMe, reflux, 1.5 h,
73–77%; (xvii) H2 (balloon), Pd/C, MeOH, 30 min, 96%; (xviii)
LiOH·H2O, 1+1 dioxane–water, 3 h, 95%; (xix) Ce(NH4)2(NO3)6, 2,6-pyr-
idinedicarboxylic acid N-oxide, 2+1 MeCN–water, 5 h, 81%.
21 L. Syper, K. Kloc, J. Mlochowski and Z. Szulc, Synthesis, 1979, 521.
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