Synthesis of (+/-)-puraquinonic acid: an inducer of cell differentiation.

Article abstract of DOI:10.1021/jo001523s

Puraquinonic acid (1) was synthesized from 2,5-dimethoxybenzoic acid by way of isochroman 2 and the indanone derivative 3, a Nazarov cyclization being used to construct the five-membered ring.

Full text of DOI:10.1021/jo001523s

954
J . Org. Chem. 2001, 66, 954-961
Syn th esis of (()-P u r a qu in on ic Acid : An In d u cer of Cell
Differ en tia tion
Derrick L. J . Clive,* Mousumi Sannigrahi, and Soleiman Hisaindee
Chemistry Department, University of Alberta, Edmonton, Alberta, Canada T6G 2G2
derrick.clive@ualberta.ca
Received October 26, 2000
Puraquinonic acid (1) was synthesized from 2,5-dimethoxybenzoic acid by way of isochroman 2
and the indanone derivative 3, a Nazarov cyclization being used to construct the five-membered
ring.
Sch em e 1a
We report the synthesis of racemic puraquinonic acid
(1).1,2 The optically active3 substance, which is a fungal
metabolite produced by cultures of Mycena pura,1 induces
differentiation of HL-60 cells (human promyelocytic
leukemia) and may therefore4 be a lead compound in the
design of drugs to treat leukemia. No synthetic work on
puraquinonic acid has been described before.
Our route proceeds by way of the isochroman 2 and
the derived indanone 3. The first key intermediate (2)
was obtained as summarized in Scheme 1. Nitration of
commercial 2,5-dimethoxybenzoic acid (4) (concentrated
a
Key: (i) HNO3, 0 °C, 3 h, 100%; (ii) K2CO3, acetone, Me2SO4,
12 h, 82% from 4; (iii) H2 (50 psi), Pd-C, EtOH, 97%; (iv) NaNO2,
HBr, water, 0 °C; then add mixture over 1 h to CuBr, water, 100
°C, then 10 min, 100 °C, 81%; (v) DIBAL-H, PhMe, -78 °C for 2
h, then warm to room temperature, 99%; (vi) PCC, CH2Cl2, 10 h,
95%; (vii) BCl3, CH2Cl2, -78 °C to room temperature, 10 h, 96%;
(viii) NaH, DMF, allyl bromide, 0 °C to room temperature, 4 h,
83% (9% of 9 is also recovered); (ix) degassed trans-decalin, 200
°C, 6.5 h, 74%; (x) K2CO3, MeI, DMF, 70 °C, 10 h, 97%; (xi)
CH(OMe)3, TsOH‚H2O (catalytic), MeOH, 70 °C, 3.5 h, 96%; (xii)
BuLi, THF, -78 °C, MeOC(O)CN, 20 min, 88%; (xiii) DIBAL-H,
hexanes-PhMe, added in two equal portions at the start and after
1 h, -78 °C, 2 h in all, 93%; (xiv) 0.1 N HCl, dioxane, 12 h, 71%
plus 24% of the corresponding methyl acetal (OMe instead of OH
in 16); the methyl acetal can be hydrolyzed to 16 (0.1 N HCl,
dioxane, 12 h, 68%); (xv) Ph3PCH2OMeBr, (Me3Si)2NK in PhMe,
-78 °C, 2 h, then 10 h at room temperature, 93% as a Z,E isomer
mixture; (xvi) 0.1 N HCl, dioxane, 60 °C, 3 h, 86%; (xvii) Et3SiH
(freshly distilled), BF3‚Et2O (freshly distilled), -78 °C, 3 h, 93%.
5
HNO3 ) and esterification (Me2SO4, K2CO3) gave 56 as the
major product, which could be isolated free of its 3- or
4-nitro isomers in 82% overall yield. Classical nitro group
reduction (5 f 6,7 Pd-C, H2, 97%) and Sandmeyer
reaction8 (6 f 7, NaNO2, HBr, CuBr, 100 °C, 81%) gave
(1) Becker, U.; Erkel, G.; Anke, T.; Sterner, O. Nat. Prod. Lett. 1997,
9, 229-236.
(2) Related compounds: Clericuzio, M.; Han, F.; Pan, F.; Pang, Z.;
Sterner, O. Acta Chem. Scand. 1998, 52, 1333-1337.
(3) Natural puraquinonic acid has [R]22 +1° (c 1.0 CHCl3) (ref 1).
D
(4) (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.
(5) Oh ki, M.; Tanaka, Y.; Yamamoto, G.; Nakamura, N. Bull. Chem.
Soc. J pn. 1983, 56, 302-305.
(6) Cf. Banerjee, P. K.; Chaudhury, D. N. J . Indian. Chem. Soc.
1962, 39, 243-246.
(7) (a) Cf. Mehta, L. K.; Parrick, J .; Payne, F. J . Chem. Res. Synop.
1998, 190-191. (b) For the corresponding acid, see: Heaney, H.;
Hollinshead, J . H.; Kirby, G. W.; Ley, S. V.; Sharma, R. P. J . Chem.
Soc., Perkin Trans. 1 1973, 1840-1843.
(8) Cf. Furniss, B. S.; Hannaford, A. J .; Smith, P. W. G.; Tatchell,
A. R. Vogel’s Textbook of Practical Organic Chemistry, 5th ed.;
Longman: Harlow, 1989.
the expected bromo ester, which was then converted into
the corresponding aldehyde (7 f 89) by hydride reduction
to the alcohol (DIBAL-H, 99%) and oxidation (PCC, 95%).
Regioselective10 demethylation, directed by the aldehyde
(9) Cf. Sardessai, M. S.; Abramson, H. N. Org. Prep. Proc. Int. 1991,
23, 419-424.
10.1021/jo001523s CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/06/2001

Synthesis of (()-Puraquinonic Acid
J . Org. Chem., Vol. 66, No. 3, 2001 955
group11 (8 f 9, BCl3, 96%), allylation (9 f 10, NaH, allyl
bromide, 83%), and thermal Claisen rearrangement
(decalin, 200 °C, 74%), then gave phenol 11. This was
methylated (11 f 12, MeI, K2CO3, 97%), and the alde-
hyde group was protected [12 f 13, CH(OMe)3, MeOH,
TsOH‚H2O, 96%]. Use of a dimethyl instead of a cyclic
acetal and the indicated order of the last four stepss
allylation, rearrangement, O-methylation, and acetaliza-
tionswas the best of several possibilities that we exam-
ined. At this point, halogen-metal exchange, and treat-
ment with Mander’s reagent,12 gave ester 14 (88%). Of
course, quenching of the intermediate anion with MeI
rather than MeOC(O)CN would seem to be a more logical
step, but such an approach eventually incurred complica-
tions, as described below. The ester group of 14, whichs
after modificationseventually serves the essential pur-
pose of protecting the C(2′) oxygen (see 1 for numbering),
was reduced with DIBAL-H (93%), and then acid hy-
drolysis of the intermediate hydroxy acetal (0.1 N HCl,
71%) afforded lactol 16. During the hydrolysis, some
(24%) of the lactol methyl ether corresponding to 16 is
also formed (OMe instead of OH in 16), but can be
hydrolyzed to the lactol (68%), raising the yield for
conversion of 15 into 16 to 87%. The second carbon of
the hydroxyethyl chain of puraquinonic acid was now
introduced by Wittig reaction [16 f 17, Ph3PCH2OMeBr,
(Me3Si)2NK,13 93%], and mild acid hydrolysis of the
resulting enol ethers (Z:E ) 1:2) gave lactol 18 (86%).
Finally, deoxygenation, using Et3SiH and BF3‚Et2O14s
both freshly distilledsbrought the route to the key
intermediate 2 (93%).
Sch em e 2a
a
Key: (i) RhCl3‚3H2O, 5:1 PhMe-MeOH, 70 °C, 3 h, 97%; (ii)
NaIO4, OsO4 (catalytic), 2:1:1 t-BuOH, CCl4, water, 1.5 h, 97%;
(iii) isopropenylmagnesium bromide, Et2O, 0 °C, 30 min, then
remove ice bath, 30 min, 86%; (iv) Dess-Martin, CH2Cl2, 1 h, 96%;
(v) concd H2SO4, 0 °C, 5 h, 83%; (vi) LDA, THF, -78 °C, 30 min,
MeOC(O)CN, 30 min, 59%, or 82% corrected for recovered 3; (vii)
NaBH4, MeOH, 0 °C, 1-2 h, 99%; (viii) SOCl2, Et3N, CH2Cl2, 12
h, 54% or 93%, after correction for recovered starting material;
(ix) Bu3SnH, PhMe, AIBN, reflux, 3 h, 95%; (x) AcCl, ZnCl2
(catalytic), CH2Cl2, reflux, 4 h, 88%; (xi) Bu3SnH, PhMe, AIBN,
reflux, 3 h, 87%; (xii) LiOH, 1:1 dioxane-water, 12 h, 90%; (xiii)
Ce(NH4)2(NO3)6, 2:3 water-MeCN, 2,6-pyridinedicarboxylic acid
N-oxide, 77%.
At this stage, the required five-membered ring was
constructed by the method summarized in Scheme 2.
Movement of the double bond of 2 into conjugation with
the aromatic ring (2 f 19, RhCl3‚3H2O, 5:1 PhMe-
MeOH,15 97%) and treatment with NaIO4 in the presence
of a catalytic amount of OsO4 gave aldehyde 20 (97%).16
This reacted17 with isopropenylmagnesium bromide (86%),
and the resulting alcohol was oxidized (Dess-Martin
reagent, 96%) to enone 22. On storage in concentrated
H2SO4 (0 °C, 5 h), the enone underwent efficient Nazarov
cyclization18 to the indanone derivative 3 (83%), which
was then deprotonated (LDA) and acylated with Mander’s
reagent (3 f 23, 59% or 82% corrected for recovered 3).
At this point, it was necessary to deoxygenate the
ketone and open the heterocyclic ring. We had planned
to effect both steps by sequential hydride reduction and
hydrogenolysis,19 but this approach was unsuccessful.
Instead, the deoxygenation was achieved by successive
treatment with NaBH4 (23 f 24, 99%), SOCl2-Et3N (24
f 25, 54% or 93%, after correction for recovered alcohol),
and Bu3SnH-AIBN (25 f 26, 95%), and the heterocyclic
ring was then opened by heating with AcCl in the
presence of ZnCl220 (26 f 27, 88%). The resulting chloride
was reduced with Bu3SnH (27 f 28, 87%). Finally, basic
hydrolysis (LiOH, aqueous dioxane, 90%) released hy-
droxy acid 29, and oxidation (77%) with Ce(NH4)2(NO3)6
in the presence of 2,6-pyridinedicarboxylic acid N-oxide21
(10) An attempt to demethylate ester 7 with boron tribromide
resulted in extensive demethylation of both ether groups. We subse-
quently found that 7 can be demethylated regioselectively with boron
trichloride, but demethylation at that stage makes no substantive
difference to the overall synthesis.
(11) (a) Dean, F. M.; Goodchild, J .; Houghton, L. E.; Martin, J . A.;
Morton, R. B.; Parton, B.; Price, A. W.; Somvichien, N. Tetrahedron
Lett. 1966, 4153-4159. (b) Review on ether cleavage: Bhatt, M. V.;
Kulkarni, S. U. Synthesis 1983, 249-282. (c) Lal, K.; Ghosh, S.;
Salomon, R. G. J . Org. Chem. 1987, 52, 1072-1078.
(12) Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1983, 24, 5425-
5428.
(13) Cf. Walton, R.; Fraser-Reid, B. J . Am. Chem. Soc. 1991, 113,
5791-5799.
(14) Kraus, G. A.; Frazier, K. A.; Roth, B. D.; Taschner, M. J .;
Neuenschwander, K. J . Org. Chem. 1981, 46, 2417-2419.
(15) Clive, D. L. J .; J oussef, A. C. J . Org. Chem. 1990, 55, 1096-
1098.
(16) In principle, compound i, available in low yield and of unestab-
lished regiochemistry (Retamal, J . I.; Ruiz, V. M.; Tapia, R. A.;
Valderrama, J . A.; Vega, J . C. Synth. Commun. 1982, 12, 279-285),
could be converted into 20 or its regioisomer (aromatic H and CHO
interchanged), but we have not investigated this approach.
(18) Carter, R. H.; Garson, M. J .; Hill, R. A.; Staunton, J .; Sunter,
D. C. J . Chem. Soc., Perkin Trans. 1 1981, 471-479.
(19) Cf. Meyer, A. L.; Turner, R. B. Tetrahedron 1971, 27, 2609-
2615.
(20) Hayler, J . D.; Howie, S. L. B.; Giles, R. G.; Negus, A.; Oxley, P.
W.; Walsgrove, T. C.; Walsh, S. E.; Dagger, R. E.; Fortunak, J . M.;
Mastrocola, A. J . Heterocycl. Chem. 1995, 32, 875-882.
(21) Syper, L.; Kloc, K.; Mlochowski, J .; Szulc, Z. Synthesis 1979,
521-522.
(17) An excess of Grignard reagent must be avoided; otherwise,
O-demethylation occurs.

956 J . Org. Chem., Vol. 66, No. 3, 2001
Clive et al.
Sch em e 3a
of Ar. Reaction mixtures were stirred by Teflon-coated mag-
netic stirring bars.
Hexane and EtOAc used for chromatography were distilled
before use.
Products were isolated from solution by evaporation under
water-aspirator vacuum at, or below, room temperature, using
a rotary evaporator.
Cannula transfers were done under slight pressure (Ar), not
by suction.
Commercial thin-layer chromatography (TLC) plates (silica
gel, Merck 60F-254) were used. Spots were detected by
spraying the plate with a solution of phosphomolybdic acid23
or p-anisaldehyde,24 followed by charring with a heat gun, or
by examination under UV light. Silica gel for flash chroma-
tography was Merck type 60 (230-400 mesh).
Dry solvents were prepared under an inert atmosphere and
transferred by syringe or cannula. Dry THF and Et2O were
distilled from sodium and benzophenone ketyl.
FTIR measurements were made as casts from the specified
solvent using potassium bromide plates.
a
Key: (i) NaBH4, MeOH, 0 °C, 90%. (ii) NaH, BnBr, THF, 0
°C, 3 h, 68%; (iii) RhCl3‚3H2O, 5:1 PhMe-MeOH, reflux, 3 h, 89%;
(iv) O3, CH2Cl2, -78 °C; Ph3P, 2 h, 76%; (v) isopropenylmagnesium
bromide, THF, -10 °C, 2 h, 44% of 35 and 18% of 34; (vi) PCC, 4
Å molecular sieves, CH2Cl2, 1 h, 89%; (vii) H2SO4, 6 h, 86%.
The symbols s′, d′, t′, and q′ used for 13C NMR signals indi-
cate zero, one, two, or three attached hydrogens, respectively.
Met h yl 3,6-Dim et h oxy-2-n it r oben zoa t e (5). (a ) 3,6-
Dim eth oxy-2-n itr oben zoic Acid . The literature method5
was modified slightly. Concentrated HNO3 (100 mL) was
placed in a three-necked flask fitted with a low temperature
thermometer and cooled to 0 °C. 2,5-Dimethoxybenzoic acid
(10.0 g, 54.9 mmol) was added in small portions over 30 min
with stirring (the temperature was not allowed to rise above
0 °C). The resulting yellow solution was stirred at 0 °C for
another 3 h and then poured onto cracked ice (300 mL). A
yellow precipitate formed immediately. It was filtered off, air-
dried overnight, and dried further under oil-pump vacuum for
4 h to yield a 5:1 mixture (12.4 g, 100%) of 3,6-dimethoxy-2-
nitrobenzoic acid and an isomer. The isomer ratio was deter-
mined from the isolated yields of the easily separable methyl
esters described in the following paragraph.
completed the synthesis of (()-puraquinonic acid (1),
which was identified by comparison of its spectral
properties with the published1 values.
As mentioned above, trapping of the carbanion derived
from 13 with Mander’s reagent (Scheme 1), rather than
with MeI, was an unusual but essential step. When we
used MeI, and elaborated the product into 30, applica-
tion of the Nazarov cyclization led to 31 (eq 1), which we
were unable to incorporate into a route to puraquinonic
acid because attempts to open the heterocycle (BBr3 or
Me3SiI) gave unidentifiable products. By using Mander’s
reagent, however, it was possible to avoid formation of
the dihydrofuran system.
(b) Meth yl 3,6-Dim eth oxy-2-n itr oben zoa te (5). K2CO3
(40.00 g, 290.0 mmol), dry acetone (250 mL), and Me2SO4 (13.3
mL, 18.4 g, 145 mmol) were added successively to the crude
acid (26.40 g, 116.2 mmol) obtained from the previous step,
and the resulting orange solution was stirred for 12 h. The
solvent was evaporated and the residue was kept under oil-
pump vacuum for 12 h. The resulting yellow solid was
dissolved in a small amount of EtOAc and purified by flash
chromatography over silica gel (4 × 27 cm), using 15:85
EtOAc-hexane, to give ester 5 (23.0 g, 82%) and an isomer
(4.4 g, 16%). Major isomer (5): mp 118-119 °C (lit.6 mp 122
°C); FTIR (CH2Cl2 cast) 1742, 1530, 1271 cm-1; 1H NMR (CD2-
Cl2, 200 MHz) δ 3.86 (s, 3 H), 3.88 (s, 3 H), 3.94 (s, 3 H), 7.09
(AB q, ∆νAB ) 5.4 Hz, J ) 9.3 Hz, 2 H); 13C NMR (CD2Cl2,
75.5 MHz) δ 53.1 (q′), 57.0 (q′), 57.2 (q′), 115.7 (d′), 116.1 (d′),
118.1 (s′), 145.3 (s′), 150.6 (s′), 163.4 (s′), 165.1 (s′); exact mass
m/z calcd for C10H11O6N 241.05860, found 241.05902.
Minor isomer (presumably methyl 2,5-dimethoxy-4-nitroben-
zoate25): mp 102.5-103.5 °C; FTIR (CH2Cl2 cast) 1706, 1517,
We also prepared key intermediate 3 by a slightly
different route (Scheme 3). During our studies, we
reduced lactol 18 (NaBH4) and protected the resulting
diol (32) as its bis-benzyl ether. The double bond in the
side chain was moved into conjugation with the aromatic
ring, as before, and then cleaved to afford aldehyde 33.
When this material was treated with isopropenylmag-
nesium bromide in a THF-Et2O mixture, the main
product (44%) was the ethyl ether 35, while the expected
product (34) was isolated in only 18% yield. Alcohol 35
was oxidized to ketone 36, and when this was subjected
to conditions for the Nazarov cyclization, indanone
derivative 3 was again formed in good yield (86%).
1
1251 cm-1; H NMR (CD2Cl2, 200 MHz) δ 3.92 (s, 3 H), 3.96
(s, 3 H), 3.98 (s, 3 H), 7.45 (s, 1 H), 7.55 (s, 1 H); 13C NMR
(CD2Cl2, 75.5 MHz) δ 52.7 (q′), 56.9 (q′), 57.2 (q′), 109.5 (d′),
117.1 (d′), 125.1 (s′), 141.5 (s′), 146.2 (s′), 152.2 (s′), 165.1 (s′);
exact mass m/z calcd for C10H11O6N 241.0586, found 241.05892.
Meth yl 2-Am in o-3,6-dim eth oxyben zoate (6). Pd-C (10%,
25.0 mg) was added to a solution of ester 5 (1.50 g, 6.22 mmol)
in EtOH (95%, 100 mL), and the mixture was shaken in a Parr
bottle under H2 (50 psi) until all the starting material was
consumed (ca. 12 h, TLC control, silica, 1:4 EtOAc-hexane).
Exp er im en ta l Section
Gen er a l P r oced u r es. Unless stated to the contrary, the
following conditions apply: Reactions were carried out under
a slight static pressure of Ar that had been purified by passage
through a column (3.5 × 42 cm) of R-311 catalyst22 and then
through a similar column of Drierite. Glassware was dried in
an oven for at least 3 h before use (120 °C) and either cooled
in a desiccator over Drierite or assembled quickly, sealed with
rubber septa, and allowed to cool under a slight static pressure
(23) Phosphomolybdic acid (15 g) and (NH4)2Ce(NO3)6 (2.5 g) dis-
solved in a mixture of water (485 mL) and concentrated H2SO4 (15
mL).
(24) p-Anisaldehyde (15 drops) was added to concentrated H2SO4
(6 mL) and EtOH (94 mL).
(25) 1H NMR data for methyl 2,5-dimethoxy-3-nitrobenzoate have
been reported: Goris, A.; Frigot, P.; Molho, D.; Aknin, J .; Muller, P.;
Cibault, M. Phytochemistry 1971, 10, 679-682.
(22) Supplied by Chemical Dynamics Corp., South Plainfield, NJ .

Synthesis of (()-Puraquinonic Acid
J . Org. Chem., Vol. 66, No. 3, 2001 957
(The apparatus was opened periodically for examination by
TLC.) The mixture was filtered through a pad (4 × 3 cm) of
silica gel, using EtOAc (50 mL). Evaporation of the filtrate
and flash chromatography of the residue over silica gel (3 ×
15 cm), using 3:2 EtOAc-hexane, gave amine 67 (1.266 g, 97%)
time oxidation was complete. The solvent was evaporated to
approximately 50 mL, and the slurry was filtered through a
pad (5 × 3 cm) of silica gel which was washed with 1:1 EtOAc-
hexane (400 mL, TLC control, silica, 1:1 EtOAc-hexane). The
filtrate was evaporated, and the residue was dissolved in
CH2Cl2 (15 mL) and purified by flash chromatography over
silica gel (5 × 15 cm), using 2:3 EtOAc-hexane, to give
aldehyde 89 (7.530 g, 95%) as a white solid: mp 99.5 °C (lit.9
1
as a pale yellow oil: FTIR (CH2Cl2 cast) 3489, 3379 cm-1; H
NMR (CDCl3, 400 MHz) δ 3.77 (s, 3 H), 3.82 (s, 3 H), 3.92 (s,
3 H), 5.35 (broad s, 2 H), 6.15 (d, J ) 8.8 Hz, 1 H), 6.75 (d, J
) 8.8 Hz, 1 H); 13C NMR (CD2Cl2, 100.6 MHz) δ 51.9 (q′), 56.4
(q′), 56.5 (q′), 98.4 (d′), 105.0 (s′), 113.1 (d′), 140.7 (s′), 141.8
(s′), 154.1 (s′), 168.8 (s′); exact mass (HR electrospray) m/z calcd
for C10H13NNaO4 (M + Na) 234.07423, found 234.07467. Anal.
Calcd for C10H13N: C, 56.87; H, 6.20; N, 6.63. Found: C, 56.71;
H, 6.31; N, 6.61.
mp 102-103 °C); FTIR (CH2Cl2 cast) 1695 cm-1 1H NMR
;
(CD2Cl2, 400 MHz) δ 3.82 (s, 3 H), 3.84 (s, 3 H), 7.00 (AB q,
∆νAB ) 49.5 Hz, J ) 9.1 Hz, 2 H), 7.11 (d, J ) 9.1 Hz, 1 H)
10.41 (s, 1 H); 13C NMR (CD2Cl2, 100.6 MHz) δ 56.6 (q′), 57.2
(q′), 111.4 (d′), 114.8 (s′), 117.1 (d′), 124.8 (s′), 150.4 (s′), 155.4
(s′), 190.8 (d′); exact mass (HR electrospray) m/z calcd for
C9H979BrNaO3 (M + Na) 266.96327, found 266.96351. Anal.
Calcd for C9H9BrO3: C, 44.11; H, 3.70. Found: C, 43.94; H,
3.26.
Meth yl 2-Br om o-3,6-d im eth oxyben zoa te (7). HBr (48%
in water, 17.0 mL) was added to amine 6 (9.232 g, 43.75 mmol),
and the mixture was stirred vigorously with a mechanical
stirrer. The resulting white solid was broken up with a glass
rod from time to time to allow reaction of the remaining amine.
The slurry was further diluted with HBr (48% in water, 7.0
mL) and cooled (0 °C). A cooled (0 °C) solution of NaNO2 (3.169
g, 45.94 mmol) in water (8.5 mL) was added dropwise by
Pasteur pipet, maintaining the temperature below 5 °C. The
resulting brownish red solution was stored in an ice bath and
was added dropwise, using a Pasteur pipet, to a refluxing
solution (100 °C) of CuBr (4.14 g, 0.66 equiv) in HBr (48% in
water, 5.0 mL). The color of the reaction mixture changed from
deep purple to black and later to brown. Upon completion of
the addition, heating was continued for 10 min. The reaction
mixture was cooled to room temperature and diluted with
boiling Et2O (10 mL). The aqueous layer was extracted with
Et2O (5 × 100 mL) until extraction was complete (TLC control,
silica, 15:85 EtOAc-hexane). The combined organic extracts
were washed with brine, dried (MgSO4), and evaporated. The
black, crude material was dissolved in hot 4:1 EtOH-acetone,
and applied directly to a column of flash chromatography silica
gel (5 × 20 cm). The column was developed using 15:85
EtOAc-hexane, to give 7 (9.698 g, 81%) as a white solid: mp
2-Br om o-6-h yd r oxy-3-m eth oxyben za ld eh yd e (9). BCl3
(1.0 M in hexanes, 59 mL, 59 mmol) was added dropwise to a
stirred and cooled (-78 °C) solution of aldehyde 8 (4.805 g,
19.69 mmol) in dry CH2Cl2 (200 mL). The resulting bright red
solution was stirred for 10 h without recharging the cold bath.
The solution was recooled to 0 °C, and ice-water (100 mL)
was added slowly. The resulting deep yellow solution was
extracted with CH2Cl2. The combined organic extracts were
washed with brine, dried (MgSO4), and evaporated. The yellow
residue was dissolved in CH2Cl2 (5 mL) and purified by flash
chromatography over silica gel (4 × 20 cm), using 15:85
EtOAc-hexane, to give aldehyde 9 (4.317 g, 96%) as a yel-
low solid: mp 89 °C; FTIR (CH2Cl2 cast) 1645 cm-1; 1H NMR
(CD2Cl2, 400 MHz) δ 3.89 (s, 3 H), 6.95 (d, J ) 9.1 Hz, 1 H),
7.21 (d, J ) 9.1 Hz, 1 H), 10.41 (s, 1 H), 11.51 (s, 1 H); 13C
NMR (CD2Cl2, 100.6 MHz) δ 57.8 (q′), 116.4 (s′), 117.8 (d′),
118.3 (s′), 122.7 (d′), 149.7 (s′), 158.2 (s′), 198.6 (d′); exact mass
m/z calcd for C8H879BrO3 (M + H) 230.96568, found 230.96632.
Anal. Calcd for C8H7BrO3: C, 41.59; H, 3.05. Found: C, 41.67;
H, 2.72.
2-Br om o-3-m et h oxy-6-(2-p r op en yloxy)b en za ld eh yd e
(10). Aldehyde 9 (6.14 g, 26.59 mmol) in DMF (5 mL) was
added dropwise to a stirred and cooled (0 °C) slurry of NaH
(772.5 mg, 30.58 mmol) in dry DMF (30 mL).26 The cold bath
was removed, and the resulting bright yellow slurry was
stirred for 1 h. The solution was recooled to 0 °C, and allyl
bromide (4.60 mL, 53.2 mmol) was added dropwise. The cold
bath was removed, and stirring was continued for 4 h. The
mixture was poured into brine (50 mL) and extracted with
Et2O. The combined organic extracts were washed with
aqueous KOH (10%, 20 mL) and brine, dried (MgSO4), and
evaporated. The pale yellow crude residue was dissolved in
CH2Cl2 (5 mL) and purified by flash chromatography over silica
gel (4 × 20 cm), using 1:4 EtOAc-hexane, to give allyl ether
10 (6.01 g, 83%) as a white, crystalline solid: mp 77 °C; FTIR
97 °C; FTIR (CH2Cl2 cast) 1737 cm-1 1H NMR (CDCl3, 400
;
MHz) δ 3.79 (s, 3 H), 3.82 (s, 3 H), 3.92 (s, 3 H), 6.83 (AB q,
∆νAB ) 16.0 Hz, J ) 9.0 Hz, 2 H); 13C NMR (CDCl3, 100.6 MHz)
δ 52.8 (q′), 56.6 (q′), 57.0 (q′), 109.9 (s′), 110.9 (d′), 113.1 (d′),
127.5 (s′), 150.3 (s′), 150.8 (s′), 166.5 (s′); exact mass (HR
electrospray) m/z calcd for C10H1179BrNaO4 (M + Na) 296.97384,
found 296.97328. Anal. Calcd for C10H11BrO4: C, 43.66; H,
4.03. Found: C, 43.59; H, 3.85.
2-Br om o-3,6-dim eth oxyben zaldeh yde (8). (a) (2-Br om o-
3,6-d im eth oxyp h en yl)m eth a n ol. DIBAL (1.0 M in hexanes,
70.7 mL, 71 mmol) was added dropwise to a stirred and cooled
(-78 °C) solution of ester 7 (9.692 g, 35.37 mmol) in dry PhMe
(250 mL). The mixture was stirred at -78 °C for 2 h and then
stirred for 1 h at 0 °C (ice bath). Stirring was continued for
another 6 h without recharging the ice bath. The solution was
recooled (-78 °C), and MeOH (10 mL), Na2SO4‚10H2O (4 g),
Celite (6.0 g), and water (2 mL) were added successively. The
cold bath was removed, and stirring was continued for 30 min.
The slurry was filtered through a sintered disk funnel and
washed with EtOAc. The filtrate was concentrated, and the
residue was dissolved in a small amount of EtOAc and purified
by flash chromatography over silica gel (5 × 20 cm), using 1:4
EtOAc-hexane, to give (2-bromo-3,6-dimethoxyphenyl)meth-
anol (8.78 g, 99%) as a white solid: mp 127-128 °C; FTIR
1
(CH2Cl2 cast), 1696 cm-1; H NMR (CD2Cl2, 400 MHz) δ 3.87
(s, 3 H), 4.57 (d, J ) 6 Hz, 2 H), 5.29 (d, J ) 12 Hz, 1 H), 5.43
(d, J ) 18 Hz, 1 H), 6.00-6.09 (m, 1 H), 7.02 (AB q, ∆νAB
)
44.5 Hz, J ) 9.1 Hz, 2 H), 7.07 (d, J ) 9 Hz, 1 H), 10.38 (s, 1
H); 13C NMR (CD2Cl2, 100.6 MHz) δ 57.4 (q′), 70.8 (t′), 113.6
(d′), 113.7 (s′), 117.3 (d′), 118.0 (t′), 125.8 (s′), 133.0 (d′), 151.1
(s′), 154.8 (s′), 190.7 (d′); exact mass (HR electrospray) m/z
calcd for C11H1179BrO3Na (M + Na) 292.97892, found 292.97870.
2-Br om o-6-h yd r oxy-3-m et h oxy-5-(2-p r op en yl)b en za l-
d eh yd e (11). trans-Decalin was degassed by several freeze-
thaw cycles (liquid N2/oil-pump vacuum). A solution of alde-
hyde 10 (810.0 mg, 3.011 mmol) in degassed decalin (3 mL)
was refluxed under Ar for 6.5 h and then cooled to room
temperature. Flash chromatography of the mixture (without
evaporation of the solvent) over silica gel (2 × 15 cm), using
1:12 EtOAc-hexane, gave phenol 11 (602.8 mg, 74%) as a
(CH2Cl2 cast) 3489 cm-1 1H NMR (CD2Cl2, 400 MHz) δ 2
;
.44 (t, J ) 7 Hz, 1 H), 3.82 (s, 6 H), 4.83 (d, J ) 7 Hz, 2 H),
6.85 (s, 2 H); 13C NMR (CD2Cl2, 100.6 MHz) δ 56.6 (q′), 57.1
(q′), 60.6 (t′), 110.6 (d′), 112.0 (d′), 115.2 (s′), 130.5 (s′), 150.7
(s′), 153.0 (s′); exact mass (HR electrospray) m/z calcd for
C9H1179BrNaO3 (M + Na) 268.97892, found 268.97943. Anal.
Calcd for C9H11BrO3: C, 43.75; H, 4.49. Found: C, 43.68; H,
4.32.
1
yellow oil: FTIR (CH2Cl2 cast) 1646 cm-1; H NMR (CDCl3,
200 MHz) δ 3.40 (d, J ) 6 Hz, 2 H), 3.87 (s, 3 H), 5.05-5.20
(m, 2 H), 5.85-6.07 (m, 1 H), 7.06 (s, 1 H), 10.40 (s, 1 H), 11.90
(s, 1 H); 13C NMR (CD2Cl2, 100.6 MHz) δ 33.5 (t′), 57.9 (q′),
(b) 2-Br om o-3,6-d im eth oxyben za ld eh yd e (8). A mixture
of PCC (9.795 g, 45.52 mmol) and powdered 4 Å molecular
sieves (3.0 g) was added to a stirred solution of (2-bromo-3,6-
dimethoxyphenyl)methanol (8.012 g, 32.52 mmol) in dry
CH2Cl2 (200 mL). Stirring was continued for 10 h, by which
(26) Cf. Martin, S. F.; Garrison, P. J . J . Org. Chem. 1982, 47, 1513.

958 J . Org. Chem., Vol. 66, No. 3, 2001
Clive et al.
113.7 (s′), 116.8 (t′), 117.6 (s′), 123.2 (d′), 129.6 (s′), 135.6 (d′),
149.2 (s′), 156.3 (s′), 198.8 (d′); exact mass (HR electrospray)
m/z calcd for C11H1179BrNaO3 (M + Na) 292.97892, found
292.97870.
(2 × 20 cm), using 1:4 EtOAc-hexane, to give 15 (504.9 mg,
93%) as a white solid: FTIR (CH2Cl2 cast) 3430 cm-1; 1H NMR
(CD2Cl2, 400 MHz) δ 2.97 (t, J ) 6 Hz, 1 H), 3.44 (d, J ) 6.5
Hz, 2 H), 3.48 (s, 6 H), 3.67 (s, 3 H), 3.81 (s, 3 H), 4.81 (d, J )
6 Hz, 2 H), 5.08-5.10 (m, 1 H), 5.11-5.13 (m, 1 H), 5.61 (s, 1
H), 5.93-6.04 (m, 1 H), 6.76 (s, 1 H); 13C NMR (CD2Cl2, 100.6
MHz) δ 34.3 (t′), 55.5 (t′), 56.4 (q′), 56.6 (q′), 62.9 (two q′), 103.9
(d′), 114.0 (d′), 116.2 (t′), 128.2 (s′), 131.7 (s′), 133.3 (s′), 137.3
(d′), 150.4 (s′), 155.0 (s′); exact mass m/z calcd for C15H22O5,
282.14671, found 282.14673.
1,3-Dih yd r o-4,7-d im eth oxy-6-(2-p r op en yl)isoben zofu -
r a n -1-ol (16) a n d 1,3-Dih yd r o-1,4,7-tr im eth oxy-6-(2-p r o-
p en yl)isoben zofu r a n . Dilute hydrochloric acid (0.1 M, 10
mL) was added dropwise to a stirred solution of acetal 15
(1.304 g, 4.624 mmol) in dioxane (10 mL). Stirring was
continued for 12 h, by which time all the starting material
had been consumed (TLC control, silica, 2:3 EtOAc-hexane).
The mixture was neutralized with saturated aqueous NaHCO3
and the aqueous layer was extracted with CH2Cl2, washed with
water and brine, dried (MgSO4), and evaporated. Flash chro-
matography of the residue over silica gel (2.5 × 18 cm), using
1:4 EtOAc-hexane, gave lactol 16 (778.1 mg, 71%) as a white
solid and the corresponding methyl ether [1,3-dihydro-1,4,7-
trimethoxy-6-(2-propenyl)isobenzofuran] (276.7 mg, 24%) as
a colorless oil. Lactol 16 had: mp 157.5 °C; FTIR (CH2Cl2 cast)
3335 cm-1; 1H NMR (CD2Cl2, 200 MHz) δ 3.31-3.45 (m, 3 H),
3.78 (s, 3 H), 3.82 (s, 3 H), 4.88 (d, J ) 12 Hz, 2 H), 5.01-5.18
(m, 2 H), 5.88-6.09 (m, 1 H), 6.59 (dd, J ) 6, 1.8 Hz, 1 H), 6.7
(s, 1 H); 13C NMR (CD2Cl2, 100.6 MHz) δ 34.4 (t′), 56.0 (q′),
61.4 (q′), 70.6 (t′), 101.0 (d′), 113.7 (d′), 115.7 (t′), 127.7 (s′),
132.3 (s′), 133.5 (s′), 137.6 (d′), 147.4 (s′), 149.7 (s′); exact mass
(HR electrospray) m/z calcd for C13H16NaO4 (M + Na) 259.09463,
found 259.09467.
1,3-Dih yd r o-1,4,7-tr im eth oxy-6-(2-p r op en yl)isoben zo-
fu r a n : 1H NMR (CD2Cl2, 200 MHz) δ 3.41 (s, 3 H), 3.42 (m, 2
H), 3.76 (s, 3 H), 3.81 (s, 3 H), 4.82-5.15 (m, 4 H), 5.85-6.12
(m, 1 H), 6.25 (d, J ) 3 Hz, 1 H), 6.68 (s, 1 H); 13C NMR
(CD2Cl2, 50.3 MHz) δ 35.9 (t′), 55.8 (q′), 57.5 (q′), 62.7 (q′), 72.3
(t′), 108.5 (d′), 115.2 (d′), 117.3 (t′), 129.8 (s′), 132.1 (s′), 134.7
(s′), 139.3 (d′), 149.0 (s′), 151.1 (s′); exact mass (HR electro-
spray) m/z calcd for C14H18NaO4 (M + Na) 273.11028, found
273.10998.
The 1,3-dihydro-1,4,7-trimethoxy-6-(2-propenyl)isobenzofu-
ran was hydrolyzed to lactol 16, as follows. Dilute hydrochloric
acid (0.1 M, 12 mL) was added dropwise to a stirred solution
of the lactol methyl ether (1.146 g, 4.58 mmol) in dioxane (10
mL). Stirring was continued for 12 h, by which time all the
starting material had been consumed (TLC control, silica, 2:3
EtOAc-hexane). The mixture was neutralized with saturated
aqueous NaHCO3 and the aqueous layer was extracted with
CH2Cl2, washed with water and brine, dried (MgSO4), and
evaporated. Flash chromatography of the residue over silica
gel (2.5 × 18 cm), using 1:4 EtOAc-hexane, gave lactol 16 (737
mg, 68%).
2-Br om o-3,6-d im et h oxy-5-(2-p r op en yl)b en za ld eh yd e
(12). MeI (4.74 g, 2.08 mL, 33.4 mmol) was added dropwise
to a stirred mixture of phenol 11 (1.808 g, 6.696 mmol) and
K2CO3 (4.587 g, 33.37 mmol) in dry DMF (20 mL). The mixture
was warmed to 70 °C, and stirring was continued for 10 h at
this temperature. The solids were filtered off, and the filtrate
was poured into brine (20 mL) and extracted with Et2O. The
combined organic extracts were washed with brine and dried
(MgSO4). Evaporation of the solvent and flash chromatography
of the residue over silica gel (3.5 × 20 cm), using 1:4 EtOAc-
hexane, gave aldehyde 12 (1.857 g, 97%) as a yellowish-white
solid: mp 50 °C; FTIR (CH2Cl2 cast) 1702 cm-1 1H NMR
;
(CDCl3, 400 MHz) δ 3.43 (dt, J ) 6.5, 1.3 Hz, 2 H), 3.80 (s, 3
H), 3.90 (s, 3 H), 5.08-5.16 (m, 2 H), 5.90-6.00 (m, 1 H), 6.95
(s, 1 H), 10.38 (s, 1 H); 13C NMR (CD2Cl2, 100.6 MHz) δ 33.7
(t′), 57.2 (q′), 63.9 (q′), 111.6 (s′), 116.9 (t′), 118.1 (d′), 129.7
(s′), 135.1 (s′), 136.4 (d′), 153.0 (s′), 153.6 (s′), 191.4 (d′); exact
mass m/z calcd for C12H1381BrO3 286.00275, found 286.00154.
1-Br om o-2-(d im eth oxym eth yl)-3,6-d im eth oxy-4-(2-p r o-
p en yl)ben zen e (13). CH(OMe)3 (3.0 mL, 27.4 mmol) was
added dropwise to a stirred solution of aldehyde 12 (1.211 g,
4.248 mmol) in dry MeOH (3 mL) containing TsOH‚H2O (5.0
mg). The mixture was warmed to 70 °C and stirring was
continued for 3.5 h at this temperature. The mixture was
cooled to room temperature and evaporated. Flash chroma-
tography of the residue over silica gel (3 × 18 cm), using 1:4
EtOAc-hexane, gave ketal 13 (1.345 g, 96%) as a colorless
oil: 1H NMR (CD2Cl2, 300 MHz) δ 3.37 (d, J ) 6.3 Hz, 2 H),
3.43 (s, 6 H), 3.71 (s, 3 H), 3.83 (s, 3 H), 5.07-5.16 (m, 2 H),
5.68 (s, 1 H), 5.90-6.04 (m, 1 H), 6.77 (s, 1 H); 13C NMR
(CD2Cl2, 100.6 MHz) δ 34.1 (t′), 56.0 (two overlapping q′), 57.0
(q′), 63.1 (q′), 105.4 (d′), 110.5 (s′), 114.0 (d′), 116.5 (t′), 132.1
(s′), 134.1 (s′), 137.0 (d′), 151.0 (s′), 152.9 (s′); exact mass m/z
calcd for C14H1979BrO4 330.0467138, found 284.00485 (M -
C2H6O).
Meth yl 3,6-Dim eth oxy-2-(d im eth oxym eth yl)-4-(2-p r o-
p en yl)ben zoa te (14). BuLi (1.6 M in hexanes, 3.7 mL, 9.2
mmol) was added dropwise to a stirred and cooled (-78 °C)
solution of bromide 13 (2.024 g, 6.116 mmol) in dry THF (50
mL), and the resultant pale brown solution was stirred at -78
°C for 25 min. MeOC(O)CN (0.85 mL, 10.7 mmol) in THF (0.85
mL) was then added dropwise over 5 min. Stirring was
continued at -78 °C for 20 min, and the cold bath was
removed. The mixture was allowed to warm to 0 °C (ca. 10
min) and was then diluted with water (20 mL) and extracted
with EtOAc. The combined organic extracts were washed with
brine, dried (MgSO4), and evaporated. Flash chromatography
of the pale yellow residue over silica gel (3 × 22 cm), using
1:3 EtOAc-hexane, gave ester 14 (1.673 g, 88%) as a colorless
oil: FTIR (CH2Cl2 cast) 1737 cm-1; 1H NMR (CD2Cl2, 300 MHz)
δ 3.34 (s, 6 H), 3.44 (d, J ) 6 Hz, 2 H), 3.73 (s, 3 H), 3.77 (s,
3 H), 3.80 (s, 3 H), 5.09-5.15 (m, 2 H), 5.47 (s, 1 H), 5.91-
6.02 (m, 1 H), 6.82 (s, 1 H); 13C NMR (CD2Cl2, 100.6 MHz) δ
34.1 (t′), 52.1 (q′), 55.2 (q′), 56.7 (q′), 62.6 (q′), 101.6 (d′), 113.9
(d′), 116.6 (t′), 121.9 (s′), 130.4 (s′), 135.6 (s′), 136.9 (d′), 150.5
(s′), 152.7 (s′), 168.0 (s′); exact mass m/z calcd for C16H22O6
310.14163, found 310.14154.
(E)- a n d (Z)-[3,6-Dim eth oxy-2-(2-m eth oxyeth en yl)-4-(2-
p r op en yl)p h en yl]m eth a n ol (17). (Methoxymethyl)triphen-
ylphosphonium bromide (511.3, 1.483 mmol) was placed in a
long-necked flask and dry THF (2 mL) was added. The white
slurry was stirred and cooled to -78 °C, and (Me3Si)2NK (0.5
M solution in PhMe, 1.7 mL, 0.85 mmol) was added dropwise
over 5 min. The resulting red slurry was stirred at -78 °C for
2 h, and a solution of lactol 16 (100.0 mg, 0.424 mmol) in dry
THF (1 mL plus 1 mL as a rinse) was added dropwise over ca.
5 min. The resulting pale orange solution was stirred for 10 h
without recharging the cold bath. The resulting white slurry
was filtered off using a sintered disk, and washed with EtOAc.
Evaporation of the filtrate and flash chromatography of the
residue over silica gel (2.5 × 15 cm), using 1:4 EtOAc-hexane,
gave the isomeric enol ethers (E)-17 (70.8 mg, 63%) and (Z)-
17 (33.5 mg, 30%) as colorless oils. Compound (E)-17: FTIR
[2-(Dim et h oxym et h yl)-3,6-d im et h oxy-4-(2-p r op en yl)-
p h en yl]m eth a n ol (15). DIBAL (1.0 M in hexanes, 3.9 mL,
3.9 mmol) was added dropwise to a stirred and cooled (-78
°C) solution of ester 14 (596.8 mg, 1.925 mmol) in dry PhMe
(20 mL). The mixture was stirred at -78 °C for 1 h and then
DIBAL (1.0 M in hexanes, 1.9 mL, 1.9 mmol) was added, and
stirring was continued for 1 h (TLC control, silica, 1:4 EtOAc-
hexane). MeOH (3 mL), Na2SO4‚10H2O (2.0 g), Celite (1.0 g)
and water (1 mL) were added successively. The cold bath was
removed and stirring was continued for 30 min. The slurry
was filtered through a short pad of Celite on a sintered disk
and the pad was washed with EtOAc. The filtrate was
evaporated and the residue was dissolved in a small amount
of EtOAc and purified by flash chromatography over silica gel
1
(CH2Cl2 cast) 3462 cm-1; H NMR (CD2Cl2, 400 MHz) δ 2.16
(t, J ) 6.9 Hz, 1 H), 3.40 (dt, J ) 1.4, 6.6 Hz, 2 H), 3.62 (s, 3
H), 3.71 (s, 3 H), 3.84 (s, 3 H), 4.65 (d, J ) 6.9 Hz, 2 H), 5.05-
5.14 (m, 2 H), 5.85 (d, J ) 15 Hz, 1 H), 5.92-6.05 (m, 1 H),
6.61 (s, 1 H), 6.99 (d, J ) 15 Hz, 1 H); 13C NMR (CD2Cl2, 75.5

Synthesis of (()-Puraquinonic Acid
J . Org. Chem., Vol. 66, No. 3, 2001 959
MHz) δ 34.7 (t′), 56.1 (q′), 56.7 (q′), 58.0 (t′), 60.4 (q′), 98.0 (d′),
110.1 (d′), 115.9 (t′), 126.0 (s′), 130.8 (s′), 133.4 (s′), 137.7 (d′),
150.1 (s′), 153.1 (d′), 154.9 (s′); exact mass (HR electrospray)
m/z calcd for C15H20NaO4 (M + Na) 287.12593, found 287.12595.
Compound (Z)-17: FTIR (CH2Cl2 cast) 3462 cm-1; 1H NMR
(CD2Cl2, 300 MHz) δ 2.78 (t, J ) 6.9 Hz, 1 H), 3.40 (dt, J )
1.4, 6.6 Hz, 2 H), 3.63 (s, 3 H), 3.64 (s, 3 H), 3.82 (s, 3 H), 4.54
(d, J ) 6.9 Hz, 2 H), 5.05-5.14 (m, 2 H), 5.41 (d, J ) 6.8 Hz,
1 H), 5.93-6.23 (m, 1 H), 6.25 (d, J ) 6.8 Hz, 1 H), 6.67 (s, 1
H); 13C NMR (CD2Cl2, 100.6 MHz) δ 34.5 (t′), 56.1 (q′), 59.2
(t′), 60.3 (q′), 61.0 (q′), 100.8 (d′), 111.3 (d′), 116.0 (t′), 127.7
(s′), 129.1 (s′), 133.0 (s′), 137.7 (d′), 148.4 (d′), 150.2 (s′), 154.8
(s′); exact mass (HR electrospray) m/z calcd for C15H20NaO4
(M + Na) 287.12593, found 287.12572.
(5 mL) and extracted with Et2O. The organic extracts were
washed with 10% aqueous NaHSO3 and water, dried (MgSO4),
and evaporated. Flash chromatography of the residue over
silica gel (1.8 × 20 cm), using 1:4 EtOAc-hexanes, gave
aldehyde 20 (117 mg, 97%) as a brown solid: mp 144-149 °C;
1
FTIR (CDCl3 cast) 1677 cm-1; H NMR (CDCl3, 400 MHz) δ
2.85 (t, J ) 5.6 Hz, 2 H), 3.83 (s, 3 H), 3.87 (s, 3 H), 3.93 (t, J
) 5.6 Hz, 2 H), 4.74 (s, 2 H), 7.12 (s, 1 H), 10.34 (s, 1 H); 13C
NMR (CDCl3, 100.6 MHz) δ 22.9 (t′), 55.6 (q′), 63.6 (q′), 64.1
(t′), 64.5 (t′), 104.5 (d′), 126.9 (s′), 129.4 (s′), 132.9 (s′), 152.1
(s′), 155.9 (s′), 189.6 (d′); exact mass m/z calcd for C12H14O4
222.0892, found 222.0893.
(5,8-Dim eth oxyisoch r om a n -6-yl)-2-m eth yl-2-p r op en -1-
ol (21). Isopropenylmagnesium bromide (0.5 M in hexanes,
6.22 mL, 3.89 mmol) was added dropwise to a stirred and
cooled (0 °C) solution of aldehyde 20 (576 mg, 2.59 mmol) in
dry Et2O (50 mL). After 30 min, the cold bath was removed
and stirring was continued for 1 h. The mixture was recooled
(0 °C), quenched with saturated aqueous NH4Cl (10 mL), and
taken up in Et2O (50 mL). The aqueous layer was extracted
with Et2O, and the combined organic extracts were washed
with water and brine, dried (MgSO4), and evaporated. Flash
chromatography of the residue over silica gel (2 × 20 cm), using
1:4 EtOAc-hexanes, gave alcohol 21 (590 mg, 86%) as a
colorless oil: FTIR (CDCl3 cast) 3417 cm-1 (br); 1H NMR
(CDCl3, 400 MHz) δ 1.69 (s, 3 H), 2.40 (br s, 1 H), 2.81 (t, J )
5.5 Hz, 2 H), 3.75 (s, 3 H), 3.79 (s, 3 H), 3.84-3.96 (m, 2 H),
4.64-4.72 (m, 2 H), 5.01-5.03 (m, 1 H), 5.21 (s, 1 H), 5.41 (s,
1 H), 6.68 (s, 1 H); 13C NMR (CDCl3, 100.6 MHz) δ 19.5 (q′),
23.5 (d′), 55.4 (q′), 61.2 (q′), 64.3 (t′), 64.4 (t′), 72.3 (d′), 105.9
(d′), 110.9 (t′), 124.5 (s′), 128.3 (s′), 132.4 (s′), 146.8 (s′), 149.4
(s′), 151.8 (s′); exact mass m/z calcd for C15H20O4 264.1362,
found 264.1360.
(5,8-Dim eth oxyisoch r om a n -6-yl)-2-m eth yl-2-p r op en -1-
on e (22). Dess-Martin periodinane (80 mg, 0.19 mmol) was
added to a stirred solution of allylic alcohol 21 (32.6 mg, 0.126
mmol) in dry CH2Cl2 (2.5 mL). After 1 h, the mixture was
diluted with EtOAc (5 mL) and then stirred for 5 min with
saturated aqueous NaHCO3 (2.5 mL) containing Na2S2O3 (250
mg). More water (10 mL) was added, and the aqueous layer
was extracted with EtOAc. The combined extracts were
evaporated. Flash chromatography of the residue over silica
gel (2 × 20 cm), using 1:4 EtOAc-hexanes, gave enone 22 (32.0
mg, 96%) as a white crystalline solid: mp 90-92 °C; FTIR
(CDCl3 cast) 1662 cm-1; 1H NMR (CDCl3, 400 MHz) δ 2.06 (s,
3 H), 2.80 (t, J ) 5.5 Hz, 2 H), 3.65 (s, 3 H), 3.77 (s, 3 H), 3.92
(t, J ) 5.6 Hz, 2 H), 4.71 (s, 2 H), 5.69 (s, 1 H), 5.96 (t, J ) 1.2
Hz, 1 H), 6.57 (s, 1 H); 13C NMR (CDCl3, 100.6 MHz) δ 17.3
(q′), 23.3 (t′), 55.5 (q′), 62.0 (q′), 64.2 (t′), 64.3 (t′), 107.1 (d′),
127.1 (s′), 128.7 (s′), 129.4 (s′), 130.6 (s′), 144.9 (s′), 149.0 (s′),
5,8-Dim eth oxy-6-(2-p r op en yl)isoch r om a n -3-ol (18). Di-
lute hydrochloric acid (0.1 M, 21.9 mL), was added dropwise
to a stirred solution of enol ethers 17 (1.822 g, 6.90 mmol) in
dioxane (70 mL), and the mixture was then heated at 60 °C
for 3 h, by which point all the starting material had reacted
(TLC control, silica, 2:3 EtOAc-hexane). The mixture was
cooled to room temperature and neutralized with saturated
aqueous NaHCO3. The aqueous layer was extracted with
CH2Cl2, washed with water and brine, dried (MgSO4), and
evaporated. Flash chromatography of the residue over silica
gel (2.5 × 20 cm), using 1:2 EtOAc-hexane, gave lactol 18
(1.500 g, 86%) as a colorless oil: FTIR (CH2Cl2 cast) 3404 cm-1
;
1H NMR (CD2Cl2, 400 MHz) δ 2.71 (dd, J ) 11.5, 5.2 Hz, 1 H),
3.00 (dd, J ) 16.6, 3.6 Hz, 1 H), 3.08 (d, J ) 4.5 Hz, 1 H), 3.39
(d, J ) 6.6 Hz, 2 H), 3.65 (s, 3 H), 3.76 (s, 3 H), 4.66 (d, J )
16 Hz, 1 H), 4.85 (d, J ) 16 Hz, 1 H), 5.05-5.14 (m, 2 H),
5.22-5.29 (m, 1 H), 5.93-6.03 (m, 1 H), 6.54 (s, 1 H); 13C NMR
(CD2Cl2, 100.6 MHz) δ 30.0 (t′), 34.4 (t′), 55.7 (q′), 60.7 (t′),
61.0 (q′), 92.4 (d′), 109.4 (d′), 115.8 (t′), 121.7 (s′), 126.2 (s′),
131.5 (s′), 137.8 (d′), 150.0 (s′), 151.6 (s′); exact mass m/z calcd
for C14H18O4 250.12051, found 250.11985.
5,8-Dim eth oxy-6-(2-p r op en yl)isoch r om a n (2). Freshly
distilled BF3‚Et2O (270 µL, 2.12 mmol) was added dropwise
to a stirred and cooled (-78 °C) mixture of Et3SiH14 (freshly
distilled, 462 µL, 2.90 mmol) and lactol 18 (482 mg, 1.93 mmol)
in dry CH2Cl2 (15 mL). After 2 h the cold bath was removed,
stirring was continued for 18 h, and the mixture was quenched
with saturated aqueous NaHCO3 solution (10 mL). The result-
ing mixture was extracted with Et2O, and the combined
organic extracts were dried (MgSO4) and evaporated. Flash
chromatography of the residue over silica gel, using 2:3
EtOAc-hexanes, gave isochroman 2 (423 mg, 93%) as a
colorless oil: 1H NMR (CDCl3, 400 MHz) δ 2.82 (t, J ) 5.6 Hz,
2 H), 3.42 (d, J ) 6.5 Hz, 2 H), 3.70 (s, 3 H), 3.77 (s, 3 H), 3.91
(t, J ) 5.6 Hz, 2 H), 4.70 (s, 2 H), 5.08-5.13 (m, 2 H), 5.94-
6.04 (m, 1 H), 6.51 (s, 1 H); 13C NMR (CDCl3, 100.6 MHz) δ
23.5 (t′), 34.1 (t′), 55.3 (q′), 60.7 (q′), 64.3 (t′), 64.5 (t′), 108.7
(d′), 115.8 (t′), 122.7 (s′), 128.1 (s′), 130.4 (s′), 137.3 (d′), 149.4
(s′), 151.6 (s′); exact mass m/z calcd for C14H18O3 234.1256,
found 234.1249.
(E)-5,8-Dim eth oxy-6-(1-pr open yl)isoch r om an (19). RhCl3‚
3H2O (22.9 mg, 5 mol %) was added to a stirred solution of
olefin 2 (406 mg, 1.73 mmol) in dry 5:1 PhMe-MeOH (28.8 mL).
The mixture was refluxed for 16 h, cooled, and evaporated.
Flash chromatography of the residue over silica, using 1:3
EtOAc-hexanes, gave olefin 19 (393 mg, 97%) as a white
crystalline solid: mp 60-65 °C; 1H NMR (CDCl3, 400 MHz) δ
1.93 (dd, J ) 6.6, 1.6 Hz, 3 H), 2.80 (t, J ) 5.6 Hz, 2 H), 3.69
(s, 3 H), 3.80 (s, 3 H), 3.91 (t, J ) 5.6 Hz, 2 H), 4.70 (s, 2 H),
6.23 (dq, J ) 15.8, 6.6 Hz, 1 H), 6.66 (dd, J ) 15.9, 1.7 Hz, 1
H), 6.75 (s, 1 H); 13C NMR (CDCl3, 100.6 MHz) δ 18.8 (q′), 23.3
(t′), 55.3 (q′), 60.9 (q′), 64.3 (t′), 64.6 (t′), 104.2 (d′), 123.6 (s′),
125.6 (d′), 126.3 (d′), 128.2 (s′), 128.7 (s′), 148.6 (s′), 151.8 (s′);
exact mass m/z calcd for C14H18O3 234.1256, found 234.1254.
5,8-Dim eth oxyisoch r om a n -6-ca r ba ld eh yd e (20). OsO4
(7.0 mg, 5 mol %) was added to a stirred solution of olefins 19
(129 mg, 0.551 mmol) in 5:2:2 CCl4-water-t-BuOH (13.5 mL)
(the starting material was dissolved in CCl4-t-BuOH, and the
water was added last). The mixture was stirred and, after 15
min, NaIO4 (300 mg, 1.38 mmol) was added in one portion.
After a further 1.5 h the suspension was diluted with water
151.0 (s′), 198.4 (s′); exact mass m/z calcd for
C15H18O4
262.1205, found 262.1203.
2,3,7,8-Tet r a h yd r o-5H -4,9-d im et h oxy-2-m et h yl-6-ox-
a cyclop en ta [b]n a p h th a len -1-on e (3). Cold (0 °C) concen-
trated H2SO4 (0.1 mL) was added to stirred enone 22. The
resulting brown solution was stirred for 5 h at 0 °C, diluted
with ice-cold water (10 mL) and extracted with Et2O. The
combined organic extracts were dried (MgSO4) and evaporated.
Flash chromatography of the residue over silica gel (1 × 20
cm), using 1:3 EtOAc-hexanes, gave indanone 3 (26.6 mg,
83%) as a white crystalline solid: mp 123 °C; FTIR (CH2Cl2
cast) 1706 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.25 (d, J ) 7.2
Hz, 3 H), 2.60-2.71 (m, 2 H), 2.81 (t, J ) 5.7 Hz, 2 H), 3.38 (q,
J ) 8.8 Hz, 1 H), 3.80 (s, 3 H), 3.86 (t, J ) 5.8 Hz, 2 H), 3.87
(s, 3 H), 4.81 (s, 2 H); 13C NMR (CDCl3, 100.6 MHz) δ 16.5
(q′), 22.9 (t′), 31.7 (t′), 42.4 (d′), 59.8 (q′), 61.4 (q′), 64.6 (d′),
64.7 (d′), 126.8 (s′), 127.4 (s′), 136.3 (s′), 142.2 (s′), 148.4 (s′),
152.0 (s′), 206.0 (s′); exact mass (HR electrospray) m/z calcd
for C15H18NaO4 (M + Na) 285.11028, found 285.10978.
Meth yl 2,3,7,8-Tetr a h yd r o-5H-4,9-d im eth oxy-2-m eth yl-
1-oxo-6-oxacyclopen ta[b]n aph th alen e-2-car boxylate (23).
BuLi (2.5 M in hexanes, 0.74 mL, 1.85 mmol) was added
dropwise to a stirred and cooled (-78 °C) solution of i-Pr2NH
(278 µL, 1.98 mmol) in THF (5 mL). Stirring was continued
for 30 min, and the resulting LDA solution was added dropwise

960 J . Org. Chem., Vol. 66, No. 3, 2001
Clive et al.
by cannula over ca. 10 min to a stirred and cooled (-78 °C)
solution of indanone 3 (371 mg, 1.42 mmol) in THF (15 mL).
Stirring was continued for 40 min and the resulting lithium
enolate was quenched with neat Mander’s reagent [MeOC(O)-
CN (184 µL, 1.98 mmol)]. After 20 min, the mixture was
transferred to a cold bath at 0 °C, and stirring was continued
for 10 min. The mixture was recooled to -78 °C, and saturated
aqueous NH4Cl (5 mL) was added. The aqueous layer was
extracted with EtOAc, and the combined organic extracts were
washed with water, dried (MgSO4), and evaporated. Flash
chromatography of the residue over silica gel (3 × 15 cm), using
1:4 EtOAc-hexanes, gave ester 23 [269 mg, 59% or 82% after
correction for recovered starting material (103 mg)] as a
colorless liquid: FTIR (CDCl3 cast) 1745, 1709 cm-1; 1H NMR
(CDCl3, 360 MHz) δ 1.59 (s, 3 H), 2.82 (t, J ) 5.7 Hz, 2 H),
2.95 (d, J ) 17 Hz, 1 H), 3.66 (d, J ) 17 Hz, 1 H), 3.69 (s, 3 H),
3.83 (s, 3 H), 3.92 (t, J ) 5.8 Hz, 2 H), 3.94 (s, 3 H), 4.81 (s, 2
H); 13C NMR (CDCl3, 100.6 MHz) δ 21.3 (q′), 22.9 (t′), 36.7
(t′), 52.8 (q′), 56.4 (s′), 60.0 (q′), 61.7 (q′), 64.60 (t′), 64.63 (t′),
125.1 (s′), 128.0 (s′), 137.3 (s′), 141.1 (s′), 148.3 (s′), 152.8 (s′),
ture of chloride 25 (138 mg, 0.405 mmol), Bu3SnH (220 µL,
0.810 mmol) and AIBN (10 mg, 0.061 mmol) in dry PhMe (5
mL) was refluxed for 3 h. The mixture was cooled and applied
to a column of silica gel (1 × 20 cm), which was developed
successively with hexanes, 1:20 EtOAc-hexanes, 1:10 EtOAc-
hexanes and 1:5 EtOAc-hexanes, to give 26 as a colorless oil
contaminated with tin residues. Flash chromatography over
silica gel, using 1:5 EtOAc-hexanes, gave ester 26 (118 mg,
95%) as a colorless oil: FTIR (CHCl3 cast) 1731 cm-1; 1H NMR
(CDCl3, 360 MHz) δ 1.36 (3 H), 2.76 (t, J ) 5.6 Hz, 2 H), 2.87
(d, J ) 15.7 Hz, 2 H), 3.46 (dd, J ) 15.8, 3.0 Hz, 2 H), 3.73-
3.74 (overlapping singlets at δ 3.73, 3.735, 3.74, 9 H in all),
3.83-3.94 (m, 2 H), 4.74 (s, 2 H); 13C NMR (CDCl3, 50.3 MHz)
δ 23.2 (t′), 25.0 (q′), 41.0 (t′), 41.2 (t′), 50.1 (t′), 52.2 (q′), 59.6
(q′), 59.7 (q′), 64.5 (t′), 64.7 (t′), 125.8 (s′), 126.9 (s′), 130.7 (s′),
131.9 (s′), 148.3 (s′), 150.0 (s′), 177.7 (s′); exact mass m/z calcd
for C17H22O5 306.1467, found 306.1464.
Meth yl 6-[2-(Acetyloxy)eth yl]-5-ch lor om eth yl-4,7-d i-
m eth oxy-2-m eth ylin d a n -2-ca r boxyla te (27). ZnCl2 (5.5 mg,
10 mol %) and AcCl (82 µL, 1.16 mmol) were added to a stirred
solution of isochroman 26 (118 mg, 0.39 mmol) in dry CH2Cl2
(6 mL), and the mixture was refluxed (Ar atmosphere) for 6
h. The solvent was then evaporated, and flash chromatography
of the residue over silica gel (1.8 × 20 cm), using 1:4 EtOAc-
hexanes, gave acetate 27 (131 mg, 88%) as a colorless oil: FTIR
(CDCl3 cast) 1736 cm-1; 1H NMR (CDCl3, 360 MHz) δ 1.36 (s,
3 H), 2.05 (s, 3 H), 2.89 (dd, J ) 16.1, 2.8 Hz, 2 H), 3.05 (t, J
) 7.2 Hz, 2 H), 3.47 (d, J ) 10.3 Hz, 1 H), 3.51 (d, J ) 10.5
Hz, 1 H), 3.74 (s, 3 H), 3.78 (s, 3 H), 3.84 (s, 3 H), 4.21 (t, J )
7.6 Hz, 2 H), 4.76 (AB q, ∆νAB ) 25.5 Hz, J ) 10.9 Hz, 2 H);
13C NMR (CDCl3, 50.3 MHz) δ 21.0 (q′), 25.0 (q′), 26.1 (t′), 38.2
(t′), 41.2 (t′), 41.6 (t′), 50.1 (t′), 52.2 (q′), 60.2 (q′), 60.9 (q′), 64.1
(t′), 128.9 (s′), 133.5 (s′), 135.2 (s′), 151.2 (s′), 151.6 (s′), 170.9
(s′), 177.5 (s′) (two signals in this spectrum overlap); exact mass
m/z calcd for C19H2535ClO6 384.1340, found 384.1337.
Meth yl 6-[2-(Acetyloxy)eth yl]-4,7-d im eth oxy-2,5-d i-
m eth ylin d a n -2-ca r boxyla te (28). Bu3SnH (136 µL, 0.51
mmol) and AIBN (7 mg, 15 mol %) were added to a stirred
solution of chloride 27 (97.8 mg, 0.25 mmol) in PhMe (6 mL),
and the mixture was refluxed for 1.5 h. Evaporation of the
solvent and flash chromatography of the residue over silica
gel (1.8 × 12 cm), using 1:9 EtOAc-hexanes, gave acetate 28
contaminated with tin residues. Flash chromatography over
silica gel (1.8 × 12 cm), using 1:9 EtOAc-hexanes, gave acetate
28 (77.3 mg, 87%) as a colorless oil: FTIR (CDCl3 cast) 1735
cm-1; 1H NMR (CDCl3, 360 MHz) δ 1.35 (s, 3 H), 2.05 (s, 3 H),
2.23 (s, 3 H), 2.87 (dd, J ) 15.4, 4.0 Hz, 2 H), 2.96 (dt, J ) 7.7,
2.2 Hz, 2 H), 3.44 (d, J ) 13.0 Hz, 1 H), 3.48 (d, J ) 12.9 Hz,
1 H), 3.69 (s, 3 H), 3.73 (s, 3 H), 3.76 (s, 3 H), 4.14 (t, J ) 7.7
Hz, 2 H); 13C NMR (CDCl3, 50.3 MHz) δ 12.1 (q′), 21.1 (q′),
25.2 (q′), 26.6 (t′), 41.1 (t′), 41.6 (t′), 50.1 (t′), 52.2 (q′), 60.0
(q′), 60.2 (q′), 63.8 (t′), 127.9 (s′), 129.3 (s′), 131.1 (s′), 133.3
(s′), 150.9 (s′), 151.5 (s′), 171.1 (s′), 177.8 (s′); exact mass m/z
calcd for C19H26O6 350.1730, found 350.1727.
6-(2-Hyd r oxyeth yl)-4,7-d im eth oxy-2,5-d im eth ylin d a n -
2-ca r boxylic Acid (29). LiOH‚H2O (28.0 mg, 0.66 mmol) was
added to a stirred solution of ester 28 (15.3 mg, 0.044 mmol)
in 1:1 dioxane-water (4 mL). After 3 h, the mixture was
acidified with hydrochloric acid (1.0 M, 4 mL) and then
extracted with EtOAc. The combined organic extracts were
dried (MgSO4) and evaporated. Flash chromatography of the
residue over silica gel (0.8 × 20 cm), using 1:19 MeOH-
CH2Cl2, gave alcohol 29 (11.6 mg, 90%) as a white solid: FTIR
(CHCl3 cast) 1701 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.41 (s,
3 H), 2.09 (s, 1 H), 2.21 (s, 3 H), 3.18-3.27 [m including dd (J
) 15.8, 3.6 Hz) at δ 3.2 and t (J ) 6.7 Hz) at δ 3.25, 4 H in
all), 3.87 (d, J ) 11.7 Hz, 1 H), 3.92 (d, J ) 11.6 Hz, 1 H), 4.11
(s, 3 H), 3.72-3.80 (m including s at δ 4.17, 5 H in all); 13C
NMR (CDCl3, 50.3 MHz) δ 12.2 (q′), 25.0 (q′), 30.5 (t′), 41.1
(t′), 41.5 (t′), 50.0 (t′), 60.0 (q′), 60.2 (q′), 62.7 (t′), 129.1 (s′),
129.2 (s′), 131.2 (s′), 133.0 (s′), 151.1 (s′), 151.2 (s′), 183.2 (s′);
exact mass m/z calcd for C16H22O5 294.1467, found 294.1467.
2,3,4,7-Tet r a h yd r o-5-(2-h yd r oxyet h yl)-2,6-d im et h yl-
4,7-d ioxo-1H-in d en e-2-ca r boxylic Acid (P u r a qu in on ic
Acid ) (1). An ice-cold solution of (NH4)2Ce(NO3)6 (277 mg,
172.5 (s′), 200.0 (s′); exact mass m/z calcd for
C17H20O6
320.1260, found 320.1253.
Meth yl 2,3,7,8-Tetr ah ydr o-1-h ydr oxy-5H-4,9-dim eth oxy-
2-m e t h yl-6-oxa cyclop e n t a [b]n a p h t h a le n e -2-ca r b oxy-
la te (24). NaBH4 (95 mg, 2.52 mmol) was added in several
portions over 40 min to a stirred and cooled (0 °C) solution of
ketone 23 (269 mg, 0.84 mmol) in dry MeOH (20 mL). After 1
h at 0 °C, water (2 mL) was added, and the resulting cooled
solution was stirred for 30 min, and then extracted with
EtOAc. The combined organic extracts were dried (MgSO4) and
evaporated. Flash chromatography of the residue over silica
gel (2 × 20 cm), using 1:24:75 MeOH-EtOAc-hexanes, gave
alcohols 24 (268 mg, 99%) as a colorless oil: FTIR (CHCl3 cast)
3430, 1729 cm-1 1H NMR (CDCl3, 400 MHz) (mixture of
;
diastereoisomers) δ 1.25 (s, 0.71), 1.35 (s, 2.4 H), 1.59 (s, 0.91
H), 2.60 (d, J ) 7.8 Hz, 0.69 H), 2.68-2.86 (m, 2 H), 2.92 (d,
J ) 15.8 Hz, 0.8 H), 3.37 (d, J ) 15.8 Hz, 0.8 H), 3.73-3.96
(m including three s, 10.5 H in all), 4.73 (s, 2 H), 5.09 (d, J )
4.5 Hz, 0.16 H); 13C NMR (CDCl3, 106 MHz) (mixture of
diastereoisomers) δ 18.3 (q′), 23.2 (t′), 23.3 (t′), 23.4 (q′), 37.2
(t′), 38.7 (t′), 52.3 (q′), 52.4 (q′), 55.2 (t′), 55.4 (t′), 59.8 (q′), 60.6
(q′), 61.4 (q′), 64.6 (t′), 64.7 (t′), 77.8 (d′), 79.3 (d′), 126.7 (s′),
126.9 (s′), 129.0 (s′), 129.5 (s′), 129.7 (s′), 131.2 (s′), 132.3 (s′),
133.0 (s′), 148.4 (s′), 150.7 (s′), 151.3 (s′), 176.9 (s′); exact mass
m/z calcd for C17H22O6 322.1416, found 322.1413.
Meth yl 1-Ch lor o-2,3,7,8-tetr a h yd r o-5H-4,9-d im eth oxy-
2-m e t h yl-6-oxa cyclop e n t a [b]n a p h t h a le n e -2-ca r b oxy-
la te (25). SOCl2 (121 µL, 1.66 mmol) was added dropwise to
a stirred and cooled (0 °C) solution of alcohols 24 (268 mg,
0.832 mmol) and Et3N (232 µL, 1.66 mmol) in dry CH2Cl2 (5
mL). After 30 min the cold bath was removed, and the mixture
was refluxed for 4 h. The mixture was cooled and poured into
water (10 mL). The aqueous layer was extracted with EtOAc,
and the combined organic extracts were washed with water,
dried (MgSO4), and evaporated. Flash chromatography of the
residue over silica gel (1 × 20 cm), using 1:5 EtOAc-hexanes,
gave chlorides 25 [153 mg, 54% or 93% after correction for
recovered starting material (114 mg)] as a colorless liquid:
FTIR (CHCl3 cast) 1737 cm-1 1H NMR (CDCl3, 400 MHz)
;
(mixture of diastereoisomers) δ 1.31 (s, 1.4 H), 1.61 (s, 2.0 H),
2.69-2.90 [m including d (J ) 20.6 Hz) at δ 2.85, 2.46 H in
all], 2.96 (d, J ) 15.6 Hz, 0.59 H), 3.60-3.65 [m including s
and d (J ) 20.6 Hz), 2.3 H in all], 3.75-4.00 [m including
singlets at δ 3.78, 3.81, 3.83, 3.89, 3.90 and d at δ 3.82 (J )
15.6 Hz), 9.4 H in all], 4.68-4.79 (m, 2 H), 5.27 (s, 0.38 H),
5.86 (s, 0.46 H); 13C NMR (CDCl3, 100.6 MHz) (mixture of
diastereoisomers) δ 21.2 (q′), 23.3 (t′), 23.8 (q′), 36.7 (t′), 37.9
(t′), 52.3 (q′), 52.8 (q′), 56.9 (t′), 57.4 (t′), 59.8 (q′), 59.9 (q′),
60.8 (q′), 60.9 (q′), 64.58 (t′), 64.61 (t′), 65.9 (d′), 66.0 (d′), 127.1
(s′), 127.2 (s′), 130.1 (s′), 130.2 (s′), 130.4 (s′), 131.1 (s′), 132.2
(s′), 133.8 (s′), 147.9 (s′), 149.0 (s′), 149.8 (s′), 150.4 (s′), 173.7
(s′), 175.4 (s′); exact mass m/z calcd for C17H2135ClO5 340.1078,
found 340.1080.
Meth yl 2,3,7,8-Tetr a h yd r o-5H-4,9-d im eth oxy-2-m eth yl-
6-oxacyclopen ta[b]n aph th alen e-2-car boxylate (26). A mix-

Synthesis of (()-Puraquinonic Acid
J . Org. Chem., Vol. 66, No. 3, 2001 961
0.506 mmol) in 1:1 MeCN-water (0.8 mL) was added slowly
to a stirred and cooled (0 °C) solution of alcohol 29 (45.8 mg,
0.156 mmol) in 2:1 MeCN-water (0.9 mL) containing pyridine-
2,6-dicarboxylic acid N-oxide (92.7 mg, 0.506 mmol). After 40
min, the mixture was diluted with water (5 mL), and extracted
with CH2Cl2. The combined organic extracts were dried
(MgSO4) and evaporated. Flash chromatography over silica gel
(1.8 × 20 cm), using CH2Cl2, gave quinone 1 (31.7 mg, 77%)
as a brown liquid with 1H and 13C NMR identical, within
experimental error, with the reported1 values.
AnorMED (Langley, BC), and Merck Frosst (Montreal)
for financial support, Stephen Wik for assistance, and
the reviewers for helpful comments.
Su p p or tin g In for m a tion Ava ila ble: NMR spectra of new
compounds for which combustion analytical data were not
obtained and experimental procedures for reactions sum-
marized in Scheme 3. This material is available free of charge
via the Internet at http://pubs.acs.org.
Ack n ow led gm en t . We thank the Natural Sci-
ences and Engineering Research Council of Canada,
J O001523S