Synthesis of optically pure (+)-puraquinonic acid and assignment of absolute configuration to natural (-)-puraquinonic acid. Use of radical cyclization for asymmetric generation of a quaternary center

Article abstract of DOI:10.1021/jo040115b

An asymmetric aldol reaction between aldehyde 31 and imide 32, followed at a later stage by ring-closing metathesis (38 → 40), are key reactions used to make optically pure allylic alcohol 40. Radical cyclization of the derived Stork bromo acetals gives lactol ethers 43, which were degraded to generate a quaternary center carrying a methoxycarboxyl group (44 → 47). Compound 47 was converted into (+)-puraquinonic acid; and comparison with a natural sample established that the configuration of the natural compound is 2R (1).

Full text of DOI:10.1021/jo040115b

Syn th esis of Op tica lly P u r e (+)-P u r a qu in on ic Acid a n d
Assign m en t of Absolu te Con figu r a tion to Na tu r a l
(-)-P u r a qu in on ic Acid . Use of Ra d ica l Cycliza tion for Asym m etr ic
Gen er a tion of a Qu a ter n a r y Cen ter
Derrick L. J . Clive,* Maolin Yu, and Mousumi Sannigrahi
Chemistry Department, University of Alberta, Edmonton, Alberta, Canada T6G 2G2
derrick.clive@ualberta.ca
Received J anuary 23, 2004
An asymmetric aldol reaction between aldehyde 31 and imide 32, followed at a later stage by ring-
closing metathesis (38 f 40), are key reactions used to make optically pure allylic alcohol 40. Radical
cyclization of the derived Stork bromo acetals gives lactol ethers 43, which were degraded to generate
a quaternary center carrying a methoxycarboxyl group (44 f 47). Compound 47 was converted
into (+)-puraquinonic acid; and comparison with a natural sample established that the configuration
of the natural compound is 2R (1).
In tr od u ction
Discu ssion
Puraquinonic acid (1)1 is a norilludalane2 fungal me-
tabolite with the property of inducing differentiation in
HL-60 cells (human promyelocytic leukemia). This is an
important property because there is evidence3 that
induction of cell differentiation suppresses cell prolifera-
tion. Puraquinonic acid may, therefore, serve as a lead
compound in the design of drugs to treat leukemia. The
absolute configuration was established by an asymmetric
synthesis reported from this laboratory;4 the present
paper gives full details of that work, as well as of model
studies on the method for constructing the quaternary
center. This method is probably a general one. The
structurally related compounds 2 (deliquinone) and 3
(2,9-epoxydeliquinone) have been isolated5 from injured
fruit bodies of the fungus Russula delica, but no evalu-
ation of the biological properties of these metabolites has
been reported.
The main obvious challenge posed by an asymmetric
synthesis6,7 of puraquinonic acid is construction of the
quaternary8 center C(2); this is a complex problem
because the asymmetry is due to structural differences
far removed from C(2) (Figure 1). Our first approach was
based on an attempt at asymmetric acylation. To this
end, indanone 4 was converted into its SAMP hydrazone
6 (Scheme 1) and subjected first to alkylation9 (LDA, MeI)
and then to conditions10 for acylation (n-BuLi, t-BuOK,
MeOC(O)CN). Although this sequence did indeed serve
to introduce both a methyl and MeO2C group, the prod-
uct 7 was a 1:1 mixture of both possible diastereoiso-
mers. We did not examine other potential methods for
asymmetric acylation11 (or alkylation8); instead, we de-
cided to generate the required quaternary center by
radical cyclization, along the lines of Scheme 2. This
scheme summarizes several experiments done with ra-
cemic materials.
Luche reduction of the simple indenone 8,12 which
served us as a test model, gave the expected racemic
(1) Becker, U.; Erkel, G.; Anke, T.; Sterner, O. Nat. Prod. Lett. 1997,
9, 229-236.
(2) Illudalanes have the skeleton (i): (a) Ayer, W. A.; Browne, L.
M. Tetrahedron 1981, 37, 2199-2248. (b) Arnone, A.; Cardillo, R.; Di
Modugno, V.; Nasini, G. J . Chem. Soc., Perkin Trans. 1 1989, 1995-
2000.
(6) Synthesis of racemic puraquinonic acid: (a) Clive, D. L. J .;
Sannigrahi, M.; Hisaindee, S. J . Org. Chem. 2001, 66, 954-961. (b)
Hisaindee, S.; Clive, D. L. J . Tetrahedron Lett. 2001, 42, 2253-2255.
(7) Synthesis of (()-deliquinone and (()-puraquinonic acid ethyl
ester: Kraus, G. A.; Choudhury, P. K. Tetrahedron Lett. 2001, 42,
6649-6650.
(8) Construction of quaternary centers: (a) Martin, S. F. Tetrahe-
dron 1980, 36, 419-460. (b) Fuji, K. Chem. Rev. 1993, 93, 2037-2066.
(c) Corey, E. J .; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37,
389-401. (d) Christoffers, J .; Mann, A. Angew. Chem., Int. Ed. 2001,
40, 4591-4597. (e) Hayashi, T.; Tang, J .; Kato, K. Org. Lett. 1999, 1,
1487-1489.
(3) (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.
(9) J ob, A.; J aneck, C. F.; Bettray, W.; Peters, R.; Enders, D.
Tetrahedron 2002, 58, 2253-2329.
(10) Enders, D.; Zamponi, A.; Raabe, G. Synlett 1992, 897-900.
(11) Compare: Mermerian, A. H.; Fu, G. C. J . Am. Chem. Soc. 2003,
125, 4050-4051 and references therein.
(12) (a) Floyd, M. B.; Allen, G. R., J r. J . Org. Chem. 1970, 35, 2647-
2653. (b) Galatsis, P.; Manwell, J . J .; Blackwell, J . M. Can. J . Chem.
1994, 72, 1656-1659.
(4) Clive, D. L. J .; Yu, M. J . Chem. Soc., Chem. Commun. 2002,
2380-2381.
(5) Clericuzio, M.; Han, F.; Pan, F.; Pang, Z.; Sterner, O. Acta Chem.
Scand. 1998, 52, 1333-1337.
10.1021/jo040115b CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/13/2004
4116
J . Org. Chem. 2004, 69, 4116-4125

Synthesis of Optically Pure (+)-Puraquinonic Acid
SCHEME 3
chemistry being controlled by the stereochemistry of the
starting alcohol. We decided not take this model sequence
any further, because we were confidant that the subse-
quent stepsshydrolysis to 12, dehydration to 13, and
degradation of 13, 14, and 15 to give the (achiral) acid
16swould be straightforward, as indeed they later proved
to be when applied to appropriately substituted com-
pounds.
F IGURE 1.
SCHEME 1
Application of the model sequence of Scheme 2 to the
actual asymmetric synthesis of puraquinonic acid de-
pends, of course, on the ability to generate an optically
pure alcohol corresponding to 9, but carrying appropriate
substituents on the aromatic ring. However, attempts to
reduce enone 17 (which we regarded as a suitable16
starting ketone) with (S)-CBS-BH3‚SMe218 or with LiAlH-
(O-menthyl)319 were unsuccessful,20 and we were prompted
to develop a different route to the required optically active
allylic alcohol. This route, which leads to allylic alcohol
40 (see Scheme 5), is based on an asymmetric aldol
reaction to set the hyrdoxyl stereochemistry (see Scheme
5, 31 f 33), followed by ring-closing metathesis to
generate the double bond of the allylic alcohol (Scheme
5, 38 f 40).
SCHEME 2 a
Aldehyde 31, required for the aldol step, was made as
summarized in Scheme 4. The known phenolic aldehyde
2021 was allylated in the standard way (NaH, DMF, allyl
bromide, 79%), and then Claisen rearrangement (ca. 200
°C, 66%) produced the expected phenol 22. This was
converted (83%) into quinone acetal 23 by oxidation25
(16) The bromine should provide an opportunity for attachment of
vinyl group that would serve as a precursor for the required
a
a
CH2CH2OH substituent. Compound ii, made by methylation (MeI,
K2CO3, DMF, 70 °C, 5 h, 64%) of the corresponding bisphenol,17 was
brominated (ii f iii, Fe, Br2, CCl4, 68%), and treatment with DBU
then gave 17:
Reagents and conditions: (a) LiBH4, CeCl3‚7H2O, MeOH, 99%;
(b) ethyl vinyl ether, -20 °C, NBS, 90%; (c) Bu3SnH and AIBN
(added in one lot), PhH, 80 °C, 70%, or Bu3SnCl, AIBN, NaBCNH3,
t-BuOH, 80 °C, 68%.
alcohol 9, and this was converted into the derived Stork
bromo acetals13 (10) by reaction with ethyl vinyl ether
in the presence of NBS. Radical cyclization then gave
the lactol ethyl ethers 11. Unlike most radical cycliza-
tions, this one worked best (70%) when the stannane and
initiator were added in one lot, rather than by slow
addition. A similar yield (68%) was obtained using
Bu3SnCl, AIBN, and NaCNBH3 in refluxing t-BuOH.14
Because the cyclization 10 f 11 is a 5-exo closure onto a
double bond contained in a five-membered ring, it must
proceed with the stereochemical outcome shown.13b,15 The
formation of 11 established that a quaternary center
could indeed be generated efficiently, with the stereo-
(17) Kundiger, D. G.; Ovist, E. B. W. U.S. Patent 2,881,218.
(18) Corey, E. J .; Helal, C. J . Angew. Chem., Int. Ed. 1998, 37, 1986-
2012.
(19) Cf. Andrisano, R.; Angeloni, A. S.; Marzocchi, S. Tetrahedron
1973, 29, 913-916.
(20) With (S)-CBS-BH3‚SMe2 the yield of allylic alcohol (of unestab-
lished chirality) was low (13%) and formation of the corresponding
saturated ketone was a major pathway (34%). With LiAlH(O-menthyl)3,
the allylic alcohol (69%) was racemic.
(21) Made from 2,5-dimethylphenol by the method of ref 22, except
that the formyl group was best generated by benzylic bromination,23
followed by oxidation with DMSO (see ref 24 and Supporting Informa-
tion).
(13) (a) Stork, G.; Mook, R., J r.; Biller, S. A.; Rychnovsky, S. D. J .
Am. Chem. Soc. 1983, 105, 3741-3742. (b) Stork, G.; Kahn, M. J . Am.
Chem. Soc. 1985, 107, 500-501.
(22) Gore, M. P.; Gould, S. J .; Weller, D. D. J . Org. Chem. 1992, 57,
2774-2783.
(23) Leed, A. R.; Boettger, S. D.; Ganem, B. J . Org. Chem. 1980,
45, 1098-1106.
(14) Stork, G.; Sher, P. M.; Chen, H.-L. J . Am. Chem. Soc. 1986,
108, 6384-6385.
(24) Compare: (a) Helms, A.; Heiler, D.; McLendon, G. J . Am. Chem.
Soc. 1992, 114, 6227-6238. (b) Epstein, W. W.; Sweat, F. W. Chem.
Rev. 1967, 67, 7, 247-260.
(15) Clive, D. L. J .; Cheshire, D. R.; Set, L. J . Chem. Soc., Chem.
Commun. 1987, 353-355.
J . Org. Chem, Vol. 69, No. 12, 2004 4117

Clive et al.
SCHEME 4 a
SCHEME 5 a
a
Reagents and conditions: (a) Bu2BOSO2CF3, i-Pr2NEt, CH2Cl2,
-78 to 25 °C, 87%; (b) t-BuMe2SiOSO2CF3, 2,6-lutidine, CH2Cl2,
1 h, 95%; (c) BnOLi, THF, 0 °C, 6 h, 89%; (d) DIBAL-H, CH2Cl2,
0 °C, 1 h, 89%; (e) o-(NO2)C6H4SeCN, Bu3P, THF, 12 h; (f) 30%
H2O2, THF, 5 h, 81% from 36; (g) Bu4NF, THF, 36 h, 95%; (h)
tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihy-
droimidazol-2-yliden][benzylidene]ruthenium(IV) dichloride (37),
CH2Cl2, reflux, 20 h, 88%.
a
Reagents and conditions: (a) NaH, allyl bromide, DMF, 2 h,
79%; (b) degassed trans Decalin, reflux, 7 h, 66%; (c) PhI(OAc)2,
MeOH, 12 h, 83%; (d) Zn powder, AcOH, 7 h, 70%; (e) MeI, K2CO3,
DMF, 12 h, 92%; (f) (MeO)3CH, TsOH‚H2O, MeOH, reflux, 12 h,
97%; (g) OsO4 (catalytic), NaIO4, 5:2:2 CCl4-water-t-BuOH, 1.5
h, 95%; (h) NaBH4, MeOH, 0 °C, 1.5 h, 95%; (i) NaH, BnBr, THF,
12 h, 92%; (j) 1:1 acetone-water, Amberlite IR-120, 12 h, 95%;
(k) Bu3(CH2dCH)Sn, CuI, Pd(PPh3)4, PhMe, reflux, 40 h, 66%.
the condensation product 33 in high yield (87%). We used
a boron-mediated aldol process because of its generally
excellent stereoselectivity, and in the event, we did not
detect any other stereoisomer. The hydroxyl was pro-
tected by silylation (33 f 34, t-BuMe2SiOSO2CF3, 2,6-
lutidine, 95%), and the chiral auxiliary was removed by
treatment with BnOLi27 (95%). The resulting ester 35
was then reduced to alcohol 36 (DIBAL-H, CH2Cl2, 89%).
At this point, conversion to olefin 37 was achieved by
replacing the hydroxyl with an o-nitrophenylseleno group
[o-(NO2)C6H4SeCN, Bu3P, THF]29 and oxidizing the re-
sulting selenide (H2O2, THF, 81% overall). Treatment of
37 with Bu4NF in THF effected desilylation (37 f 38,
95%), and the stage was now set for the crucial ring-
closing metathesis that would form the five-membered
ring of puraquinonic acid. Heating alcohol 38 with
tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-
4,5-dihydroimidazol-2-ylidene][benzylidene]ruthenium-
(IV) dichloride30 (39) in CH2Cl2 gave the optically active
allylic alcohol 40 in 88% yield. The ring-closing meta-
thesis is sensitive to steric factors, since attempts to effect
the reaction with the silicon protecting group in place
were unsuccessful.31 Examination of alcohol 40 by HPLC,
using a chiral column, and comparison with a racemic
sample32 showed that 40 had ee >98%.
with PhI(OAc)2 in MeOH, and the benzene ring was then
regenerated by reduction with Zn dust26 (23 f 24, 70%).
Finally, the remaining phenolic hydroxyl was protected
by O-methylation (MeI, K2CO3, DMF, 92%), bringing the
work as far as aldehyde 25.
At this point it was necessary to replace the bromine
by a vinyl group and to cleave the pendant double bond
oxidatively. To this end, aldehyde 25 was protected as
its dimethyl acetal [25 f 26, (MeO)3CH, MeOH, TsOH‚
H2O, 97%], and the pendant double bond was cleaved
with the OsO4-NaIO4 combination (26 f 27, 95%);
reduction (NaBH4) then gave an alcohol (27 f 28, 95%),
which was protected as its benzyl ether (28 f 29; NaH,
BnBr, 92%). Acid-catalyzed hydrolysis of the acetal
function (29 f 30, 95%) and Stille coupling with tribu-
tylvinylstannane in the presence of (Ph3P)4Pd served to
introduce the required vinyl group (30 f 31, 66%),
bringing us to the point at which we were ready to try
the asymmetric aldol reaction.
Condensation of 31 with (S)-4-isopropyl-3-propionyl-
2-oxazolidinone (32),27 mediated by Bu2BOSO2CF3,28 gave
(28) (a) Evans, D. A.; Bartroli, J .; Shih, T. L. J . Am. Chem. Soc.
1981, 103, 2127-2129. (b) Entwistle, D. A.; J ordan, S. I.; Montgomery,
J .; Pattenden, G. Synthesis 1998, 603-612.
(29) Grieco, P. A.; Gilman, S.; Nishizawa, M. J . Org. Chem. 1976,
41, 1485-1486.
(30) Lee, C. W.; Grubbs, R. H. Org. Lett. 2000, 2, 2145-2147.
(31) We tried Schrock’s catalyst (2,6-diisopropylphenylimidoneo-
phylidene molybdenum(VI) bis(hexafluoro)-tert-butoxide) and Grubbs’
first generation catalyst (bis(tricyclohexylphosphine)benzylidene ru-
thenium(IV) dichloride).
(25) (a) Pelter, A.; Elgendy, S. M. A. J . Chem. Soc., Perkin Trans. 1
1993, 1891-1896. (b) Camps, P.; Gonza´lez, A.; Mun˜oz-Torreo, D.;
Simon, M.; Zu´n˜iga, A.; Martins, M. A.; Font-Bardia, M.; Solans, X.
Tetrahedron 2000, 56, 8141-8151.
(26) Compare: Iguchi, M.; Nishiyama, A.; Etoh, H.; Okamoto, K.;
Yamamura, S.; Kato, Y. Chem. Pharm. Bull. 1986, 34, 4910-4915.
(27) Evans, D. A.; Dow, R. L.; Shih, T. L.; Takacs, J . M.; Zahler, R.
J . Am. Chem. Soc. 1990, 112, 5290-5313.
4118 J . Org. Chem., Vol. 69, No. 12, 2004

Synthesis of Optically Pure (+)-Puraquinonic Acid
SCHEME 6 a
The absolute configuration of 40 is, of course, set by
the configuration of the aldol product 33. We initially4
assigned the anti stereochemistry (Ha and Me at C(2′) in
33 interchanged) because the coupling constant for the
C(1′)Ha signal (J ab ) 9.3 Hz) suggested33,34 such a
relationship for the substituents at C(1′) and C(2′). This
interpretation assumes the extended conformation shown
for 33, and we later sought additional evidence for the
assignment. Attempts to obtain a crystalline derivative
eventually led us to hydrogenate 35 (Pd/C, H2). The
resulting alcohol 41 is crystalline, and X-ray analysis
revealed that the aldol reaction actually gives the normal
syn product shown (33). The C(2′) stereochemistry is
destroyed in a later step (36 f 37), but the X-ray
determination serves both to clarify the outcome of the
aldol condensation and confirm the absolute configura-
tion at the hydroxyl-bearing carbon. The alcohol was
converted into the Stork bromo acetals (40 f 42, 91%)
by adding bromine to ethyl vinyl ether, followed by
addition of a mixture of the alcohol and 2,6-lutidine. This
procedure generally works well for making bromo ac-
etals.35 The acetals were then subjected to free radical
cyclization (42 f 43, 85%), by adding Bu3SnH and AIBN
in one lot, conditions that had been established in the
model study of Scheme 2. The next task was to degrade
the newly formed heterocycle so as to eventually release
both the desired carboxyl and the original hydroxyl; the
latter, having served its purpose, would then be removed.
Acid hydrolysis of the lactol ethyl ethers 43 replaced the
ethoxy group by a hydroxyl (43 f 44, 91%), and mesy-
lation in refluxing THF then gave the required elimina-
tion product 45 directly (75%). The stage was now set
for cleavage of the heterocyclic ring. This was best done
with OsO4 and NaIO4 rather than with O3 and gave
aldehyde formate 46. The aldehyde group was oxidized
directly under standard conditions36 to a carboxyl group,
which was immediately trapped as its methyl ester.
Finally, methanolysis (MeOH, K2CO3) served to hydro-
lyze the formyl ester at C(1) (45 f 46 f 47, 54% overall).
The resulting hydroxyl group was removed by Barton
deoxygenation6b,37 via the thiocarbonylimidazolide (47 f
48, 96%; 48 f 49, 77%). The benzyl group was now
removed by hydrogenolysis (49 f 50, Pd-C, H2, 96%),
and the ester was hydrolyzed (LiOH‚H2O, THF, 95%),
bringing the work as far as the bismethyl ether 51.
a
Reagents and conditions: (a) ethyl vinyl ether, Br2, CH2Cl2,
2,6-lutidine, 20 h, 91%; (b) Bu3SnH and AIBN (both added in one
portion), PhMe, reflux, 1.5 h, 85%; (c) 1:4 AcOH-water, THF,
reflux, 12 h, 91%; (d) MsCl, Et3N, THF, 2 h, then reflux, 1 h,
75%; (e) OsO4 (catalytic), NaIO4, 5:2:2 CCl4-water-t-BuOH,
9 h; (f) NaClO2, 2-methyl-2-butene, NaH2PO4, t-BuOH, 3 h;
(g) CH2N2, Et2O, then MeOH, K2CO3, 54% from 45; (h) Im2CS,
DMAP, CH2Cl2, reflux, 19 h, ca. 96%; (i) Bu3SnH, AIBN, PhMe,
reflux, 1.5 h, 73-77%; (j) H2 (balloon), Pd-C, MeOH, 30 min,
96%; (k) LiOH‚H2O, 1:1 dioxane-water, 3 h, 95%; (l) Ce(NH4)2-
(NO3)6, 2,6-pyridinedicarboxylic acid N-oxide, 2:1 MeCN-water,
5 h, 81%.
Generation of the quinone was initially troublesome, but
we quickly found that (NH4)2Ce(NO2)6 in the presence of
2,6-pyridinedicarboxylic acid N-oxide38 is an effective
reagent combination, which liberates (+)-puraquinonic
acid (52) in 81% yield. The presence of the pyridine di-
acid is essential; without it there is hardly any oxidation.
(32) Made by reduction (LiBH4, CeCl3‚7H2O; 90%) of the ketone
corresponding to 40. We thank S. Hisaindee of this laboratory for a
sample of the ketone.
(33) Cf. Danda, H.; Hansen, M. M.; Heathcock, C. H. J . Org. Chem.
1990, 55, 173-181.
(34) Heathcock, C. H. In Asymmetric Synthesis; Morrison, J . D., Ed.;
Academic Press: Orlando, FL, 1984; Vol. 3, pp 111-212.
(35) For another example where this method was the best of several
we tried, see: Clive, D. L. J .; Huang, X. Tetrahedron 2002, 58, 10243-
10250.
(36) Bal, B. S.; Childers, W. E., J r.; Pinnick, H. W. Tetrahedron 1981,
37, 2091-2096.
(37) Compare: Miyazaki, T.; Sato, H.; Sakakibara, T.; Kajihara, Y.
J . Am. Chem. Soc. 2000, 122, 5678-5694.
Our synthetic material has [R]22 +3.2 (c 0.3 CHCl3),
D
[R]22 +3.1 (c 0.7 CH2Cl2), values close to that reported
D
([R]22 +1 (c 1.0 CHCl3)]. However, HPLC comparison
D
(CHIRACEL OD-RH) with an authentic sample showed
that the synthetic and natural compounds were enan-
tiomeric. Consequently, we remeasured the specific rota-
tion of the natural compound and found that the value
(38) Syper, L.; Kloc, K.; Mlochowski, J .; Szulc, Z. Synthesis 1979,
521-522.
J . Org. Chem, Vol. 69, No. 12, 2004 4119

Clive et al.
3-Allyl-6-br om o-2-h yd r oxy-5-m eth oxy-4-m eth ylben za l-
d eh yd e (24). Zinc powder (2.30 g, 35.4 mmol) was added to a
stirred solution of ketal 23 (3.75 g, 11.8 mmol) in AcOH (80
mL), and the mixture was stirred for 7 h. The excess of Zn
powder was removed by gravity filtration, and the mixture was
diluted with water (20 mL) and then extracted with EtOAc
(3 × 100 mL). The combined organic extracts were dried
(Na2SO4) and evaporated. Flash chromatography of the resi-
due over silica gel (3 × 21 cm), using 1:20 EtOAc-hexane,
gave phenol 24 (2.36 g, 70%) as yellow oil: FTIR (CH2Cl2
is actually -2.2 [c 0.55, CHCl3]; therefore we assign the
2R absolute configuration to natural (-)-puraquinonic
acid, as shown in 1.
Con clu sion
The present synthesis illustrates how sequential use
of an asymmetric aldol reaction, ring-closing metathesis,
and radical cyclization can be used to construct a
quaternary asymmetric center whose stereochemistry is
determined by the outcome of the initial aldol process.
In the case of puraquinonic acid, the asymmetry of C(2)
is due to differences far removed from that site, and the
present approach is probably a general one for handling
such situations. Our work has also established the
absolute configuration of puraquinonic acid.
1
cast) 1638 cm-1; H NMR (CDCl3, 500 MHz) δ 2.32 (s, 3 H),
3.40-3.42 (m, 2 H), 3.74 (s, 3 H), 4.91-5.01 (m, 2 H), 5.82-
5.90 (m, 1 H), 10.26 (s, 1 H), 12.24 (s, 1 H); 13C NMR (CDCl3,
100 MHz) δ 13.6 (q), 29.7 (t), 60.5 (q), 115.4 (t), 115.5 (s), 119.1
(s), 127.7 (s), 134.3 (d), 142.7 (s), 148.5 (s), 158.7 (s), 197.7 (d);
exact mass m/z calcd for
C
12H1379BrO3 284.00479, found
284.00464.
3-Allyl-6-b r om o-2,5-d im e t h oxy-4-m e t h ylb e n za ld e -
h yd e (25). MeI (1.06 mL, 17.0 mmol) was added dropwise over
ca. 5 min to a stirred mixture of phenol 24 (483 mg, 1.70 mmol)
and K2CO3 (2.35 g, 17.0 mmol) in dry DMF (40 mL). Stirring
was continued overnight, and the solids were then filtered off.
The filtrate was poured into brine (20 mL) and extracted with
CH2Cl2 (3 × 30 mL). The combined organic extracts were
washed with water (2 × 10 mL) and brine (10 mL), dried
(Na2SO4), and evaporated. Flash chromatography of the
residue over silica gel (2 × 20 cm), using 1:20 EtOAc-hexane,
gave aldehyde 25 (464.5 mg, 92%) as a colorless oil: FTIR
Exp er im en ta l Section
2-Allyloxy-6-br om o-4-m eth ylben za ld eh yd e (21). A solu-
tion of aldehyde 2021,22 (0.783 g, 3.66 mmol) in dry DMF (3
mL) was added dropwise over ca. 5 min to a stirred and cooled
(0 °C) slurry of NaH (60% in mineral oil, 182.8 mg, 4.57 mmol)
in dry DMF (10 mL). The cool bath was removed, and stirring
was continued for 2 h. The solution was recooled to 0 °C, and
allyl bromide (0.628 mL, 7.3 mmol) was added dropwise over
ca. 5 min. The cold bath was removed, and stirring was
continued for 7 h. The mixture was poured into brine (10 mL)
and extracted with Et2O (4 × 20 mL). The combined organic
extracts were washed with KOH (10%, 2 × 5 mL) and brine
(10 mL), dried (Na2SO4), and evaporated. Flash chromatog-
raphy of the residue over silica gel (3 × 20 cm), using 1:20
EtOAc-hexane, gave allyl ether 21 (0.733 g, 79%) as white
1
(CH2Cl2 cast) 1738, 1699 cm-1; H NMR (CDCl3, 400 MHz) δ
2.30 (s, 3 H), 3.41-3.43 (m, 2 H), 3.76 (s, 3 H), 3.77 (s, 3 H),
4.84-4.89 (m, 1 H), 5.02-5.05 (m, 1 H), 5.84-5.94 (m, 1 H),
10.31 (s, 1 H); 13C NMR (CDCl3, 100 MHz), δ 13.6 (q), 30.5 (t),
60.4 (q), 64.0 (q), 115.8 (t), 118.1 (s), 126.5 (s), 133.6 (s), 135.0
(d), 139.4 (s), 152.4 (s), 156.8 (s), 190.7 (d); exact mass m/z
calcd for C13H15O379Br 298.02045, found 298.02097.
1
needles: mp 59 °C; FTIR (acetone cast) 1690 cm-1; H NMR
1-Allyl-4-br om o-3-d im eth oxym eth yl-2,5-d im eth oxy-6-
m eth ylben zen e (26). HC(OMe)3 (5 mL, 45.75 mmol) was
added dropwise over ca. 5 min to a stirred solution of aldehyde
25 (464.5 mg, 1.56 mmol) in dry MeOH (20 mL) containing
TsOH‚H2O (29.6 mg, 0.156 mmol). The mixture was refluxed
overnight, cooled, filtered, and evaporated. Flash chromatog-
raphy of the residue over silica gel (3 × 20 cm), using 1:20
EtOAc-hexane, gave acetal 26 (520.5 mg, 97%) as a colorless
oil: FTIR (CH2Cl2 cast) 1637 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 2.22 (s, 3 H), 3.38-3.42 (m, 2 H), 3.44 (s, 6 H), 3.719 (s, 3
H), 3.722 (s, 3 H), 4.82-4.87 (m, 1 H), 4.99-5.02 (m, 1 H),
5.64 (s, 3 H), 5.86-5.96 (m, 1 H); 13C NMR (CDCl3, 100 MHz)
δ 13.0 (q), 31.0 (t), 55.9 (q), 60.2 (q), 63.4 (q), 105.2 (d), 115.4
(t), 116.2 (s), 128.8 (s), 132.6 (s), 133.5 (s), 135.6 (d), 152.2 (s),
154.2 (s); exact mass m/z calcd for C15H21O479Br 344.06232,
found 344.06215.
(CDCl3, 400 MHz) δ 2.29 (s, 3 H), 4.56 (d, J ) 5.2 Hz, 2 H),
5.27 (d, J ) 12.0 Hz, 1 H), 5.43 (d, J ) 18.0 Hz, 1 H), 5.94-
6.04 (m, 1 H), 6.68 (s, 1 H), 7.00 (s, 1 H), 10.34 (s, 1 H); 13C
NMR (CDCl3, 100 MHz) δ 21.7 (q), 69.5 (t), 113.1 (d), 118.0
(t), 121.0 (s), 124.3 (s), 127.4 (d), 132.0 (d), 146.3 (s), 161.1 (s),
189.5 (d); exact mass m/z calcd for C11H1179BrO2 253.99425,
found 253.99434.
3-Allyl-6-br om o-2-h yd r oxy-4-m eth ylben za ld eh yde (22).
trans-Decalin was degassed by several freeze-thaw cycles (dry
ice/acetone and oil-pump vacuum). A solution of allyl ether 21
(197.9 mg, 0.778 mmol) in degassed Decalin (8 mL) was
refluxed under N2 for 7 h and then cooled to room temperature.
Flash chromatography of the mixture (without evaporation of
the solvent) over silica gel (1.5 × 20 cm), using 1:40 EtOAc-
hexane, gave phenol 22 (130.2 mg, 66%) as a slightly yellow
oil: FTIR (CH2Cl2 cast) 1639 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 2.26 (s, 3 H), 3.35-3.37 (m, 2 H), 4.88-4.99 (m, 2 H), 5.76-
5.92 (m, 1 H), 6.94 (s, 1 H), 10.17 (s, 1 H), 12.31 (s, 1 H); 13C
NMR (CDCl3, 125 MHz) δ 19.9 (q), 29.3 (t), 115.2 (t), 115.7
(s), 124.7 (s), 126.2 (d), 126.7 (s), 134.3 (d), 148.3 (s), 162.0 (s),
197.4 (d); exact mass m/z calcd for C11H1179BrO2 253.99425,
found 253.99411.
(4-Br om o-3-d im et h oxym et h yl-2,5-d im et h oxy-6-m et h -
ylp h en yl)a ceta ld eh yd e (27). OsO4 (1.4 mg, 5% mol) was
added to a stirred solution of acetal 26 (38 mg, 0.11 mmol) in
5:2:2 CCl4-H2O-t-BuOH (5 mL) (the starting material was
dissolved in CCl4-t-BuOH, and H2O was added last). After
30 min, NaIO4 (59 mg, 0.276 mmol) was added in one portion.
Stirring was continued for 1.5 h, and the suspension was
diluted with H2O (3 mL) and extracted with CH2Cl2 (3 × 10
mL). The combined organic extracts were washed with 10%
aqueous NaHSO3 (8 mL) and water (8 mL), dried (Na2SO4),
and evaporated. Flash chromatography of the residue over
silica gel (1.5 × 15 cm), using 7:40 EtOAc-hexane, gave
aldehyde 27 (36.5 mg, 95%) as a colorless oil: FTIR (CH2Cl2
5-Allyl-2-br om o-3,3-d im eth oxy-4-m eth yl-6-oxo-1,4-cy-
cloh exa d ien eca r b a ld eh yd e (23). A solution of PhI(OAc)2
(362 mg, 1.126 mmol) in MeOH (5 mL) was added dropwise
over 30 min to a stirred solution of phenol 22 (130 mg, 0.512
mmol) in MeOH (5 mL), and stirring was continued overnight.
Evaporation of the solvent and flash chromatography of the
yellow residue over silica gel (2 × 20 cm), using 7:40 EtOAc-
hexane, gave ketal 23 (133 mg, 83%) as a yellow oil: FTIR
1
cast) 1725 cm-1; H NMR (CDCl3, 400 MHz) δ 2.18 (s, 3 H),
1
(CH2Cl2 cast) 1737, 1710 cm-1; H NMR (CDCl3, 300 MHz) δ
3.45 (s, 6 H), 3.67 (s 3 H), 3.72-3.73 (m, 5 H), 5.63 (s, 1 H),
9.68 (s, 1 H); 13C NMR (CDCl3, 100 MHz) δ 13.7 (q), 42.5 (t),
56.0 (q), 60.3 (q), 62.9 (q), 105.4 (d), 118.0 (s), 126.7 (s), 129.3
(s), 133.6 (s), 152.3 (s), 154.4 (s), 198.3 (d); exact mass m/z calcd
for C14H19O579Br 346.04160, found 346.04108.
1.20 (s, 3 H), 3.07 (s, 6 H), 3.21 (d, J ) 6.2 Hz, 2 H), 4.99-5.06
(m, 2 H), 5.68-5.82 (m, 1 H), 10.07 (s, 1 H); 13C NMR (CDCl3,
100 MHz) δ 13.4 (q), 29.5 (t), 51.1 (q), 97.3 (s), 116.2 (t), 133.6
(d), 137.2 (s), 138.4 (s), 150.6 (s), 150.9 (s), 180.2 (s), 189.0 (d);
exact mass m/z calcd for
C
13H1579BrO4 314.01538, found
2-(4-Br om o-3-d im eth oxym eth yl-2,5-d im eth oxy-6-m eth -
314.01534.
ylp h en yl)eth a n ol (28). A solution of aldehyde 27 (400 mg,
4120 J . Org. Chem., Vol. 69, No. 12, 2004

Synthesis of Optically Pure (+)-Puraquinonic Acid
1.18 mmol) in dry MeOH (20 mL) was cooled in an ice bath,
and NaBH4 (52 mg, 1.36 mmol) was added. Stirring at 0 °C
was continued for 1.5 h, water (15 mL) was added, and the
mixture was extracted with CH2Cl2 (3 × 40 mL). The combined
organic extract was dried (Na2SO4) and evaporated. Flash
chromatography of the residue over silica gel (3 × 15 cm), using
1:1 EtOAc-hexane, gave alcohol 28 (380 mg, 95%) as a
colorless oil: FTIR (CH2Cl2, cast) 3439 cm-1 (br); 1H NMR
(CDCl3, 300 MHz) δ 1.88 (br s, 1 H), 2.29 (s, 3 H), 2.91 (t, J )
7.0 Hz, 2 H), 3.45 (s, 6 H), 3.73-3.77 (m, 5 H), 3.78 (s, 3 H),
5.62 (s, 1 H); 13C NMR (CDCl3, 125 MHz) δ 13.5 (q), 30.6 (t),
56.0 (q), 60.3 (q), 62.3 (t), 63.2 (q), 105.2 (d), 116.6 (s), 128.8
(s), 131.7 (s), 133.2 (s), 152.3 (s), 154.3 (s); exact mass m/z calcd
for C14H2179BrO5 348.05722, found 348.05776.
(q), 69.3 (t), 72.9 (t), 122.8 (t), 126.6 (s), 127.51 (d), 127.53 (d),
128.3 (d), 129.9 (d), 132.1 (s), 133.1 (s), 138.3 (s), 138.4 (s),
152.7 (s), 156.5 (s), 191.5 (d); exact mass calcd for C21H24O4
340.16745, found 340.16690.
(4S)-3-[(2S,3S)-3-[3-(2-Ben zyloxyeth yl)-2,5-d im eth oxy-
4-m eth yl-6-vin ylp h en yl]-3-h yd r oxy-2-m eth ylp r op ion yl]-
4-isop r op yloxa zolid in -2-on e (33). A solution of Bu2BOSO2-
CF3 (1.0 M in CH2Cl2, 12.97 mL, 12.97 mmol) was added
dropwise over 20 min to a stirred and cooled (0 °C) solution of
oxazolidinone 32 (2.00 g, 10.8 mmol) in CH2Cl2 (30 mL) under
N2. i-Pr2NEt (2.54 mL, 14.59 mmol) was then added over 10
min. The mixture was stirred at 0 °C for 30 min, then cooled
to -78 °C, and stirred for a further 1.5 h. Aldehyde 31 (3.60
g, 10.59 mmol) in CH2Cl2 (10 mL) was added over 10 min.
Stirring at -78 °C was continued for 1.5 h, the ice bath was
removed, and stirring was continued for 6 h. The solution was
cooled to 0 °C and quenched by addition of a mixture of MeOH
(60 mL) and aqueous buffer (pH ) 7, 30 mL). H2O2 (30%, 35
mL) was then added, and the solution was stirred at 0 °C for
1 h and extracted with CH2Cl2 (3 × 100 mL). The combined
organic extracts were washed with brine (50 mL), dried
(Na2SO4), and evaporated. Flash chromatography of the
residue over silica gel (3 × 20 cm), using 1:4 EtOAc-hexane,
gave alcohol 33 (4.85 g, 87%) as a colorless oil: [R]25D +40.154
(c 1.3, CH2Cl2); FTIR (CH2Cl2 cast) 3490 cm-1 (br); 1H
NMR (C6D6, 300 MHz) δ 0.31 (d, J ) 7.0 Hz, 3 H), 0.47 (d, J
) 7.0 Hz, 3 H), 1.62 (d, J ) 7.0 Hz, 3 H), 1.92-2.04 (m, 1 H),
2.15 (s, 3 H), 2.21 (d, J ) 6.5 Hz, 1 H), 2.92-3.08 (m, 2 H),
3.10-3.14 (m, 1 H), 3.22-3.28 (m, 1 H), 3.36 (s, 3 H), 3.50-
3.60 (m, 2 H), 3.64-3.69 (m, 1 H), 3.70 (s, 3 H), 4.34 (s, 2 H),
1-(2-Ben zyloxyeth yl)-4-br om o-3-d im eth oxym eth yl-2,5-
d im eth oxy-6-m eth ylben zen e (29). A solution of alcohol 28
(301 mg, 0.865 mmol) in THF (10 mL) was added dropwise
over about 10 min to a stirred and cooled (0 °C) slurry of NaH
(60% in oil, 66 mg, 1.72 mmol) in THF (10 mL). The cooling
bath was removed, and stirring was continued for 3.5 h. The
mixture was then recooled to 0 °C, and BnBr (0.197 mL, 1.67
mmol) was added dropwise over ca. 2 min. The cold bath was
left in place, and stirring was continued overnight. Brine (10
mL) was added, and the mixture was extracted with CH2Cl2
(3 × 30 mL). The combined organic extracts were dried
(MgSO4) and evaporated. Flash chromatography of the resi-
due over silica gel (3 × 20 cm), using 7:40 EtOAc-hexane,
gave benzyl ether 29 (346 mg, 92%) as a colorless oil: FTIR
1
(CH2Cl2 cast) 2933, 2856 cm-1; H NMR (CDCl3, 300 MHz) δ
2.27 (s, 3 H), 2.96 (t, J ) 7.5 Hz, 2 H), 3.44 (s, 6 H), 3.55 (t, J
) 7.5 Hz, 2 H), 3.72 (s, 3 H), 3.74 (s, 3 H), 4.49 (s, 2 H), 5.61
(s, 1 H), 7.22-7.33 (m, 5 H); 13C NMR (CDCl3, 100 MHz) δ
13.3 (q), 27.9 (t), 55.9 (q), 60.2 (q), 63.3 (q), 69.3 (t), 72.9 (t),
105.2 (d), 116.3 (s), 127.5 (d), 128.3 (d), 128.8 (s), 131.8 (s),
133.4 (s), 138.3 (s), 152.2 (s), 154.6 (s); exact mass (electro-
spray) m/z calcd for C21H2779BrNaO5 (M + Na) 461.093955,
found 461.093774.
5.00-5.12 (m, 1 H), 5.44-5.50 (m, 2 H), 5.68 (AB q, ∆νAB
)
18.0 Hz, J ) 2.5 Hz, 1 H), 7.02-7.22 (m, 6 H); 13C NMR
(C6D6, 100 MHz) δ 12.7 (q), 14.7 (q), 16.9 (q), 17.5 (q), 28.4 (t),
28.7 (d), 44.1 (d), 58.3 (q), 59.4 (q), 62.8 (t), 62.9 (d), 70.0 (t),
72.2 (d), 72.9 (t), 120.5 (t), 127.5 (d), 127.6 (d), 128.5 (d), 131.6
(s), 132.16 (s), 132.20 (s), 133.0 (d), 139.2 (s), 153.2 (s), 153.5
(s), 154.5 (s), 175.2 (s), (one peak is obscured by a solvent
signal); exact mass m/z calcd for C30H39NO7 525.27264, found
525.27148.
3-(2-Ben zyloxyet h yl)-6-b r om o-2,5-d im et h oxy-4-m et h -
ylben za ld eh yd e (30). Amberlite IR 120 (10 mg) was added
to a stirred solution of acetal 29 (60 mg, 0.137 mmol) in acetone
(5 mL) containing H2O (5 mL), and stirring was continued
overnight. The resin was removed by gravity filtration, and
the filtrate was dried (Na2SO4) and evaporated. Flash chro-
matography of the residue over silica gel (2 × 10 cm), using
1:8 EtOAc-hexane, gave aldehyde 30 (51 mg, 95%) as a
colorless oil: FTIR (CH2Cl2 cast) 1699 cm-1; 1H NMR (CDCl3,
400 MHz) δ 2.36 (s, 3 H), 2.98 (t, J ) 7.0 Hz, 2 H), 3.58 (t, J
) 7.0 Hz, 2 H), 3.76 (s, 3 H), 3.77 (s, 3 H), 4.49 (s, 2 H), 7.22-
7.32 (m, 5 H), 10.31 (s, 1 H); 13C NMR (CDCl3, 100 MHz) δ
14.1 (q), 27.6 (t), 60.4 (q), 63.8 (q), 69.1 (t), 76.0 (t), 118.5 (s),
126.1 (s), 127.4 (d), 127.5 (d), 128.3 (d), 132.9 (s), 138.1 (s),
139.5 (s), 152.2 (s), 157.0 (s), 190.6 (d); exact mass m/z calcd
for C19H2179BrO4 392.06232, found 392.06222.
(4S)-3-[(2S,3S)-3-[3-(2-Ben zyloxyeth yl)-2,5-d im eth oxy-
4-m eth yl-6-vin ylph en yl]-3-(ter t-bu tyldim eth ylsilan yloxy))-
2-m eth ylp r op ion yl]-4-isopr op yloxa zolidin -2-on e (34). Dry
2,6-lutidine (0.40 mL, 3.45 mmol) and then t-BuMe2SiOSO2-
CF3 (0.396 mL, 1.726 mmol) were added dropwise over ca. 3
min to a stirred and cooled (0 °C) solution of alcohol 33 (302
mg, 0.575 mmol) in CH2Cl2 (3 mL). The ice bath was removed,
and stirring was continued for 1 h. Evaporation of the solvent
and flash chromatography of the residue over silica gel (3 ×
20 cm), using 30:10:1 CH2Cl2-hexanes-EtOAc, gave silyl
ether 34 (350 mg, 95%) as a colorless oil: [R]22 +8.1 (c 1.0,
D
CH2Cl2); FTIR (CH2Cl2 cast) 1697, 1785 cm-1; 1H NMR (C6D6,
300 MHz) (mixture of rotamers) δ -0.14 (s, 1.34 H), -0.10 (s,
1.70 H), 0.22 (s, 1.31 H), 0.27 (s, 1.76 H), 0.29-0.32 (m, 3 H),
0.46-0.52 (m, 3.49 H), 0.89 (s, 4.08 H), 0.94 (s, 5.35 H), 1.66
(d, J ) 6.2 Hz, 1.32 H), 1.70 (d, J ) 6.8 Hz, 1.78 H), 1.94-
2.04 (m, 1 H), 2.14 (s, 1.23 H), 2.18 (s, 1.73 H), 2.94-3.18 (m,
3 H), 3.22-3.32 (m, 1 H), 3.37 (s, 3 H), 3.50-3.72 (m, 3 H),
3.91 (s, 1.27 H), 4.00 (s, 1.75 H), 4.38-4.42 (m, 2 H), 5.08-
5.18 (m, 0.59 H), 5.44-5.56 (m, 0.86 H), 5.62-5.73 (m, 1.63
3-(2-Ben zyloxyeth yl)-2,5-d im eth oxy-4-m eth yl-2-vin yl-
ben za ld eh yd e (31). (Ph3P)4Pd (13.2 mg, 0.011 mmol) was
added to a stirred mixture of bromide 30 (90 mg, 0.229 mmol),
tributyl vinyl tin (87.1 mg, 0.275 mmol), CuI (3.0 mg, 0.016
mmol), and PhMe (15 mL) under N2. The mixture was stirred
and refluxed for 4 h, and then a second portion of (Ph3P)4Pd
(ca 6.0 mg, 0.005 mmol) was added. Refluxing was continued
for 24 h, and a third portion of (Ph3P)4Pd (ca 6.0 mg, 0.005
mmol) was added. Refluxing was continued for 12 h, and the
solution was cooled, filtered, and evaporated. Flash chroma-
tography of the residue over silica gel (2 × 17 cm), using 30:
10:1 CH2Cl2-hexanes-EtOAc, gave aldehyde 31 (51 mg, 66%)
H), 6.03-6.14 (m, 1 H), 7.0-7.30 (m, 5 H), 7.48 (AB q, ∆νAB
)
18.0 Hz, J ) 11.8 Hz, 0.72 H); 13C NMR (CD3OD, 100 MHz)
(mixture of rotamers) δ -5.0 (q), -4.7 (q), -4.3 (q), -3.8 (q),
12.9 (q), 15.14 (q), 15.19 (q), 17.68 (q), 17.74 (q), 17.94 (q), 17.99
(q), 19.08 (s), 19.11 (s), 26.4 (q), 26.6 (q), 28.7 (t), 29.2 (t), 30.14
(d), 30.19 (d), 44.9 (d), 46.2 (d), 59.7 (q), 59.9 (q), 60.1 (q), 60.2
(q), 62.7 (d), 63.5 (d), 64.83 (t), 64.86 (t), 70.50 (t), 70.60 (t),
72.6 (d), 73.7 (t), 73.8 (t), 74.5 (d), 120.3 (t), 122.0 (t), 128.58
(d), 128.61 (d), 128.63 (d), 128.76 (d), 129.3 (d), 129.4 (d), 130.9
(s), 132.0 (s), 132.76 (s), 132.79 (s), 133.1 (d), 133.3 (s), 133.4
(s), 133.6 (d), 139.8 (s), 139.9 (s), 153.4 (s), 154.2 (s), 154.6 (s),
155.2 (s), 155.4 (s), 155.8 (s), 176.1 (s), 177.1 (s); exact mass
as a colorless oil: FTIR (CH2Cl2 cast) 1693, 1716, 1759 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 1.53 (s, 3 H), 3.00 (t, J ) 7.5 Hz,
2 H), 3.58 (t, J ) 7.5 Hz, 2 H), 3.60 (s, 3 H), 3.79 (s, 3 H), 4.50
(s, 2 H), 5.47 (AB q, ∆νAB ) 17.5 Hz, J ) 2.0 Hz, 1 H), 5.63
(AB q, ∆νAB ) 11.5 Hz, J ) 2.0 Hz, 1 H), 7.03 (AB q, ∆νAB
)
17.5 Hz, J ) 11.5 Hz, 1 H), 7.23-7.28 (m, 5 H), 10.18 (s, 1 H);
13C NMR (CDCl3, 100 MHz) δ 13.2 (q), 27.5 (t), 60.0 (q), 64.1
J . Org. Chem, Vol. 69, No. 12, 2004 4121

Clive et al.
(electrospray) m/z calcd for C36H53NNaO7Si (M + Na) 662.
(s), 131.5 (s), 131.9 (s), 132.1 (d), 132.2 (d), 132.5 (s), 138.4 (s),
152.0 (s), 152.2 (s), 154.6 (s), 155.0 (s); exact mass m/z calcd
for C30H46O5Si 514.31146, found 514.31153.
348902, found 662.348778.
(2S,3S)-3-[3-(2-Ben zyloxyeth yl)-2,5-d im eth oxy-4-m eth -
yl-6-vin ylp h e n yl]-3-(t er t -b u t yld im e t h ylsila n yloxy)-2-
m eth ylp r op ion ic Acid Ben zyl Ester (35). n-BuLi (2.5 M
in hexane, 6.11 mL, 15.3 mmol was added dropwise over ca. 5
min to a stirred and cooled (0 °C) solution of BnOH (2.09 g,
19.1 mmol) in THF (9 mL). Stirring at 0 °C was continued for
15 min, and an aliquot of the solution (0.3 mL, 0.262 mmol)
was added dropwise over ca. 2 min to a stirred and cooled (0
°C) solution of imide 34 (28 mg, 0.0438 mmol) in THF (3 mL).
Stirring at 0 °C was continued for 6 h. Water (2 mL) was
added, and the mixture was extracted with CH2Cl2 (3 × 15
mL). The combined organic extracts were dried (Na2SO4) and
evaporated. Flash chromatography of the residue over silica
gel (2 × 15 cm), using 1:10 EtOAc-hexane, gave ester 35 (24
[(S)-1-[3-(2-Ben zyloxyet h yl)-2,5-d im et h oxy-4-m et h yl-
6-vin ylp h e n yl]-2-m e t h yla llyloxy]-t er t -b u t yld im e t h yl-
silan e (37). (a) [(1S,2S)-1-[3-(2-Ben zyloxyeth yl)-2,5-dim eth -
oxy-4-m eth yl-6-vin ylp h en yl]-2-m eth yl-3-(2-n itr op h en ylse-
la n yl)p r op oxy]-ter t-bu tyld im eth ylsila n e. n-Bu3P (0.027
mL, 0.109 mmol) was added dropwise over ca. 2 min to a
stirred solution of alcohol 36 (28 mg, 0.0545 mmol) and
o-nitrobenzeneselenocyanate (24.7 mg, 0.109 mmol) in THF
(1 mL). Stirring was continued overnight. Evaporation of the
solvent and flash chromatography of the residue over silica
gel (1.5 × 20 cm), using 1:10 EtOAc-hexane, gave the expected
selenide (ca. 35 mg, 93%) as a yellow oil, which was used
directly in the next step.
mg, 89%) as a colorless oil: [R]22 -58.1 (c 1.6, CH2Cl2); FTIR
D
(b) [(S)-1-[3-(2-Ben zyloxyeth yl)-2,5-d im eth oxy-4-m eth -
yl-6-vin ylp h en yl]-2-m eth yla llyloxy]-ter t-bu tyld im eth yl-
sila n e (37). H2O2 (30%, 0.051 mL, 0.504 mmol) was added
dropwise to a stirred and cooled (0°) solution of the above
selenide (ca. 35 mg, 0.0504 mmol) in THF (1 mL). After
addition, the ice bath was removed, and stirring was continued
for 5 h. Ice-water (3 mL) was added to quench the reaction,
and the organic solvent was evaporated in vacuo. The aqueous
layer was extracted with CH2Cl2 (3 × 15 mL), and the
combined organic extracts were dried (Na2SO4) and evapo-
rated. Flash chromatography of the residue over silica gel (1.5
× 18 cm), using 1:25 EtOAc-hexane, gave olefin 37 (22 mg,
(CH2Cl2 cast) 1731 cm-1; H NMR (CD3OD, 400 MHz) (mix-
1
ture of rotamers) δ -0.34 (s, 2.15 H), -0.24 (s, 0.81 H), 0.06
(s, 2.13 H), 0.12 (s, 0.86 H), 0.79 (s, 6.55 H), 0.82 (s, 2.66 H),
1.28 (d, J ) 6.8 Hz, 3 H), 2.17 (s, 0.82 H), 2.20 (s, 2.20 H),
2.80-2.86 (m, 2 H), 3.36-3.54 (m, 8 H), 3.76 (s, 1 H), 4.34-
4.45 (m, 2 H), 4.62-4.67 (m, 1.19 H), 4.79-4.86 (m, 0.56 H),
4.99-5.01 (m, 0.26 H), 5.12-5.15 (m, 0.95 H), 5.38-5.51 (m,
1.26 H), 5.67 (AB q, ∆νAB ) 18.0 Hz, J ) 2.5 Hz, 0.68 H), 6.71
(AB q, ∆νAB ) 18.0 Hz, J ) 11.8 Hz, 0.26 H), 6.81-6.85 (m,
1.87 H), 7.08-7.34 (m, 8.75 H); 13C NMR (CD3OD, 100 MHz)
(mixture of rotamers) δ -5.0 (q), -4.7 (q), -4.3 (q), -3.7 (q),
12.95 (q), 13.05 (q), 16.1 (q), 16.7 (q), 19.1 (s), 19.2 (s), 26.4
(q), 26.7 (q), 28.8 (t), 29.2 (t), 46.6 (d), 47.1 (d), 59.9 (q), 60.3
(q), 62.8 (q), 63.7 (q), 66.8 (t), 66.9 (t), 70.4 (t), 70.6 (t), 72.9
(d), 73.8 (t), 74.3 (d), 120.5 (t), 122.0 (t), 128.6 (d), 128.7 (d),
128.77 (d), 128.82 (d), 129.2 (d), 129.3 (d), 129.5 (d), 129.6 (d),
131.88 (s), 131.94 (s), 132.1 (s), 132.5 (s), 132.7 (s), 132.9 (s),
133.20 (d), 133.28 (s), 133.31 (d), 137.2 (s), 137.4 (s), 139.75
(s), 139.80 (s), 153.4 (s), 154.0 (s), 155.0 (s), 156.6 (s), 175.9
(s), 176.5 (s); exact mass m/z calcd for C37H50O6Si 618.33765,
found 618.33653.
81% over two steps) as a colorless oil: [R]22 -75.5 (c 1.7,
D
CH2Cl2); FTIR (CH2Cl2 cast) 2951 cm-1; 1H NMR (CD3OD, 500
MHz) δ -0.31 (s, 3 H), 0.04 (s, 3 H), 0.81 (s, 9 H), 1.74 (s, 3
H), 2.23 (s, 3 H), 2.99 (t, J ) 8 Hz, 2 H), 3.50-3.55 (m, 4 H),
3.59-3.65 (m, 4 H), 4.49 (AB q, ∆νAB ) 15.0 Hz, J ) 11.2 Hz,
2 H), 4.80-4.85 (m, 2 H), 5.25 (AB q, ∆νAB ) 7.0 Hz, J ) 3.0
Hz, 1 H), 5.68-5.69 (m, 1 H), 5.80 (AB q, ∆νAB ) 18.0 Hz, J )
3.0 Hz, 1 H), 7.00 (AB q, ∆νAB ) 18.0 Hz, J ) 7.0 Hz, 1 H),
7.23-7.29 (m, 5 H); 13C NMR (CDCl3, 100 MHz) δ -5.1 (q),
-5.0 (q), 12.6 (q), 18.3 (s), 20.7 (q), 25.9 (q), 28.3 (t), 29.2 (q),
62.3 (q), 69.7 (t), 71.3 (d), 72.9 (t), 110.8 (t), 118.1 (t), 127.4
(d), 127.5 (d), 128.2 (d), 129.9 (s), 130.0 (s), 131.3 (s), 131.9 (s),
132.3 (d), 138.4 (s), 147.1 (s), 153.1 (s), 153.8 (s); exact mass
m/z calcd for C30H44O4Si 496.30090, found 496.29948.
(2R,3S)-3-[3-(2-Ben zyloxyeth yl)-2,5-d im eth oxy-4-m eth -
yl-6-vin ylp h e n yl]-3-(t er t -b u t yld im e t h ylsila n yloxy)-2-
m eth ylp r op a n -1-ol (36). i-Bu2AlH (1.0 M in CH2Cl2, 0.0223
mL, 0.0223 mmol) was added dropwise over 5 min to a stirred
and cooled (-78 °C) solution of ester 35 (23 mg, 0.0372 mmol)
in CH2Cl2 (5 mL). Stirring at -78 °C was continued for 45
min, and then the cooling bath was replaced by an ice bath.
Stirring at 0 °C was continued for 1 h. MeOH (0.5 mL) was
added to quench the excess of i-Bu2AlH. The mixture was
diluted with CH2Cl2 (3 mL), and aqueous sodium potassium
tartrate (0.5 M, 3 mL) was added over 10 min. The mixture
was stirred at room temperature for 4 h. The organic layer
was separated, and the aqueous layer was extracted with
CH2Cl2 (3 × 15 mL). The combined organic extracts were dried
(Na2SO4) and evaporated. Flash chromatography of the residue
over silica gel (2 × 15 cm), using 1:10 EtOAc-hexane, gave
(S)-1-[3-(2-Ben zyloxyeth yl)-2,5-d im eth oxy-4-m eth yl-6-
vin ylp h en yl]-2-m eth ylp r op -2-en -1-ol (38). A solution of
Bu4NF (1.0 M in THF, 0.675 mL, 0.675 mmol) was added to a
stirred and cooled (0 °C) solution of bisolefin 37 (67 mg, 0.135
mmol) in THF (3 mL), and stirring was continued for 36 h.
Brine (2 mL) was added, the layers were separated, and the
aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The
combined organic extracts were dried (Na2SO4) and evapo-
rated. Flash chromatography of the residue over silica gel (2
× 15 cm), using 1:10 EtOAc-hexane, gave bisolefin 38 (49
mg, 95%), as a colorless oil: [R]22D -38.9 (c 1.5, CH2Cl2); FTIR
1
(CH2Cl2 cast) 3468 cm-1 (br); H NMR (CD3OD, 300 MHz) δ
alcohol 36 (7.1 mg, 89%) as a colorless oil: [R]22 -58.0 (c 1.5,
2.25 (s, 3 H), 2.99-3.01 (m, 2 H), 3.54 (s, 3 H), 3.56-3.62 (m,
2 H), 3.71 (s, 3 H), 4.35 (d, J ) 6.2 Hz, 1 H), 4.52 (s, 2 H),
D
CH2Cl2); FTIR (CH2Cl2 cast) 3458 cm-1 (br); 1H NMR (CDCl3,
400 MHz) (mixture of rotamers) δ -0.22 (s, 3 H), 0.10 (s, 3
H), 0.84 (s, 1.06 H), 0.88 (s, 8.10 H), 1.08 (d, J ) 6.8 Hz, 0.35
H), 1.17 (d, J ) 6.8 Hz, 2.71 H), 2.12-2.16 (m, 1 H), 2.23 (s, 3
H), 2.30-2.34 (m, 1 H), 2.98 (t, J ) 7.8 Hz, 2 H), 3.13-3.16
(m, 1 H), 3.21-3.25 (m, 1 H), 3.48-3.65 (m, 5 H), 3.79 (s, 2.67
H), 3.81 (s, 0.35 H), 4.51 (AB q, ∆νAB ) 22.5 Hz, J ) 12.0 Hz,
2 H), 4.76 (d, J ) 9.5 Hz, 0.14 H), 4.94 (d, J ) 10.0 Hz, 0.95
H), 5.35-5.46 (m, 1 H), 5.57 (AB q, ∆νAB ) 11.5 Hz, J ) 2.2
Hz, 0.16 H), 5.72 (AB q, ∆νAB ) 18.0 Hz, J ) 2.5 Hz, 0.96 H),
6.77 (AB q, ∆νAB ) 18.0 Hz, J ) 11.5 Hz, 0.16 H), 7.25-7.38
(m, 6 H); 13C NMR (CDCl3, 100 MHz) (mixture of rotamers) δ
-5.2 (q), -4.7 (q), 12.4 (q), 14.7 (q), 15.2 (q), 18.1 (s), 18.2 (s),
25.8 (q), 26.0 (q), 27.7 (t), 28.2 (t), 40.8 (d), 42.3 (d), 59.2 (q),
59.8 (q) 62.0 (q), 62.9 (q), 65.2 (t), 65.6 (t), 69.3 (t), 69.5 (t),
72.4 (d), 72.8 (t), 72.9 (t), 74.3 (d), 118.8 (t), 121.3 (t), 127.5
(d), 127.58 (d), 127.59(d), 128.36 (d), 128.38 (d), 129.7 (s), 130.1
4.85-4.86 (m, 1 H), 4.99-5.00 (m, 1 H), 5.35 (AB q, ∆νAB
)
11.8 Hz, J ) 2.8 Hz, 1 H), 5.51-5.52 (m, 1 H), 5.73 (AB q,
∆νAB ) 18.0 Hz, J ) 2.8 Hz, 1 H), 7.00 (AB q, ∆νAB ) 18.0 Hz,
J ) 11.8 Hz, 1 H), 7.24-7.32 (m, 5 H); 13C NMR (CD3OD, 125
MHz) δ 12.7 (q), 20.5 (q), 28.8 (t), 59.6 (q), 62.9 (q), 70.3 (t),
71.7 (d), 73.2 (t), 109.7 (t), 119.2 (t), 128.0 (d), 128.1 (d), 128.9
(d), 131.0 (s), 131.7 (s), 131.9 (s), 132.6 (s), 132.8 (d), 139.8 (s),
148.4 (s), 154.1 (s), 154.5 (s); exact mass m/z calcd for C24H30O4
382.21442, found 382.21384.
(S)-6-(2-Ben zyloxyeth yl)-4,7-d im eth oxy-2,5-d im eth yl-
1H-in d en -1-ol (40). Tricyclohexylphosphine[1,3-bis(2,4,6-tri-
methylphenyl)-4,5-dihydroimidazol-2-ylidene][benzylidine] ru-
thenium(IV) dichloride (39) (12.3 mg, 0.0144 mmol) was added
to a stirred solution of bisolefin 38 (55 mg, 0.144 mmol) in
CH2Cl2 (6 mL) under N2. The mixture was refluxed for 20 h,
cooled, and evaporated. Flash chromatography of the residue
4122 J . Org. Chem., Vol. 69, No. 12, 2004

Synthesis of Optically Pure (+)-Puraquinonic Acid
over silica gel (2 × 16 cm), using 1:6 EtOAc-hexane, gave
H), 7.24-7.32 (m, 5 H); 13C NMR (CDCl3, 125 MHz) (mixture
of two isomers) δ 12.3 (q), 12.4 (q), 15.0 (q), 15.4 (q), 25.8 (q),
26.9 (q), 27.9 (t), 43.80 (t), 43.84 (t), 47.1 (t), 47.2 (t), 48.9 (s),
49.8 (s), 59.7 (q), 59.8 (q), 61.4 (q), 61.7 (q), 62.0 (t), 63.1 (t),
69.7 (t), 69.8 (t), 72.84 (t), 72.87 (t), 90.7 (d), 92.5 (d), 105.2
(d), 127.4 (d), 127.5 (d), 128.2 (d), 128.7 (s), 129.2 (s), 130.9
(s), 131.1 (s), 131.7 (s), 132.9 (s), 135.0 (s), 135.4 (s), 138.50
(s), 138.51 (s), 150.28 (s), 150.34 (s), 152.3 (s), 152.4 (s); exact
mass m/z calcd for C26H34O5 426.24063, found 426.24038.
allylic alcohol 40 (45 mg, 88%) as a colorless oil: [R]22 +91.8
D
1
(c 1.2, CH2Cl2); FTIR (CH2Cl2 cast) 3386 cm-1 (br); H NMR
(CD3OD, 300 MHz) δ 2.01-2.02 (m, 3 H), 2.17 (s, 3 H), 2.94 (t,
J ) 7.5 Hz, 2 H), 3.53 (t, J ) 7.5 Hz, 2 H), 3.68 (s, 3 H), 3.92
(s, 3 H), 4.50 (s, 2 H), 5.03 (s, 1 H), 6.37-6.38 (m, 1 H), 7.20-
7.40 (m, 5 H); 13C NMR (CD3OD, 100 MHz) δ 12.4 (q), 13.9
(q), 28.6 (t), 60.3 (q), 61.8 (q), 70.8 (t), 73.8 (t),78.7 (d), 123.6
(d), 128.5 (s), 128.6 (d), 128.8 (d), 129.3 (d), 132.3 (s), 133.5
(s), 136.0 (s), 139.8 (s), 148.0 (s), 148.9 (s), 152.9 (s); exact mass
(3a R,8b S)-7-(2-Ben zyloxyet h yl)-5,8-d im et h oxy-3a ,6-
d im eth yl-3,3a ,4,8b-tetr a h yd r o-2H-in d en o[1,2-b]fu r a n -2-
ol (44). AcOH-H2O (1:4, 5 mL) was added dropwise to a
stirred solution of lactol ethyl ethers 43 (17 mg, 0.040 mmol)
in THF (3 mL). The mixture was then stirred at 50 °C for 12
h, cooled, and extracted with EtOAc (3 × 15 mL). The
combined organic extracts were washed with brine (5 mL),
dried (Na2SO4), and evaporated. Flash chromatography of the
residue over silica gel (1 × 20 cm), using 7:30 EtOAc-hexane,
gave the two isomeric lactols 44 (14.5 mg, 91%) as a colorless
oil: [R]22D +54.3 (c 0.8, CH2Cl2); FTIR (CH2Cl2 cast) 3430 cm-1
(br); 1H NMR (CDCl3, 500 MHz) (mixture of two isomers) 1.28
(s, 1.25 H), 1.41 (s, 1.96 H), 1.97 (AB q, ∆νAB ) 8.5 Hz, J ) 2.2
Hz, 0.67 H), 2.02-2.08 (m, 0.5 H), 2.13-2.67 (m, 4.5 H), 2.68
(d, J ) 3.0 Hz, 0.61 H), 2.76-2.81 (m, 1.01 H), 2.94-3.04 (m,
2.63 H), 3.45 (d, J ) 16.5 Hz, 0.4 H), 3.50-3.58 (m, 2.05 H),
3.65 (s, 1.66 H), 3.66 (s, 1.31 H), 3.87 (s, 1.68 H), 3.89 (s, 1.17
H), 4.52 (s, 1.90 H), 5.14 (s, 0.29 H), 5.35 (s, 0.55 H), 5.59-
5.62 (m, 0.90 H), 7.24-7.31 (m, 5 H); 13C NMR (CDCl3, 125
MHz) (mixture of two isomers) δ 12.4 (q), 26.2 (q), 26.5 (q),
27.9 (t), 43.3 (t), 43.6 (t), 47.7 (t), 47.8 (t), 49.5 (s), 49.7 (s),
59.82 (q), 59.84 (q), 61.3 (q), 61.6 (q), 69.7 (q), 72.9 (q), 91.4
(d), 92.8 (d), 100.0 (d), 100.8 (d), 127.4 (d), 127.5 (d), 128.2 (d),
129.2 (s), 129.4 (s), 131.3 (s), 131.6 (s), 131.8 (s), 132.7 (s), 134.6
(s), 134.9 (s), 138.5 (s), 150.4 (s), 150.5 (s), 152.33 (s), 152.34
(s); exact mass m/z calcd for C24H30O5 398.20932, found
398.20915.
m/z calcd for
C22H26O4 354.18311, found 354.18259. The
compound had ee >98% (HPLC, Chiracel OD-RH column, 1:1
i-PrOH-water).
(S)-6-(2-Ben zyloxyeth yl)-1-(2-br om o-1-eth oxyeth oxy)-
4,7-d im eth oxy-2,5-d im eth yl-1H-in d en e (42). Br2 (0.076 mL,
1.2 mmol) was added dropwise to a stirred and cooled (-78
°C) solution of ethyl vinyl ether (0.183 mL, 1.92 mmol) in
CH2Cl2 (4 mL) under N2. After 20 min, the cooling bath was
removed, and stirring was continued for ca. 1 h. A solution of
allylic alcohol 40 (85 mg, 0.24 mmol) and 2,6-lutidine (0.139
mL, 1.20 mmol) in CH2Cl2 (6 mL) was added slowly to the
resulting solution of 1,2-dibromoethyl ethyl ether at -78 °C.
After 30 min at -78 °C, the cold bath was removed, and
stirring was continued for 20 h. The solution was diluted with
CH2Cl2 (30 mL), washed with aqueous Na2S2O3 (10%, 10 mL)
and brine (10 mL), dried (Na2SO4), and evaporated. Flash
chromatography of the residue over silica gel (2 × 15 cm), using
1:15 EtOAc-hexane, gave bromo acetals 42 (100 mg, 91%),
as a yellow oil that was a mixture (ca. 1:1; 1H NMR) of
diastereoisomers. Early and late fractions from the chroma-
tography provided samples of the individual compounds. Less
polar diastereoisomer: [R]22 +161.6 (c 1.1, CH2Cl2); FTIR
D
(CH2Cl2 cast) 1626 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.06 (t,
J ) 7.0 Hz, 3 H), 2.08-2.09 (m, 3 H), 2.21 (s, 3 H), 2.94-3.01
(m, 2 H), 3.22-3.33 (m, 4 H), 3.44-3.58 (m, 2 H), 3.70 (s, 3
H), 3.89 (s, 3 H), 4.28 (t, J ) 5.0 Hz, 1 H), 4.51 (s, 2 H), 5.22
(s, 1 H), 6.44-6.45 (m, 1 H), 7.23-7.30 (m, 5 H); 13C NMR
(CDCl3, 100 MHz) δ 12.3 (q), 14.5 (q), 15.0 (q), 27.8 (t), 33.0
(t), 58.5 (q), 61.4 (q), 63.8 (t), 69.6 (t), 72.8 (t), 82.9 (d), 98.6
(d), 123.5 (d), 126.3 (s), 127.40 (d), 127.48 (s), 127.50 (d), 128.3
(d), 132.3 (s), 135.2 (s), 138.6 (s), 146.2 (s), 146.8 (s), 151.3 (s);
(3a R,8b S)-7-(2-Ben zyloxyet h yl)-5,8-d im et h oxy-3a ,6-
d im eth yl-4,8b-d ih yd r o-3aH-in d en o[1,2-b]fu r a n (45). Et3N
(0.039 mL, 0.28 mmol) and then MeSO2Cl (0.008 mL, 0.106
mmol) were added dropwise to a stirred and cooled (0 °C)
solution of lactols 44 (14 mg, 0.035 mmol) in THF (2 mL).
Stirring at 0 °C was continued for 15 min, the cooling bath
was removed, and stirring was continued for 2 h. The mixture
was then refluxed for 1 h, cooled, and filtered through a pad
of Celite (2 × 3 cm). Evaporation of the filtrate and flash
chromatography of the residue over silica gel (1 × 15 cm), using
2:25 EtOAc-hexane, gave 45 (9.9 mg, 75%) as a colorless oil:
exact mass m/z calcd for
C
26H3379BrO5 504.15112, found
504.15179. More polar diastereoisomer: [R]22 +143.3 (c 1.2,
D
CH2Cl2); FTIR (CH2Cl2 cast) 1626 cm-1; 1H NMR (CDCl3, 400
MHz) δ 1.00 (t, J ) 7.0 Hz, 3 H), 2.069-2.074 (m, 3 H), 2.21
(s, 3 H), 2.92-3.04 (m, 2 H), 3.28-3.45 (m, 4 H), 3.46-3.60
(m, 2 H), 3.71 (s, 3 H), 3.91 (s, 3 H), 4.53 (AB q, ∆νAB ) 14.0
Hz, J ) 12.0 Hz, 2 H), 4.66 (AB q, ∆νAB ) 6.0 Hz, J ) 4.2 Hz,
1 H), 5.20 (s, 1 H), 6.52-6.53 (m, 1 H), 7.24-7.32 (m, 5 H);
13C NMR (CDCl3, 100 MHz) δ 12.2 (q), 14.5 (q), 15.0 (q), 27.8
(t), 32.9 (t), 59.4 (q), 61.4 (q), 63.1 (t), 69.6 (t), 72.8 (t), 82.2
(d), 99.6 (d), 125.5 (d), 127.4 (d), 127.5 (d), 127.9 (s), 128.3 (d),
129.2 (d), 132.1 (d), 134.5 (d), 138.5 (d), 143.6 (d), 147.1 (d),
151.6 (d).
[R]25 +183.8 (c 1.1, CH2Cl2); FTIR (CH2Cl2 cast) 1615 cm-1
;
D
1H NMR (CDCl3, 500 MHz) δ 1.38 (s, 3 H), 2.21 (s, 3 H), 2.85
(d, J ) 16.5 Hz, 1 H), 2.94-3.04 (m, 2 H), 3.14 (d, J ) 16.5
Hz, 1 H), 3.55 (t, J ) 8.0 Hz, 2 H), 3.66 (s, 3 H), 3.89 (s, 3 H),
4.52 (s, 2 H), 4.91 (d, J ) 2.8 Hz, 1 H), 5.60 (s, 2 H), 6.21 (d,
J ) 2.8 Hz, 1 H), 7.30-7.31 (m, 5 H); 13C NMR (CDCl3, 125
MHz) δ 12.5 (q), 26.9 (q), 27.8 (t), 43.9 (t), 53.1 (s), 59.7 (q),
61.2 (q), 69.7 (t), 72.9 (t), 93.7 (d), 110.0 (d), 127.4 (d), 127.5
(d), 128.2 (d), 129.7 (s), 131.7 (s), 132.2 (s), 134.5 (s) 138.5 (s),
143.4 (d), 150.4 (s), 152.4 (s); exact mass m/z calcd for C24H28O4
380.19876, found 380.19782.
(3aR,8bS)-7-(2-Ben zyloxyeth yl)-2-eth oxy-5,8-dim eth oxy-
3a ,6-d im et h yl-3,3a ,4,8b -t et r a h yd r o-2H -in d en o[1,2-b]fu -
r a n (43). Bu3SnH (0.112 mL, 0.416 mmol) and AIBN (6.8 mg,
0.0416 mmol) were added to a stirred solution of bromo acetals
42 (105 mg, 0.208 mmol) in PhMe (15 mL). The flask was then
lowered into a preheated oil bath set at 115 °C, and the
reaction mixture was stirred at this temperature for 1.5 h and
then cooled. Flash chromatography of the solution over silica
gel (2 × 15 cm, using 3:80 EtOAc-hexane, gave the isomeric
F or m ic Acid (1R,2S)-6-(2-Ben zyloxyeth yl)-2-for m yl-
4,7-d im eth oxy-2,5-d im eth ylin d a n -1-yl Ester (46). OsO4
(0.35 mL, 2.5w/w% in t-BuOH) was added to a stirred solution
of 45 (53 mg, 0.139 mmol) in CCl4-H2O-t-BuOH (5:2:2, 9 mL).
The mixture was stirred for 30 min, and then NaIO4 (0.155 g,
0.724 mmol) was added in one portion. Stirring was continued
for 9 h, and the mixture was then extracted with CH2Cl2 (3 ×
25 mL). The combined organic extracts were washed with
brine, dried (Na2SO4), and evaporated. Flash chromatography
of the residue over silica gel (2 × 5 cm), using 1:3 EtOAc-
hexane, gave crude aldehyde formate 46 (75 mg) as a colorless
oil, which was used directly in the next step.
lactol ethyl ethers 43 (75 mg, 85%) as a colorless oil: [R]22
D
+50.4 (c 1.3, CH2Cl2); FTIR (CH2Cl2 cast) 3028, 2971, 2868
1
cm-1; H NMR (CDCl3, 500 MHz) (mixture of isomers) δ 0.76
(t, J ) 7.0 Hz, 1.27 H), 1.22 (t, J ) 7.0 Hz, 1.72 H), 1.28 (s,
1.39 H), 1.33 (s, 1.73 H), 1.94-1.99 (m, 1.06 H), 2.13-2.21 (m,
4.09 H), 2.75-2.80 (m, 1.03 H), 2.95-3.01 (m, 2.58 H), 3.16-
3.22 (m, 0.45 H), 3.30-3.38 (m, 0.47 H), 3.42-3.48 (m, 1.02
H), 3.52-3.56 (m, 2.09 H), 3.64 (two s, 2.94 H), 3.77-3.79 (m,
0.60 H), 3.91 (two s, 2.97 H), 4.52 (s, 2 H), 5.14-5.23 (m, 1.94
(1R,2S)-6-(2-Ben zyloxyeth yl)-1-h ydr oxy-4,7-dim eth oxy-
2,5-d im eth ylin d a n -2-ca r boxylic Acid Meth yl Ester (47).
J . Org. Chem, Vol. 69, No. 12, 2004 4123

Clive et al.
(a ) (1R,2S)-6-(2-Ben zyloxyeth yl)-1-for m yloxy-4,7-d im eth -
oxy-2,5-d im eth ylin d a n -2-ca r boxylic Acid . A solution of
NaClO2‚2H2O (126 mg, 1.395 mmol) and NaH2PO4‚H2O (126
mg, 0.91 mmol) in H2O (1 mL) was added to a stirred and
cooled (0 °C) solution of the above crude aldehyde formate 46
(ca 75 mg) in t-BuOH (2.5 mL) containing 2-methyl-2-butene
(1 mL). The ice bath was removed, and stirring was continued
for 3 h. The organic solvents were evaporated under reduced
pressure. The residue was diluted with H2O (2 mL), acidified
with 1 N HCl (to pH ca. 3), saturated with NaCl and extracted
with EtOAc (4 × 30 mL). The combined organic extracts were
dried (Na2SO4) and evaporated to give a sticky residue, which
was used directly in the next step.
(b) (1R,2S)-6-(2-Ben zyloxyeth yl)-1-for m yloxy-4,7-dim eth -
oxy-2,5-d im eth ylin d a n -2-ca r boxylic Acid Meth yl Ester .
Freshly prepared CH2N2 in Et2O was added dropwise to a
stirred and cooled (0 °C) solution of the above crude acid (80
mg) in Et2O (5 mL). The resulting solution was stirred at 0 °C
for 10 min and evaporated to give a thick oil (85 mg), which
was used directly in the next step.
(8.5 mg, 0.0214 mmol) was dissolved in MeOH (5 mL) covering
10% Pd-C (5 mg), and the flask was flushed with H2
(hydrogen-filled balloon). The mixture was stirred for 30 min
and then filtered through a pad of Celite (1 × 2.5 cm), which
was washed with MeOH. Evaporation of the filtrate and
flash chromatography of the residue over silica gel (1 × 10
cm), using 1:1 EtOAc-hexane, gave alcohol 50 (6.3 mg, 96%)
as a colorless oil: [R]22 -4.0 (c 0.4, CH2Cl2); FTIR (CH2Cl2
D
cast) 3435, 1731 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.35 (s, 3
H), 1.90 (br s, 1 H), 2.20 (s, 3 H), 2.84-2.93 (m containing a
doublet of doublets at δ 2.86, J ) 16.0, 3.5 Hz and a triplet of
triplets at δ 2.91, J ) 6.80 Hz, 4 H in all), 3.43 (d, J ) 15.8
Hz, 1 H), 3.47 (d, J ) 15.8 Hz, 1 H), 3.69 (s, 3 H), 3.72-3.75
(m containing two singlets at δ 3.72 and 3.75, 8 H in all); 13C
NMR (CDCl3, 100 MHz) δ 12.1 (q), 25.2 (q), 30.5 (t), 41.1 (t),
41.5 (t), 50.0 (s), 52.1 (q), 59.9 (q), 60.0 (q), 62.7 (t), 129.0 (two
overlapping s), 131.1 (s), 133.0 (s), 151.06 (s), 151.17 (s), 177.7
(s); exact mass m/z calcd for C17H24O5 308.16238, found
308.16249.
(S)-5-(2-Hyd r oxyeth yl)-4,7-d im eth oxy-2,6-d im eth ylin -
d a n -2-ca r boxylic Acid (51). LiOH‚H2O (57.2 mg, 1.364
mmol) was added to a stirred solution of ester 50 (21 mg, 0.068
mmol) in 1:1 dioxane-H2O (4 mL). After 3 h, the mixture was
acidified with hydrochloric acid (1.0 M, 4 mL), saturated with
NaCl, and extracted with EtOAc (3 × 30 mL). The combined
organic extracts were dried (MgSO4) and evaporated. Flash
chromatography of the residue over silica gel (1 × 10 cm), using
1:15 MeOH-CH2Cl2, gave acid 51 (9.1 mg, 95%) as a colorless
(c) (1R,2S)-6-(2-Ben zyloxyeth yl)-1-h yd r oxy-4,7-d im eth -
oxy-2,5-d im eth ylin d a n -2-ca r boxylic Acid Meth yl Ester
(47). K2CO3 (0.2 g) was added to a stirred solution of the above
crude ester in dry MeOH (6 mL). The mixture was stirred for
1 h. The solvent was evaporated, and EtOAc (30 mL) was
added. The mixture was washed with brine (10 mL), dried
(Na2SO4), and evaporated. Flash chromatography of the resi-
due over silica gel (1 × 21 cm), using 1:2 EtOAc-hexane, gave
hydroxy ester 47 (31 mg, 54% over 4 steps) as a colorless oil:
oil: [R]22D -0.7 (c 0.7, CH2Cl2); FTIR (CH2Cl2 cast) 1702 cm-1
;
[R]22 -1.739 (c 1.2, CH2Cl2); FTIR (CH2Cl2 cast) 3436, 1732
D
1H NMR (CDCl3, 400 MHz) δ 1.40 (s, 3 H), 2.19 (s, 3 H), 2.85-
2.93 (m, 4 H), 3.47 (d, J ) 12.0 Hz, 1 H), 3.51 (d, J ) 11.5 Hz,
1 H), 3.68 (s, 3 H), 3.71-3.78 (m containing one singlet at δ
3.74, 5 H in all); 13C NMR (CDCl3, 100 MHz) δ 12.1 (q), 24.9
(q), 30.4 (t), 41.0 (t), 41.4 (t), 49.9 (s), 59.9 (q), 60.1 (q), 62.7
(t), 129.08 (s), 129.11 (s), 131.0 (s), 132.9 (s), 151.0 (s), 151.1
(s), 182.9 (s); exact mass m/z calcd for C16H22O5 294.14673,
found 294.14641.
cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.22 (s, 3 H), 2.20 (s, 3 H),
2.77 (d, J ) 16.0 Hz, 1 H), 2.78 (d, J ) 4.5 Hz, 1 H), 2.95-3.00
(m, 2 H), 3.51-3.56 (m, 2 H), 3.60 (d, J ) 16.0 Hz, 1 H), 3.69
(s, 3 H), 3.78 (s, 3 H), 3.87 (s, 3 H), 4.52 (s, 2 H), 5.04 (d, J )
3.5 Hz, 1 H), 7.22-7.32 (m, 5 H); 13C NMR (CDCl3, 100 MHz)
δ 12.3 (q), 23.3 (q), 27.7 (t), 36.9 (t), 52.1 (q), 55.1 (s), 60.0 (q),
62.2 (q), 69.6 (t), 72.8 (t), 79.8 (d), 127.46 (d), 127.54 (d), 128.3
(d), 129.8 (s), 131.6 (s), 132.1 (s), 133.3 (s), 138.5 (s), 151.1 (s),
152.5 (s), 176.1 (s); exact mass m/z calcd for C24H30O6 414.20425,
found 414.20339.
(S)-5-(2-Hyd r oxyet h yl)-2,6-d im et h yl-4,7-d ioxo-2,3,4,7-
tetr a h yd r o-1H-in d en e-2-ca r boxyylic Acid (52) [(+)-P u r -
a qu in on ic Acid ]. An ice-cold solution of (NH4)2Ce(NO3)6 (46.6
mg, 0.085 mmol) in 1:1 MeCN-water (0.6 mL) was added
over ca. 3 min to a stirred and cooled (0 °C) solution of bis-
ether 51 (10 mg, 0.034 mmol) in 2:1 MeCN-water (0.6 mL)
containing pyridine-2,6-dicarboxylic acid N-oxide (15.6 mg,
0.085 mmol). The solution was stirred at 0 °C for 1 h, the cold
bath was removed, and stirring was continued for 5 h. The
resulting solution was diluted with water (5 mL) and extracted
with CH2Cl2 (3 × 20 mL). The combined organic extracts were
dried (Na2SO4) and evaporated. Flash chromatography of the
residue over silica gel (1 × 17 cm), using 1:3 CH2Cl2-EtOAc,
gave (+)-puraquinonic acid 52 (8.0 mg, 81%) as a yellowish
oil: [R]22D +3.2 (c 0.3, CHCl3); [R]22D +3.1 (c 0.7, CH2Cl3); FTIR
(1R ,2S )-6-(2-Be n zyloxye t h yl)-1-(im id a zole -1-ca r b o-
th ioyloxy)-4,7-d im eth oxy-2,5-d im eth ylin d a n -2-ca r boxy-
lic Acid Meth yl Ester (48). DMAP (0.88 mg, 0.0072 mmol)
and 1,1′-thiocarbonydiimidazole (64.5 mg, 0.362 mmol) were
added to a stirred solution of hydroxy ester 47 (30 mg, 0.0725
mmol) in CH2Cl2 (2 mL). The mixture was refluxed for 19 h.
The solution was then cooled, and MeOH (0.2 mL) was added,
followed by EtOAc (30 mL). The mixture was washed with
brine (5 mL), dried (Na2SO4), and evaporated. Flash chroma-
tography of the residue over silica gel (1 × 10 cm), using 17:
20 EtOAc-hexane, gave imidazolide 48 (37 mg, 96%) as a
colorless oil, which was used without further purification in
the next step.
1
(CH2Cl2 cast) 1705, 1649 cm-1; H NMR (CDCl3, 300 MHz) δ
(S)-5-(2-Ben zyloxyeth yl)-4,7-dim eth oxy-2,6-dim eth ylin -
d a n -2-ca r boxylic Acid Meth yl Ester (49). A mixture of
imidazolide 48 (37 mg, 0.070 mmol), Bu3SnH (0.056 mL, 0.211
mmol), and AIBN (3.4 mg, 0.021 mmol) in dry PhMe (4 mL)
was refluxed for 1.5 h (oil bath). The solution was cooled and
evaporated. Flash chromatography of the residue over silica
gel (1 × 18 cm), using 1:12 EtOAc-hexane, gave ester 49 (20.3
1.41 (s, 3 H), 2.06 (s, 3 H), 2.69-2.79 (m, 4 H), 3.33-3.41 (m,
2 H), 3.74 (t, J ) 6.5 Hz, 2 H); 13C NMR (CDCl3, 125 MHz) δ
12.3 (q), 25.8 (q), 30.0 (t), 42.35 (t), 42.39 (t), 46.92 (s), 61.5
(t), 141.3 (s), 142.7 (s), 145.2 (s), 145.6 (s), 181.2 (s), 185.5 (s),
186.0 (s); exact mass m/z calcd for C14H16O5 264.09976, found
264.09970. HPLC comparison with a racemic sample and also
with the natural product was done using a Chiracel OD-RH
column (1:1 i-PrOH-water, 0.3 mL/min, sample dissolved in
MeOH).
mg, 73%) as a colorless oil: [R]22 +2.58 (c 3.1, CH2Cl2); FTIR
D
(CH2Cl2 cast) 1734 cm-1; H NMR (CDCl3, 300 MHz) δ 1.33
1
(s, 3 H), 2.18 (s, 3 H), 2.84 (AB q, ∆νAB ) 16.0 Hz, J ) 2.0 Hz,
2 H), 2.93-2.98 (m, 2 H), 3.46-3.83 (m, 2 H), 3.49-3.55 (m, 2
H), 3.66 (s, 3 H), 3.69 (s, 3 H), 3.70 (s, 3 H), 4.52 (s, 2 H), 7.23-
7.31 (m, 5 H); 13C NMR (CDCl3, 100 MHz) δ 12.0 (q), 25.1 (q),
27.7 (t), 41.1 (t), 41.5 (t), 50.0 (s), 52.1 (q), 59.9 (q), 60.2 (q),
69.7 (t), 72.8 (t), 127.4 (d), 127.5 (d), 128.3 (d), 128.9 (s), 129.1
(s), 131.1 (s), 132.7 (s), 138.5 (s), 150.8 (s), 151.3 (s), 177.8 (s);
exact mass m/z calcd for C24H30O5 398.20932, found 398.20915.
Ack n ow led gm en t. We thank both the Natural
Sciences and Engineering Research Council of Canada
and AnorMED (Langley, BC) for financial support. We
thank S. Hisaindee for the experiments with 17; 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 natural puraquinonic
(S)-5-(2-Hyd r oxyeth yl)-4,7-d im eth oxy-2,6-d im eth ylin -
d a n -2-ca r boxylic Acid Meth yl Ester (50). Benzyl ether 49
4124 J . Org. Chem., Vol. 69, No. 12, 2004

Synthesis of Optically Pure (+)-Puraquinonic Acid
experimental general techniques; and procedures for 9-11, 41
and for 2-bromo-5-methoxy-4-methylbenzaldehyde. This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
acid. M.Y. holds a University of Alberta Graduate
Research Assistantship.
Su p p or tin g In for m a tion Ava ila ble: X-ray data for 41;
13C NMR spectra of compounds 9-11, 21-31, 33-38, 40, 41,
42 (more polar), 42 (less polar), 43-45, 47, and 49-52;
J O040115B
J . Org. Chem, Vol. 69, No. 12, 2004 4125