Evidence for a trianion intermediate in the metalation of 4-hydroxy-6,7-dimethoxy-8-methyl-2-naphthoic acid. methodology and application to racemic 5,5′-didesisopropyl-5,5′-dialkylapogossypol derivatives

Article abstract of DOI:10.1021/jo102147s

The metalation of 4-hydroxy-6,7-dimethoxy-8-methyl-2-naphthoic acid (8) affording trianion 6 is presented and applied to the regioselective efficient construction of a series of 5,5′-didesisopropyl-5,5′- dialkylapogossypol derivatives 3 that are potent pa

Full text of DOI:10.1021/jo102147s

pubs.acs.org/joc
Evidence for a Trianion Intermediate in the Metalation of 4-Hydroxy-6,7-
dimethoxy-8-methyl-2-naphthoic Acid. Methodology and Application
0
0
to Racemic 5,5 -Didesisopropyl-5,5 -dialkylapogossypol Derivatives
‡
Tin Thanh Le, Nguyet Trang Thanh Chau, Tai Tan Nguyen, Josselin Brien,
‡,§
‡
‡
‡
‡
‡
§
Trieu Tien Thai, Arnaud Nourry, Anne-Sophie Castanet, Kim Phi Phung Nguyen, and
,‡
Jacques Mortier*
‡
Universit eꢀ du Maine and CNRS, Unit eꢀ de Chimie Organique Mol eꢀ culaire et Macromol eꢀ culaire (UMR
011), Facult eꢀ des Sciences, avenue Olivier Messiaen, 72085 Le Mans Cedex 9, France, and University of Ho
§
6
ꢀ
Chi Minh City, Ecole des Sciences naturelles, Laboratoire de Chimie Organique, 227/2 Nguyen van Cu.
Arrondissement 5, Ho Chi Minh City, Viet Nam
jacques.mortier@univ-lemans.fr
Received October 28, 2010
The metalation of 4-hydroxy-6,7-dimethoxy-8-methyl-2-naphthoic acid (8) affording trianion 6 is
0
presented and applied to the regioselective efficient construction of a series of 5,5 -didesisopropyl-
0
5,5 -dialkylapogossypol derivatives 3 that are potent pan-active inhibitors of antiapoptotic Bcl-2
family proteins.
Introduction
Due to the ample ortho substitution present in the com-
plex polyphenolic binaphthyl gossypol (1) (Figure 1), the
yellow main pigment of cotton seed, restricted rotation
about the symmetrically structural aryl-aryl bond shows
relatively stable axially chiral enantiomers and indeed both
1
have been isolated from natural sources. Compound 1
displays multiple pharmacological applications: male oral
contraceptive, treatment of bronchitis, total inhibitor of the
replication of HIV 1, in vitro antiviral activity against herpes
FIGURE 1. Gossypol (1) and apogossypol (2).
1
type 2 virus, influenza virus.
These are gossypol’s anticancer properties that have most
recently generated the most interest. Gossypol is a potent
inhibitor of Bcl-2, Bcl-XL, and Mcl-1, functioning as a BH3
*
To whom correspondence should be addressed. Fax: þ33 (0) 243 83 39 02.
1) Reviews: (a) Kenar, J. A. J. Am. Oil Chem. Soc. 2006, 83, 269–302.
b) Dodou, K. Expert Opin. Invest. Drugs 2005, 14, 1419–1434.
2) (a) Kitada, S.; Leone, M.; Sareth, S.; Zhai, D.; Reed, J. C.; Pellecchia,
(
(
(
M. J. Med. Chem. 2003, 46, 4259–4264. (b) Zhang, M.; Liu, H.; Guo, R.;
Ling, Y.; Wu, X.; Li, B.; Roller, P. P.; Wang, S.; Yang, D. Biochem.
Pharmacol. 2003, 66, 93–103.
(3) Ascenta Therapeutics Web site. http://www.ascenta.com/develop-
ment/index.php#at101 (accessed October 27, 2010). See also : Wang, S.;
Yang, D. US2003008924A1, 2003.
DOI: 10.1021/jo102147s
r 2010 American Chemical Society
Published on Web 12/21/2010
J. Org. Chem. 2011, 76, 601–608 601

Le et al.
JOCArticle
2
mimetic. It is currently in phase II clinical trials, displaying
single-agent antitumor activity in patients with advanced
3
malignancies.
In spite of its broad biological interest, very little attention
has been paid to the total synthesis of 1. A formal racemic
4
synthesis was reported by Edwards and Cashaw in 1956. In
the course of their synthesis of desapogossypol hexamethyl
ether, Shirley reported an organolithium-CoBr oxidative
2
5
coupling that proceeded in poor yield (25%). The first
asymmetric total synthesis of (S)-(þ)-gossypol was described
by Meyers using chiral oxazolines as the naphthyl substitu-
ent via an asymmetric Ullmann coupling.
6
Whereas many efforts were focused on modifying the
hydrophilicity of gossypol’s structure by hemisynthesis to
1
enhance its therapeutic effects while minimizing its toxicity,
almost nothing is known about the influence of the two
0
0
hydrophobic 5,5 -diisopropyl and 3,3 -dimethyl moieties.
Recent docking studies suggest that it might be possible to
modulate the biological activity in terms of efficiency and
0
0
FIGURE 2. 5,5 -Didesisopropyl-5,5 -dialkylapogossypol derivatives
from naphthoic acid precursors 8 and 9.
3
0
specificity by modifying the substitution pattern at the 5,5
7
positions. In mice studies, compound 1 displays some
known to promote 1,4-addition of metallating agents to the
12
toxicity and off target effects likely due to the two reactive
aldehyde groups, which are important for targeting other
cellular proteins such as dehydrogenases, for example. Apo-
gossypol (2), a degradation derivative of 1 that lacks the
aldehydes, retains activity against antiapoptotic Bcl-2 family
naphthalene π-system.
Since lateral lithiation of 8 involves the formation of a
trianion 6 that is unprecedented in the naphthalene series,
metalation of trimethoxylated naphthoic acid 9 via the inter-
mediacy of dianion 7 was preliminarily tested. Last, reduc-
tion of the carboxylate of compound 4 followed by dimeriza-
tion of the resulting R-naphthol should provide apogossypol
derivatives 3.
8
proteins in vitro and in cells.
A recent report by Pellecchia et al. describing an hemi-
9
0
synthesis to 5,5 -substituted apogossypol derivatives 3 that
replaces the isopropyl groups with alkyl groups prompts
us to describe our own results in reaching these important
substances. Retrosynthetic analysis pointed to a naphthoic
acid such as 8 as a possible precursor to the apogossypol
skeleton (Figure 2). Lateral lithiation of 8 followed by
alkylation should afford in principle naphthoic acid 4 posses-
sing the requisite alkyl substituent. Parent 1- and 2-naphthoic
acids display a rather complex reactivity toward organolithium
SCHEME 1. Preparation of 4-Hydroxy-6,7-dimethoxy-8-
methyl-2-naphthoic Acid (8) and 4,6,7-Trimethoxy-8-methyl-2-
naphthoic Acid (9)
10
reagents. Therefore, compound 8 can be metalated poten-
11
10
tially by strong bases ortho to the carboxy and methoxy
functions, i.e., in positions 1, 3, and 5. The CO H group is also
2
(
4) (a) Edward, J. D., Jr.; Cashaw, J. L. J. Am. Chem. Soc. 1956, 78, 3224–
225. See also: (b) Ognyanov, V. I.; Petrov, O. S.; Tiholov, E. P.; Mollov,
N. M. Helv. Chim. Acta 1989, 72, 353–360. (c) Venuti, M. C. J. Org. Chem.
981, 46, 3124–3127.
3
1
(
(
5) Shirley, D. A.; Dean, W. L. J. Am. Chem. Soc. 1957, 79, 1205–1207.
6) (a) Meyers, A. I.; Willemsen, J. J. Chem. Commun 1997, 1573–1574.
(
b) Meyers, A. I.; Willemsen, J. J. Tetrahedron 1998, 54, 10493–10511.
7) Brown, W. M.; Metzger, L. E.; Barlow, J. P.; Humsaker, L. A.; Deck,
L. M.; Royer, R. E.; Vander Jagt, D. L. Chem.-Biol. Interact 2003, 143-144,
81–491.
8) Becattini, B.; Kitada, S.; Leone, M.; Monosov, E.; Chandler, S.; Zhai,
D.; Kipps, T. J.; Reed, J. C.; Pellecchia, M. Chem. Biol. 2004, 11, 389–395.
9) Wei, J.; Kitada, S.; Rega, M. F.; Stebbins, J. L.; Zhai, D.; Cellitti, J.;
(
Results and Discussion
4
(
Naphthoic acids 8 and 9 were prepared according to
Scheme 1. Reduction of 3,4-dimethoxy-2-methylbenzoic acid
(
13
14
(
Aldehyde 11 was subjected to Stobbe condensation condi-
10) providing aldehyde 11 was achieved with LiAlH /PCC.
4
Yuan, H.; Emdadi, A.; Dahl, R.; Zhang, Z.; Yang, L.; Reed, J. C.; Pellecchia,
M. J. Med. Chem. 2009, 52, 4511–4523.
(10) Tilly, D.; Castanet, A.-S.; Mortier, J. Chem. Lett. 2005, 34, 446–447.
4c
tions by using t-BuOK/dimethyl succinate to give the half-
(11) (a) Nguyen, T. H.; Chau, N. T. T.; Castanet, A.-S.; Nguyen, K. P. P.;
ester acid 12, which was not isolated but directly treated with
sodium acetate in AcOH/Ac O (1:1). After saponification, naph-
thoic acid 8 was isolated in 68% yield (3 steps). Subsequent
Mortier, J. J. Org. Chem. 2007, 72, 3419–3429. (b) Nguyen, T. H.; Castanet,
A.-S.; Mortier, J. Org. Lett. 2006, 8, 765–768. (c) Nguyen, T. H.; Chau,
N. T. T.; Castanet, A.-S.; Nguyen, K. P. P.; Mortier, J. Org. Lett. 2005, 7,
2
2
1
445–2448. (d) Substitution of the methoxy group in unprotected 2-methoxy-
-naphthoic acid and 1-methoxy-2-naphthoic acid to afford the correspond-
ing anthranilic acids occurs upon reaction with lithioamides: Belaud-
Rotureau, M.; Le, T. T.; Phan, T. H. T.; Nguyen, T. H.; Aissaoui, R.; Gohier,
F.; Derdour, A.; Nourry, A.; Castanet, A.-S.; Nguyen, K. P. P.; Mortier, J.
Org. Lett. 2010, 12, 2406–2409.
(13) Prepared by metalation of veratric acid with LTMP (4 equiv) at 0 °C
followed by quench with iodomethane. See: Chau, N. T. T.; Nguyen, T. H.;
Castanet, A.-S.; Nguyen, K. P. P.; Mortier, J. Tetrahedron 2008, 64, 10552–
10557.
(12) Plunian, B.; Mortier, J.; Vaultier, M.; Toupet, L. J. Org. Chem. 1996,
1, 5206–5207.
6
(14) Borchardt, R. T.; Bhatia, P. J. Med. Chem. 1982, 25, 263–271.
6
02 J. Org. Chem. Vol. 76, No. 2, 2011

Le et al.
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SCHEME 2. Lateral Lithiation of 4,6,7-trimethoxy-8-methyl-2-naphthoic Acid (9) and 4-Hydroxy-6,7-dimethoxy-8-methyl-2-
naphthoic Acid (8)
methylation of 8 to give 9 was performed under standard
conditions.
Best results were obtained when the reaction was carried out
with 7 equiv of LTMP in THF at 0 °C, after in situ formation
of the dilithium salt 13 with 2 equiv of n-BuLi at -78 °C,
followed by addition of MeI. The excess of LTMP produced
a trilithium reagent presumed to be 6 as a reddish brown
solution. No traces of ortho-substitution products were
detected in the crude reaction mixture. An excess of LTMP
was required presumably because the p-electrons of the
methoxy and lithium alkoxide groups coordinate strongly
Lateral lithiation of benzenes requires an ortho-stabilizing
group capable of either delocalizing a negative charge or
1
5
stabilizing the organolithium by coordination. Primary,
allylic, and benzylic halides usually give good yields of
laterally alkylated products. Secondary and acetylenic halides
have been used in several instances. Successful reaction with
these substrates is noteworthy since many aryllithiums arising
from ortho-lithiation reactions do not alkylate or give poor
19
with the base. According to these optimized conditions, 6
also reacted with a variety of iodoalkanes to give the sub-
stitution products 4b-d in excellent yields. The hydroxy
substituent as the lithium alkoxide at position 4, which is
expected to decrease the electrophilicity of the carbonyl group
by an electronic effect, confers stability to 6: self-condensation
was not observed even at 0 °C. To the best of our knowledge,
the formation of a trianion in the naphthalenic series is
16
yields with halides other than iodomethane. Whereas lateral
lithiation of o-toluic acids is readily accomplished by treatment
with LDA, reaction of o-methylanisole with organolithium
15
reagents suffers from competing ortho-lithiation.
LTMP (5 equiv) deprotonated laterally the trimethoxy-
lated naphthoic acid 9 to dianion 7 stabilized by coordina-
tion of the benzylic lithium with the etherial oxygen in
position 7 (Scheme 2). Subsequent alkylation with MeI and
EtI afforded 5a (90%) and 5b (77%). With dimethyl disulfide,
the monosubstitution product 5d was remetalated during the
20,21
unprecedented.
The pentasubstituted naphthalenes 8 and 4a-d were con-
verted to the alcohols 14 and 15a-d by treatment with LiAlH4
in refluxing THF (Scheme 3). Catalytic hydrogenation of 14,
15a-d to give 5-alkyl-6,7-dimethoxy-3-methylnaphthalen-1-ols
17
quench to provide 5c exclusively. Under in situ quench (ISQ)
conditions, in which 9 was added to a mixture of LTMP/
18
TMSCl at -78 °C, 5e was isolated in 88% yield.
To our delight, lateral lithiation/alkylation of naphthoic
acid 8 with LTMP/MeI afforded 4a in excellent yield (96%).
(19) Marsais, F.; Cronnier, A.; Trecourt, F.; Qu ꢀe guiner, G. J. Org. Chem.
1
987, 52, 1133–1136.
20) Only one example of lateral lithiation of a naphthoic acid derivative
(
was mentioned in the literature: Hauser, F. M.; Rhee, R. J. Am. Chem. Soc.
1977, 99, 4533–4534. Compound A, upon treatment with LDA, was con-
verted to a dilithium anion B which was carboxylated and hydrolyzed to give
naphthaleneacetic acid C. The benzylic anion is stabilized by coordination of
the lithium with the carboxylate.
(
15) (a) Clark, R. D.; Jahangir, A. Org. React. 1995, 47, 1–314. (b) Clayden,
J. Organolithiums: Selectivity forSynthesis; Pergamon: Oxford, 2002; pp 73-85.
16) (a) Bennetau, B.; Mortier, J.; Moyroud, J.; Guesnet, J. L. J. Chem.
Soc., Perkin Trans. 1 1995, 1265–1271. (b) Flippin, L. A. Tetrahedron Lett.
991, 32, 6857–6860. (c) Buttery, C. D.; Knight, D. W.; Nott, A. P. Tetra-
(
1
hedron Lett. 1982, 23, 4127–4130. (d) Comins, D. L.; Brown, J. D.; Mantlo,
N. B. Tetrahedron Lett. 1982, 39, 3979–3982.
(17) Remetalation of 5d presumably occurs faster than destruction of the
excess of LTMP by the electrophile. See: Gohier, F.; Castanet, A.-S.;
Mortier, J. J. Org. Chem. 2005, 70, 1501–1504.
(18) Krizan, T.; Martin, J. J. Am. Chem. Soc. 1983, 105, 6155–6157.
J. Org. Chem. Vol. 76, No. 2, 2011 603

Le et al.
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0
0
SCHEME 3. Synthesis of 5,5 -Didesisopropyl-5,5 -dialkylapogossypol (3)
2
2,23
1
6, 17a-d was not straightforward.
The presence of three
oxygen atoms makes the naphthalene ring easily reducible.
was obtained (55:45). Best yields of 16, 17a-d were ob-
tained when the reduction was carried out with 10% Pd/C
6
Under the experimental conditions used by Meyers, 14 was
directly transformed into 1,2,3,4-tetrahydronaphthalene 21
86%). At higher temperature (70 °C) a mixture of 16, 21
under a pressure of 3.5 bar of H and a catalytic amount of
2
2
4
HCl for a shorter reaction time (10-45 min).
The phenolic coupling of 14 leading to binaphthalenediol
(
2
5
1
was determined by the NOESY technique. Upon warming
8 was achieved with t-Bu O in 72% yield. Structure of 18
2 2
2
6
(
21) Lateral lithiations involving trianions are very scarce. See: (a) Tahara,
N.; Fukuda, T.; Iwao, M. Tetrahedron Lett. 2004, 45, 5117–5120. (b) Katz,
A. H.; Demerson, C. A.; Shaw, C. C.; Asselin, A. A.; Humber, L. G.; Conway,
K. M.; Gavin, G.; Guinosso, C.; Jensen, N. P.; Mobilio, D.; Noureldin, R.;
Schmid, J.; Shah, U.; Van Engen, D.; Chau, T. T.; Weichman, B. M. J. Med.
Chem. 1988, 31, 1244–1250.
22) Hudlicky, M. Reductions in Organic Chemistry; Wiley: New York,
984; pp 76-81.
23) (a) Bringmann, G.; Ochse, M.; G o€ tz, R. J. Org. Chem. 2000, 65,
(24) Frija, L. M. T.; Cristiano, M. L. S.; Guimar ~a es, E. M. O.; Martins,
N. C.; Loureiro, R. M. S.; Bickley, J. F. J. Mol. Catal. A: Chem. 2005, 242
(1-2), 241–250.
(
(25) Armstrong, D. R.; Breckenbridge, R. J.; Cameron, C.; Nonhebel,
D. C.; Pauson, P. L.; Perkins, P. G. Tetrahedron Lett. 1983, 24, 1071–1074.
(26) The protons H4,H4 (7.60 ppm) show clear interactions with the
1
0
(
2
2
069–2077. (b) Bringmann, G.; Hamm, A.; Schraut, M. Org. Lett. 2003, 5,
805–2808.
methyl group at 2.54 ppm. There are also spatial interactions between H8,
H8 (7.50 ppm) and MeO (3.91 ppm).
0
6
04 J. Org. Chem. Vol. 76, No. 2, 2011

Le et al.
JOCArticle
at 200 °C, neat compounds 16, 17a-d dimerized to binaph-
thols 19, 20a-d in high yields. Binaphthol 19 was also ob-
tained by catalytic hydrogenation of 18 (90%). Subsequent
(20 mL), then the DCM solution was washed with water (3 ꢀ 10
4
mL), dried over MgSO , and concentrated in vacuo. Chromatog-
raphy on silica gel (cyclohexane/ethylacetate 9:1) gave methyl
4,6,7-trimethoxy-8-methyl-2-naphthoate as a white solid (0.260 g,
27
demethylation with boron tribromide afforded the expected
0
1
0
90%). Mp 125-126 °C. H NMR (200 MHz, CDCl
3
) δ 8.28
5
,5 -didesisopropyl-5,5 -dialkylapogossypols 3, 3a-d.
(
(
s, 1H), 7.48 (s, 1H), 7.36 (s, 1H), 4.05 (s, 3H), 4.01 (s, 3H), 3.97
s, 3H), 3.87 (s, 3H), 2.64 (s, 3H). C NMR (50 MHz, CDCl )
3
13
Conclusion
δ167.7, 154.6, 153.7, 147.8, 128.8, 127.7, 125.7, 125.2, 119.9, 102.6,
-
1
9.6, 60.7, 55.7, 55.6, 52.1, 11.6. IR (ATR, cm ) 3002, 2947, 1709,
9
This straightforward de novo synthesis gives access to a
variety of apogossypol derivatives which are not accessible
1599. Anal. Calcd for C16
65.95, H, 6.25. HRMS m/z calcd for C16
H
18
O
5
: C, 66.19, H, 6.25. Found: C,
([M þ H] )
þ
9
by conventional hemisynthetic means. The mesylates/tosy-
H
19
O
5
2
91.1232, found 291.1241.
Methyl 4,6,7-trimethoxy-8-methyl-2-naphtoate (0.260 g,
.896 mmol) was dissolved in aq 1 M KOH (12.5 mL). The
lates derived from 14, 15a-d and 18 are particularly useful
in that they may be used in substitution reactions with a wide
variety of nucleophiles to give apogossypol analogues mod-
0
resulting mixture was heated to reflux overnight, cooled to rt,
and acidified to pH 2 (aq 2 M HCl). The white precipitate was
filtered off, washed with water, and dissolved in ethylacetate.
0
28
0
ified in the 3,3 positions. The 2,2 -binaphthalenes 3 were
screened to determine their effect on the development of
tumoral cells. These results will be reported elsewhere.
4
The organic layer was dried over MgSO and concentrated in
vacuo to provide pure 4,6,7-trimethoxy-8-methyl-2-naphthoic
acid (9) as a white solid (0.228 g, 92%). Mp 126-127 °C.
Experimental Section
1
3
H NMR (200 MHz, CDCl ) δ 8.41 (s, 1H), 7.50 (s, 1H), 7.42
(
s, 1H), 4.07 (s, 3H), 4.02 (s, 3H), 3.88 (s, 3H), 2.66 (s, 3H).
C NMR (100 MHz, DMSO-d ) δ 167.7, 154.0, 153.2, 147.4,
A. Preparation of 4-Hydroxy-6,7-dimethoxy-8-methyl-2-
naphthoic Acid (8). To a solution of 3,4-dimethoxy-2-methylben-
zaldehyde (11) (6.50 g, 0.036 mol) and dimethyl succinate (4.8
mL, 0.036 mol) in dry DMF (150 mL) was added t-BuOK (4.83 g,
1
3
6
29
1
1
28.0, 126.9, 126.1, 124.7, 118.9, 102.7, 99.3, 60.2, 55.6, 55.4,
1.2. IR (ATR, cm ) 2940, 1678, 1603. HRMS m/z calcd for
-
1
þ
C H O ([M þ H] ) 277.1076, found 277.1073.
0.043 mol). The mixture was allowed to stir at rt overnight. Water
15 17
5
C. Lateral Lithiation of 4,6,7-Trimethoxy-8-methyl-2-naphthoic
Acid (9) and 4-Hydroxy-6,7-dimethoxy-8-methyl-2-naphthoic Acid
(
100 mL) was added and the mixture was washed with diethyl
ether (3 ꢀ 100 mL). The aqueous layer was acidified to pH 3 by
(
8). Lateral Lithiation of 4,6,7-Trimethoxy-8-methyl-2-naphthoic
adding aq 3 M HCl and extracted with diethyl ether (3 ꢀ 100 mL).
Acid (9). General Procedure. 4,6,7-Trimethoxy-8-methyl-2-naphthoic
acid (9) in dry THF (20 mL/mmol of 9) was added dropwise to a
solution of LTMP in THF (1.5 M, 5 equiv) at 0 °C. The resulting
mixture was allowed to warm to rt, stirred for 2 h, and treated with
an electrophile (8-10 equiv). After 2 h of stirring, water (15 mL)
was added. The aqueous layer was washed with diethyl ether (2 ꢀ
4
The combined organic layers were dried over MgSO , and the
solvent was evaporated in vacuo to yield half ester acid 12
10.26 g). The crude compound 12 was then dissolved in acetic
acid/acetic anhydride (1:1, 200 mL), dry sodium acetate (6.50 g,
.079 mol) was added, and the mixture was refluxed overnight.
The resulting solution was cooled at 0 °C and neutralized to pH
(
0
1
5 mL), acidified to pH 1-2 by adding aq 2 M HCl, and extracted
6-7 with aq 2.5 M NaOH. Diethyl ether (100 mL) was added to
with diethyl ether (3 ꢀ 15 mL). The combined organic layers were
dissolve the yellow precipitate. The aqueous layer was extracted
withdiethylether (5ꢀ 100 mL). The combined organiclayers were
dried over MgSO and concentrated in vacuo. The crude residue
4
was recrystallized to give naphthoic acids 5a-d.
8
pared from 4,6,7-trimethoxy-8-methyl-2-naphthoic acid (9)
(
(
4
dried over MgSO and the solvent was evaporated in vacuo to give
-Ethyl-4,6,7-trimethoxy-2-naphthoic Acid (5a). 5a was pre-
a crude residue (21.71 g) that was dissolved in aq 2.5 M NaOH/
methanol (1:1, 250 mL). The mixture was refluxed overnight.
After evaporation of MeOH, the resulting solution was acidified
at 0 °C to pH 2 by adding aq 3 M HCl, then the precipitate
was filtered and washed with hot chloroform. The precipitate
was dissolved in ethylacetate, then the organic layer was dried
0.414 g, 1.5 mmol), LTMP (7.5 mmol), and iodomethane
0.93 mL, 15 mmol) according to the general procedure. Recrys-
tallization (cyclohexane/ethylacetate) gave 8-ethyl-4,6,7-tri-
methoxy-2-naphthoic acid (5a) as a white solid (0.392 g, 90%).
1
Mp 234 °C. H NMR (200 MHz, acetone-d
6
) δ 8.22 (s, 1H), 7.44
(
MgSO ) and concentrated in vacuo to yield 4-hydroxy-6,7-
4
(
(
s, 1H), 7.29 (s, 1H), 3.96 (s, 3H), 3.89 (s, 3H), 3.78 (s, 3H), 3.02
q, J=7.5 Hz, 2H), 1.16 (t, J=7.5 Hz, 3H). CNMR(100 MHz,
dimethoxy-8-methyl-2-naphthoic acid (8) as a pale yellow solid
6.37 g, 68% calculated from 3,4-dimethoxy-2-methylbenzalde-
13
[
1
DMSO-d ) δ 167.8, 154.2, 153.2, 146.9, 132.9, 127.0, 126.5, 125.0,
1
2940, 2826, 2637, 1682, 1464. HRMS calcd for C16
H] ) 291.1232, found 291.1230.
,6,7-Trimethoxy-8-propyl-2-naphthoic Acid (5b). 5b was pre-
pared from 4,6,7-trimethoxy-8-methyl-2-naphthoic acid (9)
hyde (11)]. Mp >250 °C dec. H NMR (400 MHz, acetone-d )
δ 8.23 (s, 1H), 7.56 (s, 1H), 7.48 (s, 1H), 4.02 (s, 3H), 3.86 (s, 3H),
2
6
6
-
1
18.5, 102.6, 99.6, 60.6, 55.6, 55.4, 18.6, 15.4. IR (KBr, cm )
13
H O
19 5
([M þ
.61 (s, 3H). C NMR (50 MHz, DMSO-d
6
) δ 167.8, 152.7, 152.4,
þ
147.2, 128.5, 126.6, 126.2, 124.4, 117.3, 106.7, 99.7, 60.2, 55.4, 11.2.
IR (ATR, cm ) 3418, 3002, 2942, 1678, 1601. HRMS calcd for
-1
4
þ
C H O
14 15 5
([M þ H] ) 263.0919, found 263.0912.
(
(
0.202 g, 0.73 mmol), LTMP (3.65 mmol), and iodoethane
0.47 mL, 5.84 mmol) according to the general procedure.
B. Preparation of 4,6,7-Trimethoxy-8-methyl-2-naphthoic
Acid (9). To a solution of 4-hydroxy-6,7-dimethoxy-8-methyl-2-
naphthoic acid (8) (0.262 g, 1 mmol) in acetone (10 mL) were
added successively potassium carbonate (0.553 g, 4 mmol) and
dimethyl sulfate (0.21 mL, 2.2 mmol). The mixture was stirred
at rt for 24 h, the insoluble was filtered off, and the filtrate
was concentrated in vacuo. The residue was dissolved in DCM
Recrystallization (cyclohexane/ethylacetate) gave 4,6,7-trimethoxy-
8-propyl-2-naphthoicacid (5b) asa white solid(0.170 g, 77%). Mp
2
1
6
23-224 °C. H NMR (200 MHz, acetone-d ) δ 8.44 (s, 1H), 7.53
(s, 1H), 7.41 (s, 1H), 4.07 (s, 3H), 4.03 (s, 3H), 3.91 (s, 3H), 3.11
(t, J = 8.0 Hz, 2H), 1.81-1.62 (m, 2H), 1.08 (t, J = 7.4 Hz, 3H).
1
3
6
C NMR (100 MHz, DMSO-d ) δ 167.8, 154.1, 153.0, 147.2,
131.3, 127.3, 126.5, 124.9, 118.6, 102.5, 99.6, 60.4, 55.5, 55.4, 27.3,
23.8, 14.2. IR (KBr, cm ) 3438, 2962, 2646, 1686, 1602, 1505,
(
27) Royer, R. E.; Deck, L. M.; Vander Jagt, T. J.; Martinez, F. J.; Mills,
R. G.; Young, S. A.; Vander Jagt, D. L. J. Med. Chem. 1995, 38, 2427–2432.
28) See: Mortier, J.; Castanet, A.-S.; Chau, N. T. T. WO2009080949A1,
009.
29) Prepared from 3,4-dimethoxy-2-methylbenzoic acid (10) according
-
1
þ
(
1
422, 1259, 1062, 838. HRMS calcd for C17
H O
21 5
([M þ H] )
2
305.1389, found 305.1391.
(
8-[Bis(methylthio)methyl]-4,6,7-trimethoxy-2-naphthoic Acid
(5c). 5c was prepared from 4,6,7-trimethoxy-8-methyl-2-naphthoic
to ref 14. Compound 10 was prepared by metalation of veratric acid with
LTMP (4 equiv) at 0 °C followed by quench with iodomethane: see ref 13.
J. Org. Chem. Vol. 76, No. 2, 2011 605

Le et al.
JOCArticle
1
acid (9) (0.120 g, 0.44 mmol), LTMP (2.2 mmol), and dimethyl
disulfide (0.33 mL, 4.4 mmol) according to the general procedure.
Recrystallization (cyclohexane/ethylacetate) gave 8-(bis(methyl-
thio)methyl)-4,6,7-trimethoxy-2-naphthoic acid (5c) as a yellow
Mp 226-228 °C. H NMR (400 MHz, acetone-d ) δ 8.26 (s, 1H),
7.57 (s, 1H), 7.45 (s, 1H), 4.01 (s, 3H), 3.89 (s, 3H), 3.08 (m, 2H),
1.69 (m, 2H), 1.05 (t, J = 7.5 Hz, 3H). C NMR (100 MHz,
acetone-d ) δ 168.3, 154.3, 153.3, 148.8, 132.5, 129.4, 126.9,
126.2, 119.3, 107.6, 101.1, 61.0, 55.9, 28.5, 24.9, 14.7. IR
(ATR, cm ) 3390, 2963, 2929, 2873, 1675, 1617, 1468. HRMS
] ) 308.1498, found 308.1495.
D. Preparation of 3-(Hydroxymethyl)-6,7-dimethoxy-5-alkyl-
naphthalen-1-ols 14 and 15a-d. 3-(Hydroxymethyl)-6,7-dimeth-
oxy-5-methylnaphthalen-1-ol (14). To a suspension of LiAlH
4
(0.30 g, 7.92 mol) in dry THF (3 mL) was added dropwise a
solution of 4-hydroxy-6,7-dimethoxy-8-methyl-2-naphthoic acid (8)
6
1
3
6
1
solid (0.095 g, 60%). Mp >250 °C dec. H NMR (200 MHz,
-
1
acetone-d
CH(SCH
6
) δ 9.14 (s, 1H), 7.67 (s, 1H), 7.44 (s, 1H), 5.91 (s, 1H,
þ
3
)
2
), 4.11 (s, 3H), 4.07 (s, 3 H), 3.96 (s, 3 H), 2.28 (s, 6H).
calcd for C16
H
22NO
5
([M þ NH
4
13
C NMR (100 MHz, DMSO-d ) δ 165.4, 151.7, 149.8, 143.9,
6
1
1
1
3
26.4, 123.4, 123.2, 123.0, 119.2, 100.5, 99.1, 58.9, 53.4, 53.3, 46.8,
-
1
4.7. IR (KBr, cm ) 3423, 2940, 2635, 1682, 1601, 1501, 1429,
þ
260, 1040, 850, 697. HRMS calcd for C H O S ([M - SCH ] )
21.0797, found 321.0782.
16
20
5
3
3
0
4
,6,7-Trimethoxy-8-[(trimethylsilyl)methyl]-2-naphthoic Acid
5e). To a solution of LTMP (4.2 mmol) in THF (10 mL) at
78 °C were added successively chlorotrimethylsilane (0.72 mL,
.7 mmol) and 4,6,7-trimethoxy-8-methyl-2-naphthoic acid (9)
0.276 g, 1 mmol). Stirring was maintained at this temperature
(1.04 g, 3.96 mmol) in dry THF (12 mL). The reaction mix-
ture was refluxed overnight, hydrolyzed (10 mL), and acidified
to pH 1-2 by adding aq 2 M HCl. The aqueous layer was
extracted with diethyl ether (3 ꢀ 20 mL). The combined organic
(
-
5
(
4
layers were dried over MgSO and concentrated in vacuo to yield
for 1 h. The reaction mixture was warmed gradually to rt over a
period of 2 h. Water (10 mL) was added and the solution was
basified to pH 10 by adding aq 2 M NaOH. The aqueous layer
was washed with diethyl ether (2 ꢀ 15 mL), acidified to pH 1-2
3-(hydroxymethyl)-6,7-dimethoxy-5-methylnaphthalen-1-ol (14)
as a beige solid (0.96 g, 98%). Mp 175-177 °C. H NMR
6
(400 MHz, acetone-d ) δ 8.84 (s, 1H), 7.50 (s, 1H), 7.38 (s, 1H),
1
6.91 (s, 1H), 4.70(d, J= 5.8Hz, 1H), 4.17 (t, J= 5.8 Hz, 2H), 3.96
(s, 3H), 3.82 (s, 3H), 2.52 (s, 3H). C NMR (100 MHz, CDCl3)
13
(
aq 2 M HCl), and extracted with diethyl ether (3 ꢀ 20 mL). The
combined organic layers were dried over MgSO and concen-
4
δ 151.8, 150.7, 146.8, 137.4, 129.4, 124.8, 120.9, 112.3, 106.4, 99.2,
64.3, 59.6, 54.5, 10.5. IR (ATR, cm ) 3419, 3169, 2935, 2872,
-
1
trated in vacuo. The residue was purified by recrystallization
(cyclohexane/ethylacetate) to yield 4,6,7-trimethoxy-8-[(trimethyl-
silyl)methyl]-2-naphthoic acid (5e) as a white solid (0.307 g, 88%).
þ
1607. HRMS calcd for C14
H
17
O
4
([M þ H] ) 249.1127, found
249.1136. Anal. Calcd for C H O : C, 67.73; H, 6.50. Found: C,
4
1
4
16
1
Mp 236.5-237.5 °C. H NMR (200 MHz, CDCl
3
) δ 8.37 (s, 1H),
67.83; H, 6.51.
General Procedure for the Preparation of 15a-d. To a suspen-
sion of LiAlH (4 equiv) in dry THF (1 mL/mmol of 4a-d) was
7
2
.44 (s, 1H), 7.40 (s, 1H), 4.07 (s, 3H), 4.03 (s, 3H), 3.88 (s, 3H),
1
.63 (s, 2H), 0.02 (s, 9H). C NMR (100 MHz, DMSO-d
3
6
)
4
δ 167.8, 153.9, 153.2, 145.8, 130.4, 127.1, 125.3, 124.8, 120.0,
added dropwise a solution of 4a-d in dry THF (3 mL/mmol).
The reaction mixture was heated at 30 °C overnight. After
hydrolysis and acidification to pH 1-2 (aq 2 M HCl), the
aqueous layer was extracted with diethyl ether (3 ꢀ 20 mL).
-
1
1
2
02.3, 98.0, 59.6, 55.5, 55.3, 16.0, -0.8. IR (KBr, cm ) 2942,
646, 1686, 1599, 1468, 1420, 1263, 1121, 1031, 839. HRMS calcd
þ
for C18
H O
25 5
Si ([M þ H] ) 349.1471, found 349.1468.
Lateral Lithiation of 4-Hydroxy-6,7-dimethoxy-8-methyl-2-
naphthoic Acid (8). General Procedure. To a stirred solution of
dilithium salt 13 [prepared by addition of 2 equiv of n-BuLi to
The combined organic layers were dried over MgSO , and
4
concentrated in vacuo to yield spectroscopically pure com-
pounds 15a-d.
5-Ethyl-3-(hydroxymethyl)-6,7-dimethoxynaphthalen-1-ol (15a).
15a was prepared according to the general procedure from
8-ethyl-4-hydroxy-6,7-dimethoxy-2-naphthoic acid (4a) (0.800 g,
2.90 mmol). Standard workup gave 5-ethyl-3-(hydroxymethyl)-
4
-hydroxy-6,7-dimethoxy-8-methyl-2-naphthoic acid (8) (0.524
g, 2 mmol) at -78 °C] in dry THF (8 mL) at 0 °C was added
dropwise LTMP (14 mmol) in dry THF (16 mL). The mixture
was stirred at 0 °C for 15 min and the electrophile (MeI, EtI, n-
PrI, n-BuI, 10 equiv) was slowly added. The resulting solution
was stirred for 1-3 h and quenched with water (5 mL). The
aqueous phase was washed with ethylacetate (2 ꢀ 20 mL),
acidified to pH 1-2 by adding aq 2 M HCl, and extracted with
ethylacetate (3ꢀ40 mL). The combined organic layers were dried
6,7-dimethoxynaphthalen-1-ol (15a) as a beige solid (0.605 g,
1
80%). Mp 150-152 °C. H NMR (400 MHz, acetone-d
6
) δ 8.71
(s, 1H), 7.50 (s, 1H), 7.43 (s, 1H), 6.88 (s, 1H), 4.70 (d, J = 5.7 Hz,
2H), 4.10 (t, J = 5.7 Hz, 1H), 3.95 (s, 3H), 3.86 (s, 3H), 3.12
(q, J= 7.5 Hz, 2H), 1.23 (t, J= 7.5 Hz, 3H). CNMR(100 MHz,
acetone-d ) δ 153.4, 152.2, 147.9, 139.3, 132.4, 129.9, 122.7, 113.3,
107.6, 101.0, 65.5, 61.0, 55.7, 19.6, 15.7. IR (ATR, cm ) 3431,
13
over MgSO
4
and concentrated in vacuo. The crude residue was
6
-
1
chromatographed over silica gel (ethylacetate) to give naphthoic
acids 4a-d.
3201, 2954, 2866, 1605, 1467, 1409, 1250, 1219. HRMS calcd for
C H O ([M] ) 262.1205, found 262.1194.
3-(Hydroxymethyl)-6,7-dimethoxy-5-propylnaphthalen-1-ol
þ
8
-Ethyl-4-hydroxy-6,7-dimethoxy-2-naphthoic Acid (4a). 4a
15
18 4
was prepared according to the general procedure with iodo-
methane (1.3 mL, 20 mmol) as an electrophile. Stirring was
maintained at 0 °C for 1 h. Purification by column chromatog-
raphy on silica gel (ethylacetate) yielded 8-ethyl-4-hydroxy-6,7-
(15b). 15b was prepared according to the general procedure from
4-hydroxy-6,7-dimethoxy-8-propyl-2-naphthoic acid (4b) (0.400 g,
1.38 mmol). Standard workup gave 3-(hydroxymethyl)-6,7-di-
dimethoxy-2-naphthoic acid (4a) as a beige solid (0.532 g, 96%).
methoxy-5-propylnaphthalen-1-ol (15b) as a beige solid (0.320 g,
1
1
Mp 226-228 °C. H NMR (400 MHz, acetone-d
6
) δ 8.28 (s, 1H),
84%). Mp 169-170 °C. H NMR (400 MHz, acetone-d
6
) δ 8.69
7
7
.59 (s, 1H), 7.49 (s, 1H), 4.03 (s, 3H), 3.91 (s, 3H), 3.15 (q, J =
.6 Hz, 2H), 1.30 (t, J = 7.6 Hz, 3H). C NMR (100 MHz,
(s, 1H), 7.50 (s, 1H), 7.42 (s, 1H), 6.87 (s, 1H), 4.68 (d, J = 5.6 Hz,
2H), 4.08 (t, J = 5.6 Hz, 1H), 3.95 (s, 3H), 3.85 (s, 3H), 3.03-2.99
1
3
13
acetone-d
6
) δ 171.1, 154.5, 153.5, 148.5, 134.2, 129.1, 127.2,
(m, 2H), 1.70-1.61 (m, 2H), 1.03 (t, J = 7.5 Hz, 3H). C NMR
(100 MHz, acetone-d ) δ 153.4, 152.1, 148.2, 139.3, 130.8, 130.2,
122.6, 113.4, 107.5, 101.0, 65.4, 60.9, 55.7, 28.6, 24.7, 14.8. IR
-
1
1
3
1
26.4, 119.2, 107.8, 101.2, 61.2, 56.0, 19.8, 15.9. IR (ATR, cm
338, 2934, 1671, 1602, 1582, 1471, 1435, 1407, 1278, 1257, 1230,
213, 1177. HRMS calcd for C15
)
6
þ
-1
H
17
O
5
([M þ H] ) 277.1076,
(ATR, cm ) 3431, 3425, 3175, 2947, 2867, 1606, 1468, 1415.
þ
found 277.1074.
-Hydroxy-6,7-dimethoxy-8-propyl-2-naphthoic Acid (4b). 4b
HRMS calcd for C16
H O
21 4
([M þ H] ) 277.1440, found 277.1436.
4
E. Preparation of 6,7-Dimethoxy-3-methyl-5-alkylnaphthalen-
1-ols 16, 17a-d and 6,7-Dimethoxy-2,8-dimethyl-1,2,3,4-tetra-
hydronaphthalene (21). General Procedure. To a solution of
was prepared according to the general procedure with iodo-
ethane (1.6 mL, 20 mmol) as an electrophile. Stirring was main-
tained at 0 °C for 2 h. Purification by column chromatography
on silica gel (ethylacetate) afforded 4-hydroxy-6,7-dimethoxy-8-
propyl-2-naphthoic acid (4b) as a beige solid (0.566 g, 98%).
(30) Tetsuya, T.; Hirohisa, D.; Tokutaro, O.; Tsuyoshi, O.; Iwao, O.;
Eiichi, K. Tetrahedron 2004, 60, 6295–6310.
6
06 J. Org. Chem. Vol. 76, No. 2, 2011

Le et al.
JOCArticle
F. Dimerization Reactions. Preparation of Binaphthalenes 19,
3
1
(
-(hydroxymethyl)-6,7-dimethoxy-5-alkylnaphthalen-1-ols 14,
5a-d in ethanol (10 mL/mmol) was added 10% Pd/C
0.160 g/mmol) and aq 1 M HCl (1 mL/mmol). The reaction
20a-d. General Procedure. The neat compounds 16, 17a-d
3
1
were heated overnight at 200 °C to give the products 19,
20a-d which were purified by sublimation.
mixture was stirred for 45 min at 25 °C (10 min for 14) under a
hydrogen pressure of 3.5 bar. The catalyst was filtered off over
Celite 545 and washed with acetone. The combined filtrates
were concentrated in vacuo to give a residue that was dissolved
in DCM (10 mL/mmol). The DCM layer was washed with sat.
2-(1-Hydroxy-6,7-dimethoxy-3,5-dimethylnaphthalen-2-yl)-
6,7-dimethoxy-3,5-dimethylnaphthalen-1-ol (19). 19 was prepared
according to the general procedure from 6,7-dimethoxy-3,5-di-
methylnaphthalen-1-ol (16) (0.400 g, 1.72 mmol). 2-(1-Hydroxy-
6,7-dimethoxy-3,5-dimethylnaphthalen-2-yl)-6,7-dimethoxy-3,5-
3 4
NaHCO and water, and dried over MgSO . Concentration in
vacuo gave a residue that was purified by chromatography on
silica gel (cyclohexane/ethylacetate 8:2).
dimethylnaphthalen-1-ol (19) was isolated as a brown solid
1
(0.364 g, 91%). Mp >290 °C dec. HNMR(400MHz, DMSO-d )
6
6,7-Dimethoxy-3,5-dimethylnaphthalen-1-ol (16). 16was prepared
δ 8.23 (s, 2H), 7.48 (s, 2H), 7.33 (s, 2H), 3.90 (s, 6H), 3.76 (s, 6H),
1
3
according to the general procedure from 3-(hydroxymethyl)-6,7-
dimethoxy-5-methylnaphthalen-1-ol (14) (1.656 g, 6.67 mmol).
Standard workup followed by recrystallization (cyclohexane/
ethylacetate) and chromatography on silica gel (cyclohexane/
ethylacetate 9:1) provided pure 6,7-dimethoxy-3,5-dimethylnaph-
2.51 (s, 6H), 1.98 (s, 6H). C NMR (100 MHz, DMSO-d
6
)
δ 150.3, 149.4, 146.6, 133.5, 128.9, 124.3, 120.7, 118.2, 115.3,
100.5, 60.2, 55.3, 20.5, 11.2. IR (ATR, cm ) 3342, 2954, 2901,
-
1
1604, 1573, 1486, 1473, 1457, 1412, 1400, 1368, 1334, 1244, 1189,
1138. HRMS calcd for C28H
31
463.2138.
þ
O
6
([M þ H] ) 463.2121, found
thalen-1-ol (16) as a beige solid (1.100 g, 71%). Mp 165 °C.
1
H NMR (400 MHz, DMSO-d ) δ 9.86 (s, 1H), 7.35 (s, 1H), 7.09
5-Ethyl-2-(5-ethyl-1-hydroxy-6,7-dimethoxy-3-methylnaphth-
alen-2-yl)-6,7-dimethoxy-3-methylnaphthalen-1-ol (20a). 20a
was prepared according to the general procedure from 5-ethyl-
6,7-dimethoxy-3-methylnaphthalen-1-ol (17a) (0.295 g, 1.20 mmol).
5-Ethyl-2-(5-ethyl-1-hydroxy-6,7-dimethoxy-3-methylnaph-
thalen-2-yl)-6,7-dimethoxy-3-methylnaphthalen-1-ol (20a) was
6
(
(
s, 1H), 6.66 (s, 1H), 3.88 (s, 3H), 3.73 (s, 3H), 2.43 (s, 3H), 2.37
13
6
s, 3H). C NMR (100 MHz, DMSO-d ) δ 152.2, 150.2, 146.7,
1
(
C
33.4, 129.6, 124.4, 119.8, 113.9, 109.5, 99.6, 60.1, 55.1, 21.7, 11.1. IR
-
1
ATR, cm ) 3342, 2932, 1605, 1583. HRMS m/z calcd for
þ
H O
14 17 3
([M þ H] ) 233.1178, found 233.1168.
5-Ethyl-6,7-dimethoxy-3-methylnaphthalen-1-ol (17a). 17a was
prepared according to the general procedure from 5-ethyl-
isolated as a brown solid (0.270 g, 92%). Mp >290 °C dec.
1
H NMR (400 MHz, DMSO-d ) δ 8.27 (s, 2H), 7.49 (s, 2H),
6
3
1
6
-(hydroxymethyl)-6,7-dimethoxynaphthalen-1-ol (15a) (0.470 g,
.80 mmol). Standard workup and purification afforded 5-ethyl-
,7-dimethoxy-3-methylnaphthalen-1-ol (17a) as a pale yellow
7.36 (s, 2H), 3.91 (s, 6H), 3.81 (s, 6H), 3.02 (q, J = 7.5 Hz, 4H),
1
3
1.97 (s, 6H), 1.24 (t, J = 7.5 Hz, 6H). C NMR (50 MHz,
DMSO-d ) δ 150.3, 149.6, 146.2, 133.6, 130.5, 127.9, 121.1,
118.0, 114.9, 100.8, 60.5, 55.3, 20.7, 18.5, 15.4. IR (ATR, cm
6
1
-1
solid (0.305 g, 69%). Mp 126-128 °C. H NMR (400 MHz,
CDCl
)
3
) δ 7.37 (s, 1H), 7.27 (s, 1H), 6.59 (s, 1H), 5.18 (s, 1H), 3.97
3383, 2958, 2925, 1600, 1573, 1456, 1401, 1367, 1236, 1191,
([M þ H] ) 491.2434, found
þ
(
(
s, 3H), 3.89 (s, 3H), 3.06 (q, J = 7.5 Hz, 2H), 2.43 (s, 3H), 1.27
t, J = 7.5 Hz, 3H). C NMR (100 MHz, CDCl
1140. HRMS calcd for C30
491.2441.
H
35
O
6
13
3
) δ 151.1, 150.8,
1
2
1
47.0, 133.5, 131.8, 129.4, 120.3, 115.8, 110.1, 99.6, 61.1, 55.5,
2-(1-Hydroxy-6,7-dimethoxy-3-methyl-5-propylnaphthalen-2-
yl)-6,7-dimethoxy-3-methyl-5-propylnaphthalen-1-ol (20b). 20b
was prepared according to the general procedure from 6,7-
dimethoxy-3-methyl-5-propylnaphthalen-1-ol (17b) (0.300 g,
1.15 mmol). 2-(1-Hydroxy-6,7-dimethoxy-3-methyl-5-propyl-
naphthalen-2-yl)-6,7-dimethoxy-3-methyl-5-propylnaphthalen-
-
1
2.0, 19.1, 15.2. IR (ATR, cm ) 3348, 2962, 2932, 1602, 1448,
409, 1373, 1264, 1232, 1215, 1201, 1148. HRMS calcd for
þ
C H O ([M þ H] ) 247.1334, found 247.1331.
1
5
19
3
6,7-Dimethoxy-3-methyl-5-propylnaphthalen-1-ol (17b). 17b
was prepared according to the general procedure from 3-
(
hydroxymethyl)-6,7-dimethoxy-5-propylnaphthalen-1-ol (15b)
0.355 g, 1.28 mmol). Standard workup and purification pro-
1-ol (20b) was isolated as a brown solid (0.260 g, 87%). Mp
1
(
vided 6,7-dimethoxy-3-methyl-5-propylnaphthalen-1-ol (17b)
247-248 °C. H NMR (400 MHz, DMSO-d ) δ 7.95 (s, 2H),
6
7.51 (s, 2H), 7.35 (s, 2H), 3.91 (s, 6H), 3.82 (s, 6H), 2.98 (t, J =
7.9 Hz, 4H), 1.99 (s, 6H), 1.64-1.70 (m, 4H), 1.04 (t, J = 7.5 Hz,
1
(
(
(
3
0.234 g, 70%) as an orange solid. Mp 132-134 °C. H NMR
400 MHz, CDCl ) δ 7.36 (s, 1H), 7.25 (s, 1H), 6.58 (s, 1H), 5.05
br s, 1H), 3.97 (s, 3H), 3.88 (s, 3H), 3.02-2.98 (m, 2H), 2.43 (s,
1
3
3
6
6H). C NMR (50 MHz, DMSO-d ) δ 150.2, 149.5, 146.5,
133.5, 128.9, 128.2, 121.1, 118.0, 115.0, 100.8, 60.4, 55.3, 27.4,
23.7, 20.7, 14.5. IR (ATR, cm ) 3429, 3392, 2931, 2868, 1600,
1
3
-1
H), 1.63-1.72 (m, 2H), 1.05 (t, J = 7.5 Hz, 3H). C NMR (100
) δ 151.0, 150.8, 147.3, 133.4, 130.3, 129.7, 120.2,
16.0, 110.1, 99.6, 61.0, 55.5, 28.0, 24.0, 22.0, 14.6. IR (ATR,
MHz, CDCl
1
3
1574, 1462, 1417, 1404, 1250, 1140, 1096. HRMS calcd for
C H O ([M þ H] ) 519.2747, found 519.2759.
þ
3
2
39
0
6
-1
0
0
0
cm ) 3401, 2956, 2924, 2868, 1601, 1582, 1464, 1411. HRMS
([M þ H] ) 261.1491, found 261.1503.
3,3 -Bis(hydroxymethyl)-6,6 ,7,7 -tetramethoxy-5,5 -dimethyl-
þ
0
0
calcd for C16
H
21
O
3
2,2 -binaphthyl-1,1 -diol (18). To a solution of 3-(hydroxy-
methyl)-6,7-dimethoxy-5-methylnaphthalen-1-ol (14) (113 mg,
0.45 mmol) in chlorobenzene (6 mL) was added di-tert-butyl
6,7-Dimethoxy-2,8-dimethyl-1,2,3,4-tetrahydronaphthalene (21).
To a solution of 3-(hydroxymethyl)-6,7-dimethoxy-5-methyl-
naphthalen-1-ol (14) (77 mg, 0.31 mmol) in ethanol (4 mL) were
added 10% Pd/C (0.15 g) and aq 3 M HCl (0.25 mL). The
reaction mixture was stirred for 24 h at 25 °C under a hydrogen
pressure of 2.7 bar. The catalyst was filtered off over Celite 545
and washed with ethanol (2 ꢀ 20 mL). The filtrate was con-
centrated in vacuo and the residue was dissolved in DCM
4
b,25,32
peroxide (82 μL, 0.45 mmol).
The mixture was heated at
105 °C for 50 h, then cooled and concentrated in vacuo. The
crude residue was recrystallized in benzene to yield 3,3 -bis-
0
0
0
0
0
(hydroxymethyl)-6,6 ,7,7 -tetramethoxy-5,5 -dimethyl-2,2 -bi-
0
naphthyl-1,1 -diol (18) as a white solid (80 mg, 72%). Mp
1
289-291 °C. H NMR (200 MHz, DMSO-d
6
) δ 8.33 (s, 2H),
7.60 (s, 2H), 7.50 (s, 2H), 5.00 (br s, 2H), 4.21 (d, J = 14.0 Hz,
2H), 4.05 (d, J = 14.0 Hz, 2H), 3.91 (s, 6H), 3.78 (s, 6H), 2.54
(s, 6H). In the NOESY spectrum, the protons H4,H4 (7.60 ppm)
show clear interactions with the methyl group at 2.54 ppm.
There are also spatial interactions between H8,H8 (7.50 ppm)
(
20 mL). The DCM layer was washed with sat. NaHCO
10 mL) and water (10 mL), dried over MgSO , and concen-
3
(
trated in vacuo to yield 6,7-dimethoxy-2,8-dimethyl-1,2,3,4-
tetrahydronaphthalene (21) as a yellow orange oil (59 mg,
8
4
0
1
6%). H NMR (200 MHz, DMSO-d
0
6
) δ 6.56 (s, 1H), 3.72
(
(
(
s, 3H), 3.60 (s, 3H), 2.72-2.49 (m, 4H), 2.04 (s, 3H), 1.80-1.72
13
m, 2H), 1.30-1.19 (m, 1H), 1.04 (d, J = 6.4 Hz, 3H). C NMR
(
31) Edward, J. D., Jr.; Cashaw, J. L. J. Am. Chem. Soc. 1957, 79, 2283–
285.
32) Armstrong, D. R.; Cameron, C.; Nonhebel, D. C.; Perkins, P. G.
J. Chem. Soc., Perkin Trans. 2 1983, 563–568.
100 MHz, CDCl ) δ 149.2, 144.1, 131.0, 129.1, 127.1, 108.9,
3
2
5
9.4, 54.6, 34.4, 30.2, 29.1, 28.4, 21.3, 10.5. HRMS, m/z calcd for
(
þ
C H NO ([M þ NH ] ) 238.1807, found 238.1813.
1
4
24
2
4
J. Org. Chem. Vol. 76, No. 2, 2011 607

Le et al.
JOCArticle
1
3
and MeO (3.91 ppm). C NMR (100 MHz, DMSO-d ) δ 150.6,
trihydroxy-3-methylnaphthalen-2-yl)-3-methylnaphthalene-
1,6,7-triol (3a) was isolated as a beige solid (0.073 g, 82%). Mp
) δ 8.86 (br s, 2H),
7.56 (s, 2H), 7.38 (s, 2H), 7.14 (s, 2H), 3.12 (q, J = 7.5 Hz, 4H),
2.07 (s, 6H), 1.30 (t, J = 7.5 Hz, 6H). C NMR (50 MHz,
acetone-d ) δ 151.0, 144.6 (2), 134.1, 130.2, 122.4, 119.7, 115.7,
6
114.6, 103.9, 21.1, 19.2, 14.7. IR (ATR, cm ) 3440, 2962, 2929,
2872, 1613, 1504, 1446, 1264, 1213, 1154. HRMS cacld for
O
3-Methyl-5-propyl-2-(1,6,7-trihydroxy-3-methyl-5-propylnaph-
6
1
6
1
49.2, 146.7, 137.6, 128.9, 124.9, 121.4, 115.0, 112.5, 100.4, 61.6,
-
1
0.2, 55.4, 11.4. IR (KBr, cm ) 3465, 3348, 2942, 1741, 1686,
1
>150 °C dec. H NMR (400 MHz, acetone-d
6
604, 1577, 1470, 1253, 1083, 1004, 844. HRMS, m/z calcd for
þ
13
C
28
H
31
O
G. Deprotection of the Methoxy Groups. Preparation of 5,5 -
8
([M þ H] ) 495.2019, found 495.2028.
0
0
-1
Didesisopropyl-5,5 -dialkylapogossypols 3, 3a-d. General Pro-
cedure. To a solution of binaphthalenes 19, 20a-d dissolved in
þ
dry DCM (40 mL/mmol) at -78 °C was added dropwise BBr
3
C
26
H
27
6
([M þ H] ) 435.1808, found 435.1803.
9
1 M in DCM) (10 equiv). The reaction mixture was stirred for
(
1
h at -78 °C and for 1 h at rt. Aq 6 M HCl (50 mL/mmol)
thalen-2-yl)naphthalene-1,6,7-triol (3b). 3b was prepared according
to the general procedure from 2-(1-hydroxy-6,7-dimethoxy-
3-methyl-5-propylnaphthalen-2-yl)-6,7-dimethoxy-3-methyl-
5-propylnaphthalen-1-ol (20b) (0.100 g, 0.19 mmol). 3-Methyl-5-
propyl-2-(1,6,7-trihydroxy-3-methyl-5-propylnaphthalen-2-yl)-
(
cooled beforehand at 0 °C) was added and the reaction mixture
was stirred at 0 °C for 1 h. The aqueous layer was extracted with
diethyl ether, then the combined organic layers were washed
with water and brine, dried over MgSO , and concentrated in
4
vacuo. The residue was purified by flash chromatography on
silica gel (cyclohexane/ethylacetate 8:2 f 5:5) and C-18 column
naphthalene-1,6,7-triol (3b) was isolated as a beige solid (0.065 g,
1
73%). Mp >150 °C dec. H NMR (400 MHz, acetone-d
6
)
0
chromatography (H
0
2
O/acetonitrile) to provide pure 5,5 -dide-
sisopropyl-5,5 -dialkylapogossypols 3, 3a-d.
δ 8.87 (br s, 2H), 7.56 (s, 2H), 7.40 (br s, 2H), 7.37 (s, 2H),
7.13 (s, 2H), 3.09-3.05 (m, 4H), 2.06 (s, 6H), 1.79-1.70 (m, 4H),
1
3
3,5-Dimethyl-2-(1,6,7-trihydroxy-3,5-dimethylnaphthalen-2-yl)-
1.09 (t, J = 7.5 Hz, 6H). C NMR (50 MHz, acetone-d
6
)
naphthalene-1,6,7-triol (3). 3 was prepared according to the
general procedure from 2-(1-hydroxy-6,7-dimethoxy-3,5-di-
methylnaphthalen-2-yl)-6,7-dimethoxy-3,5-dimethylnaphtha-
len-1-ol (19) (0.112 g, 0.24 mmol). 3,5-Dimethyl-2-(1,6,7-
trihydroxy-3,5-dimethylnaphthalen-2-yl)naphthalene-1,6,7-triol (3)
δ 150.9, 145.0, 144.5, 134.0, 130.5, 121.0, 119.6, 115.9, 114.6,
103.9, 28.1, 23.9, 21.1, 14.8. IR (ATR, cm ) 3445, 2956, 2929,
-
1
2864, 1698, 1614, 1504, 1447, 1376, 1349, 1243, 1210, 1148, 1089.
([M] ) 462.2042, found 462.2052.
þ
HRMS calcd for C28H O
30 6
was isolated as a beige solid (0.077 g, 78%). Mp >150 °C dec.
1
Acknowledgment. T.T.L. and N.T.T.C. are indebted to
the French Ministry of Research and Technologies and the
Agence Universitaire de la Francophonie for doctoral fel-
lowships. We also express appreciation to Patricia Gangnery
and Fr ꢀe d ꢀe ric Legros (Universit ꢀe du Maine) for technical
assistance.
H NMR (200 MHz, acetone-d ) δ 7.54 (s, 2H), 7.30
6
13
(
(
1
2
1
s, 2H), 7.20 (br s, 2H), 2.52 (s, 6H), 2.08 (s, 6H). C NMR
50 MHz, acetone-d ) δ 150.8, 145.1, 144.6, 134.0, 131.1, 119.4,
6
-
1
16.0, 115.8, 114.7, 103.6, 21.0, 11.1. IR (KBr, cm ) 3442,
921, 1691, 1639, 1619, 1508, 1458, 1349, 1310, 1232, 1165,
041, 854. HRMS calcd for C24
þ
H
23
O
6
([M þ H] ) 407.1495,
found 407.1478.
-Ethyl-2-(5-ethyl-1,6,7-trihydroxy-3-methylnaphthalen-2-yl)-
-methylnaphthalene-1,6,7-triol (3a). 3a was prepared according
5
3
Supporting Information Available: Complete experimental
information and details of compound characterization. This
material is available free of charge via the Internet at http://
pubs.acs.org.
to the general procedure from 5-ethyl-2-(5-ethyl-1-hydroxy-6,7-
dimethoxy-3-methylnaphthalen-2-yl)-6,7-dimethoxy-3-methyl-
naphthalen-1-ol (20a) (0.101 g, 0.21mmol). 5-Ethyl-2-(5-ethyl-1,6,7-
6
08 J. Org. Chem. Vol. 76, No. 2, 2011