Synthesis of hemigossypol and its derivatives

Article abstract of DOI:10.1016/j.tetlet.2010.08.089

Hemigossypol (3), a sesquiterpene natural product, was previously isolated from Gossypium barbadense and was shown to display improved anti-fungal activity compared to gossypol (1), the disesquiterpene dimer of hemigossypol (3). Gossypol exhibits multiple biological activities. In order to study whether hemigossypol and its derivatives retain the various bioactivities of gossypol, we developed a short and convenient synthetic scheme to synthesize hemigossypol. This is the first de novo synthesis of this natural product. In addition derivatives of hemigossypol with various 2,5-alkyl substituents were synthesized. Modification of the synthetic scheme also afforded the natural product hemigossylic lactone (4) and its 2,5-substituted derivatives.

Full text of DOI:10.1016/j.tetlet.2010.08.089

Tetrahedron Letters 51 (2010) 5757–5760
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of hemigossypol and its derivatives
a,
b
b
a,
⇑
Jun Wei , David L. Vander Jagt , Robert E. Royer , Lorraine M. Deck
a
Department of Chemistry, University of New Mexico, Albuquerque, NM 87131, United States
Department of Biochemistry and Molecular Biology, University of New Mexico School of Medicine, Albuquerque, NM 87131, United States
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Hemigossypol (3), a sesquiterpene natural product, was previously isolated from Gossypium barbadense
and was shown to display improved anti-fungal activity compared to gossypol (1), the disesquiterpene
dimer of hemigossypol (3). Gossypol exhibits multiple biological activities. In order to study whether
hemigossypol and its derivatives retain the various bioactivities of gossypol, we developed a short and
convenient synthetic scheme to synthesize hemigossypol. This is the first de novo synthesis of this nat-
ural product. In addition derivatives of hemigossypol with various 2,5-alkyl substituents were synthe-
sized. Modification of the synthetic scheme also afforded the natural product hemigossylic lactone (4)
and its 2,5-substituted derivatives.
Received 11 August 2010
Revised 27 August 2010
Accepted 30 August 2010
Available online 6 September 2010
Keywords:
Hemigossypol
Gossypol
Ó 2010 Elsevier Ltd. All rights reserved.
Hemigossylic lactone
Gossypol (1), a natural product from cottonseed, is a disesquiter-
pene exhibiting atropisomerism owing to restricted rotation around
the binaphthyl bond (Fig. 1). Gossypol exhibits multiple biological
to explore SAR of hemigossypol and hemigossylic lactone, we
developed a short and convenient synthetic scheme to synthesize
hemigossypol and its 2,5-alkyl-substituted derivatives. Modifica-
tion of the synthetic scheme also afforded hemigossylic lactone
and its 2,5-alkyl-substituted derivatives.
properties, including spermicidal, antiparasitic,2 anticancer, and
1
3
4
antiviral activities. Gossypol displays potent inhibition against
anti-apoptotic Bcl-2 family proteins where it functions as a BH3 mi-
Synthetic Scheme 1 features the incorporation of the carbon
atoms for the second ring of the naphthalene system in one step
by the reaction of the Grignard reagent formed from 1-bromo-2-
isopropyl-3,4-dimethoxybenzene (5a) and 1-bromo-3,4-dime-
thoxy-2-propylbenzene (5c) with ethyl 3-methyl-4-oxobutanoate
(6a) and ethyl 2,3-dimethyl-4-oxobutanoate (6b) to form lactones
5
mic. (ꢀ)-Gossypol is currently in phase II clinical trails, displaying
single-agent antitumor activity in patients with advanced malig-
6
,7
nancies. Multiple bioactivities of gossypol have stimulated wide
interest in the development of gossypol derivatives to explore struc-
8
–13
ture–activity relationships.
We have previously reported that
9
19
gossylic lactone (2) (Fig. 1), in which the aldehyde groups of gossy-
pol that contribute to toxicity have been modified, retains antima-
larial activity and exhibits enhanced inhibitory activity compared
to gossypol against aldose reductase, an enzyme implicated in the
7a, 7b, and 7c in 63–70% yield. The precursor bromides are read-
ily prepared from commercially available starting materials using
2
0–22
procedures described in the literature.
In some preparations
2
2
of the bromides using the Edward’s procedure small amounts
9,14
etiology of diabetic complications.
The question of interest is whether hemigossypol (3) and hemi-
gossylic lactone (4) (Fig. 1), the monomers of gossypol and gossylic
lactone, respectively, still retain the various bioactivities of gossy-
pol. Hemigossypol, a natural product isolated from the verticillium-
infected stele tissue of Gossypium barbadense,15 is at least threefold
more toxic to the cotton seedling disease pathogen, Rhizoctonia
O
CHOOH
O
OH
OH
OH
OH
HO
HO
HO
HO
OH CHO
O
O
1
6
solani, than gossypol. Furthermore, it was reported that methyl-
Gossypol (1)
Gossylic Lactone (2)
ated hemigossypol displayed comparable spermicidal activity as
1
7
O
gossypol. Hemigossylic lactone with a methoxy group on posi-
CHOOH
O
tion six is a natural product isolated from the root bark of Bombax
HO
HO
1
8
HO
HO
malabarium; however, bioactivity has not been reported. In order
⇑
Corresponding author. Tel.: +1 505 277 5438.
E-mail address: ldeck@unm.edu (L.M. Deck).
Present address: Sanford-Burnham Institute Medical Research Institute, La Jolla,
Hemigossypol (3)
Hemigossylic Lactone (4)
CA 92037, United States.
Figure 1.
0
040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.089

5
758
J. Wei et al. / Tetrahedron Letters 51 (2010) 5757–5760
OH
H3CO
CH3
H3CO
H3CO
R2
COOEt
CH3
H CO
3
(
a) Mg
(b) H SO4
2
+
H3CO
Br
R2
OHC
H CO
R1
O
3
R1
a, 5c
(g) BBr3,
CH(OEt)3
O
(f) BBr3, CH(OEt)3
8
5
6a, 6b
7a-7c
(c) BBr3
CHOOH
O
OCH3
CHO
OH
OH
HO
HO
R2
O
R2
H3CO
H3CO
HO
CHO
HO
HO
R2
(d) TiCl4,
(
h)
+
HO
(CH3O)2SO2, HO
K2CO3
2
Cl CHOCH3
R1
R1
10a-10c
R1
9a-9c
(
e) H3O+
12
11
3a-3c
a: R = CH(CH ) , R = H
1
3 2
2
b: R1 = CH(CH3)2, R2 = CH3
c: R1 = (CH2)2CH3, R2 = CH3
Scheme 1. Synthesis of hemigossypol. Reagents and conditions: (a) Mg (3 equiv), BrCH
0% of 7a, 66% of 7b, 63% of 7c; (b) concentrated sulfuric acid, rt, 60 °C, 2.0 h, 5%; (c) BBr
5 equiv), Et O/CH Cl , 0 °C, 15 min, then Cl CHOCH (2 equiv), 0 °C, 3 h, rt, 18 h, 16% of 3a, 10% of 3b, 20% of 3c, and 4% of 10a, 34% of 10b, 25% of 10c; or 9b,
hexamethylenetetramine (0.5 equiv), HAc, 100 °C, 1.0 h, then H SO /H O, 60 °C, 2 h, 25% 10b; (e) CH CN/H O, 6 M HCl, rt, 18 h, 90% of 3b, 100% of 3c; (f) BBr (7 equiv),
CH Cl , 0 °C, then reflux 3 h, 0 °C, CH(OC (6 equiv), reflux, 1.0 h, rt, 24 h, 10% of 10b from 7b, 10% of 10c from 7c; (g) BBr (5 equiv), CH Cl , 0 °C, reflux, 3 h, then
CH(OC (6 equiv), 0 °C, reflux, 1 h, rt, 24 h, 25%; (h) (CH O) SO (6.5 equiv), K CO (6.5 equiv), (CH C@O, reflux, 24 h, 90%.
2
CH
2
Br (0.1 equiv), THF, reflux, 1.0 h then 6 (1.2 equiv), 0 °C to rt, 12 h, H
2
O/HCl, rt, 5 h,
7
(
3
(5 equiv), CH Cl
2
2
, 2.0 h, ꢀ78 °C, 24 h, rt, 90% of 9a, 70% of 9b, 81% 9c; (d) TiCl
4
2
2
2
2
3
2
4
2
3
2
3
2
2
2
H
)
5 3
3
2
2
2
H
)
5 3
3
2
2
2
3
3 2
)
4
0
(
5–10%) of the isomeric bromides 5-bromo-3-alkyl-1,2-dime-
triethylorthoformate to give compound 11 in 25% yield. Unfortu-
23
41
thoxybenzene were formed. An alternate highly regioselective
nately, compound 11 is the 2-formyl regioisomer of compound 3
silica gel catalyzed bromination, using N-bromosuccinimide
and its structure was verified by methylation to give the known
compound 12. Using the same conditions on compound 7b,
which has a methyl group in position two, 10% of compound 10b
was obtained.
2
4
17
proved more effective. The precursors ethyl 3-methyl-4-oxobut-
anoate (6a) and ethyl 2,3-dimethyl-4-oxobutanoate (6b) were
prepared by a Horner–Emmons–Wadsworth reaction followed by
hydrogenation of the alkene bond and hydrolysis of the resulting
Since formylation of naphthalenols 9 resulted in poor yields of
product, compounds 9a and 9b were methylated using dimethyl-
acetal as previously described.2
5,26
In our hands hydrogenation
4
2
using palladium on charcoal resulted in loss of a methoxy group
of the acetal but use of palladium on calcium carbonate gave the
desired acetal, which was then hydrolyzed.
sulfate to give compounds 13a and 13b. (Scheme 2). Formylation
0
0
0
0
reactions on the dimeric (5,5 -diisopropyl-1,1 ,6,6 ,7,7 -hexame-
0
0
thoxy-3,3 -dimethyl-2,2 -binaphthalene) and the monomeric form
of compound 13a have been published by Meltzer. Meltzer found
27
37
In the synthesis of gossypol performed by Venuti compound
5
a was transformed to naphthalenol compound 8 in six steps. In
that bisformylation and concomitant loss of both isopropyl groups
occurred on reaction of the dimeric form of compound 13a using
titanium tetrachloride and dichloromethyl methyl ether. Identical
treatment of the monomeric compound, 13a, resulted in formyla-
tion in the 8 position, peri to the isopropyl group. Using these same
conditions we reacted compound 13b and obtained a mixture of
products with the major product lacking an isopropyl group. Fortu-
nately, formylation of compound 13a using t-butyllithium fol-
lowed by the electrophile N-methylformanilide and hydrolysis
gave a 49% yield of compound 14 (Scheme 2) whereas reaction of
one of the steps Venuti proposed compound 7a as an intermediate,
but it was never isolated. We envisioned that lactone 7a could be
converted to naphthalenol 8 in one step using a strong Lewis acid
which would cause the opening of the lactone ring followed by
Friedel–Crafts cyclization of the resulting acid, dehydration, and
2
8
aromatization. Attempts using dilute hydrochloric acid, phos-
phorous trichloride, or titanium tetrachloride failed and concen-
trated sulfuric acid afforded only 5% of the product. However
lactones 7a–7c were successfully converted to naphthalenols
a–9c using boron tribromide in 70–90% yield.29 Compound 9a is
13b using these conditions failed to give the desired product.
17,43
9
1
0
slightly unstable and degrades during chromatography. The alde-
hyde group was introduced by formylation of naphthalenols
Demethylation of compound 14 with boron tribromide afforded
an 80% yield of compound 3a.
9
a–9c with titanium tetrachloride and dichloromethyl methyl
Synthesis of hemigossylic lactone 4a and its derivative, 4c, is
similar to the synthesis of compound 14 except for the electro-
phile. The reaction of compound 13a with t-butyllithium followed
3
0,31
ether
followed by hydrolysis, to successfully afford the natural
product hemigossypol 3a and its derivatives 3b and 3c in moderate
yield. The proton NMR spectrum of compound 3a generally agreed
3
2
44
by methylchloroformate resulted in ester 15a. Bromination of
1
5
43,45
with the literature. Anhydrohemigossypol 10a has been observed
compound 15a gave bromide 15c.
The methyl ether groups
in the mass spectrum of hemigossypol1 and anhydrogossypol, the
5
in compounds 15 were readily removed using boron tribromide
and the resulting mixtures were gently refluxed in dilute hydro-
chloric acid to undergo intramolecular lactonization and afford lac-
3
3,34
dimer of compound 10a, is well documented in the literature.
The proton NMR spectrum of anhydrohemigossypol 10a and its
derivatives 10b and 10c is similar to that of anhydrogossypol.
3
5
46
tones 4a and 4c in 71–80% yield.
The anhydro compounds 10a–10c could be converted back to alde-
hydes 3a–3c using dilute hydrochloric acid in acetonitrile.
Alternate synthetic methods for the formation of compounds 3
from naphthalenols 9a and 9b were investigated in hopes of
A one step transformation from the readily available intermedi-
ate 7b to naphtholactone 16 is an attractive route to explore. Since
lactones 7a–7c have been successfully converted to naphthalenols
8 and 9a–9c in one step using Lewis acids (Scheme 1), we further
envisioned that chlorosulfonyl isocyanate (CSI), a strong Lewis
acid containing a reactive electrophilic isocyanate group, could
convert lactone 7b into naphtholactone 16 in one step. Treatment
of compound 7b with excess CSI followed by an acidic hydrolysis
(Scheme 3) successfully afforded naphtholactone 16 in a 10% yield
along with the unexpected amide compound 17 in 30% yield.48 We
4
7
increasing the yield of product. Vilsmeier and N,N-diphenylform-
amidine methods did not afford product.3
6–38
The Duff reaction,
which involves the use of hexamethylenetetramine in the presence
of acetic acid, on compound 9b gave the dehydrated compound
3
9
1
0b in a 25% yield. These disappointing results led to the one
pot reaction of compound 7a with boron tribromide followed by

J. Wei et al. / Tetrahedron Letters 51 (2010) 5757–5760
OCH3
5759
CHOOCH3
H3CO
3
H CO
(a) (CH3O)2SO2
R
(b) t-BuLi
(c) BBr3
9a, 9b
3a
K2CO3
H3CO
HCON(CH )C H
H CO
3
6
5
3
13a, 13b
14
(
d) t-BuLi,
ClCO2CH3
O
CH3OOC
H3CO
O
OCH3
(e) BBr ,
3
HO
HO
R
a: R = H
R
HCl
b: R = CH
c: R = Br
3
H3CO
1
5a, 15c
f)
Br2
4a, 4c
(
Scheme 2. Synthesis of hemigossylic lactone and derivatives. Reagents and conditions: (a) (CH
b) t-BuLi (8 equiv), C 12, 0 °C, 18 h then HCON(CH )C (2.5 equiv), 8 h, 49%; (c) BBr
°C, then 18 h, rt, then ClCOOCH
3
O)
2
SO
2
(13 equiv), K
2 3 3 2
CO (13 equiv), (CH ) C@O, reflux, 85% of 13a and 13b;
(
0
6
H
3
6
H
5
3
(3 equiv), CH
2
Cl
2
, ꢀ78 °C, 1.0 h, 0 °C, 1.0 h, rt, 1.0 h, 80%; (d) t-BuLi (7 equiv), C
6 12
H ,
3
(19 equiv), ꢀ10 °C, 8 h, 60% of 15a; (e) BBr
3
(4 equiv), CH
2
Cl
2
, ꢀ78 °C, 1.0 h, 0 °C, 1.0 h, rt, 3 h, 6 M HCl, reflux, 3 h, 80% of 4a and 71% 4c; (f)
Br
2
(1 equiv), CHCl
3
, 0 °C, 2 h, 88% of 15c.
O
O
O
O
H3CO
H3CO
CH3
O
H3CO
H3CO
H CO
3
ClSO2NCO
H3O+
+
CH3
3
H CO
O
CONH2
7b
1
6
17
Scheme 3. Synthesis of dimethylhemigossylic lactones. Reagents and conditions: (a) ClSO
of 17.
2
NCO (9 equiv), CH
Cl
2 2
, rt, 24 h, then HCl/H O, EtOH, reflux, 1.0 h, 10% of 16 and 30%
2
propose that initially the CSI acts as a Lewis acid and readily con-
verts the lactone 7b to the 2-methyl-substituted naphthalenol ad-
duct of compound 8. This naphthalenol adduct further reacts with
the electrophilic carbonyl carbon in the CSI and hydrolysis using
dilute acid causes intramolecular attack of the carbonyl by the peri
hydroxyl group on position one resulting in the formation of lac-
tone 16. Amide 17 was formed by the reaction of CSI with the
substituted naphthalenol at position four followed by acidic hydro-
lysis. Because of the brevity of this synthetic sequence and the
promising results, reaction conditions are being investigated to im-
prove the yield.
6. Meng, Y.; Tang, W.; Dai, Y.; Wu, X.; Liu, M.; Ji, Q.; Ji, M.; Pienta, K.; Lawrence, T.;
Xu, L. Mol. Cancer Ther. 2008, 7, 2192–2202.
7
.
Van Poznak, C.; Seidman, A. D.; Reidenberg, M. M.; Moasser, M. M.; Sklarin, N.;
Van Zee, K.; Borgen, P.; Gollub, M.; Bacotti, D.; Yao, T. J.; Bloch, R.; Ligueros, M.;
Sonenberg, M.; Norton, L.; Hudis, C. Breast Cancer Res. Treat. 2001, 66, 239–248.
Royer, R. E.; Deck, L. M.; Campos, N. M.; Hunsaker, L. A.; Vander Jagt, D. L. J. Med.
Chem. 1986, 29, 1799–1801.
8
.
.
9
Deck, L. M.; Vander Jagt, D. L.; Royer, R. E. J. Med. Chem. 1991, 34, 3301–3305.
10. 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.
1
1. Deck, L. M.; Royer, R. E.; Chamblee, B. B.; Hernandez, V. M.; Malone, R. R.;
Torres, J. E.; Hunsaker, L. A.; Piper, R. C.; Makler, M. T.; Vander Jagt, D. L. J. Med.
Chem. 1998, 41, 3879–3887.
1
2. Wei, J.; Kitada, S.; Rega, M. F.; Emdadi, A.; Yuan, H.; Cellitti, J.; Stebbins, J. L.;
Zhai, D.; Sun, J.; Yang, L.; Dahl, R.; Zhang, Z.; Wu, B.; Wang, S.; Reed, T. A.;
Lawrence, N.; Sebti, S.; Reed, J. C.; Pellecchia, M. Mol. Cancer Ther. 2009, 8, 904–
913.
In conclusion, a short and convenient synthetic scheme was
developed to afford the bioactive natural product hemigossypol
1
3. Wei, J.; Rega, M. F.; Kitada, S.; Yuan, H.; Zhai, D.; Risbood, P.; Seltzman, H. H.;
Twine, C. E.; Reed, J. C.; Pellecchia, M. Cancer Lett. 2009, 273, 107–113.
4. Brown, W. M.; Yowell, C. A.; Hoard, A.; Vander Jagt, T. A.; Hunsaker, L. A.; Deck,
L. M.; Royer, R. E.; Piper, R. C.; Dame, J. B.; Makler, M. T.; Vander Jagt, D. L.
Biochemistry 2004, 43, 6219–6229.
3
a and its 2,5-substituted derivatives 3b and 3c. The modification
of the synthetic scheme afforded hemigossylic lactones 4a and 4c
as derivatives of the natural product 3-methylhemigossylic lac-
tone. Bioactivities of hemigossypol, hemigossylic lactones, and
their derivatives are currently being investigated.
1
1
1
1
1
1
5. Bell, A. A.; Stipanovic, R. D.; Howell, C. R.; Fryxell, P. A. Phytochemistry 1975, 14,
225–231.
6. Howell, C. R.; Hanson, L. E.; Stipanovic, R. D.; Puckhaber, L. S. Phytopathology
2000, 90, 248–252.
7. Manmade, A.; Herlihy, P.; Quick, J.; Duffley, R. P.; Burgos, M.; Hoffer, A. P.
Experientia 1983, 39, 1276–1277.
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Acknowledgments
This research was supported in part by grant HL68598 from the
National Institutes of Health. High resolution mass spectra (HRMS)
were obtained at UNM Mass Spec Facility, Albuquerque, New
Mexico.
9. Data for lactones 7: dihydro-5-(2-isopropyl-3,4-dimethoxyphenyl)-4-methyl-2-
furanone 7a: yellow oil; 1H NMR (CDCl
6
2
, 250 MHz) d 7.09 (d, J = 8.7 Hz, 1H),
.79 (d, J = 8.7 Hz, 1H), 5.80 (d, J = 5.4 Hz, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 2.89 (m,
H), 2.34 (d, 1H), 1.34 (d, J = 6.4 Hz, 3H), 1.33 (s, 3H), 0.66 (d, J = 7.0 Hz, 3H); 13
3
C
3
NMR (CDCl , 250 MHz) d 176.1, 152.4, 148.2, 137.2, 125.6, 120.4, 109.7, 82.0,
References and notes
60.3, 55.3, 37.8, 34.4, 28.4, 21.6, 21.2, 15.4. HRMS (EI) calcd for C16
22 4
H O
[
M+H]+: 279.1596; found, 279.1592. Dihydro-5-(2-isopropyl-3,4-dimethoxy-
1
1
2
.
.
Waller, D. P.; Zaneveld, L. J.; Fong, H. H. Contraception 1980, 22, 183–187.
Montamat, E. E.; Burgos, C.; Gerez de Burgos, N. M.; Rovai, L. E.; Blanco, A.;
Segura, E. L. Science 1982, 218, 288–289.
Jaroszewski, J. W.; Kaplan, O.; Cohen, J. S. Cancer Res. 1990, 50, 6936–6943.
Dorsett, P. H.; Kerstine, E. E.; Powers, L. J. J. Pharm. Sci. 1975, 64, 1073–1075.
Wang, S.; Yang, D. In U.S. patent applications series no. 2003008924, 2002.
phenyl)-3,4-dimethyl-2-furanone 7b: yellow oil; H NMR (CDCl , 250 MHz) d
7.11 (d, J = 8.7 Hz, 1H), 6.79 (d, J = 8.7 Hz, 1H), 5.66 (d, J = 5.4 Hz, 1H), 3.87 (s,
3H), 3.86 (s, 3H), 3.02 (m, 1H), 2.92 (m, 1H), 2.76 (m, 1H), 1.34 (t, J = 7.2 Hz,
6H), 1.21 (d, J = 7.2 Hz, 3H), 0.51 (d, J = 7.2 Hz, 3H); 13C NMR: d 178.4, 152.4,
148.3, 137.2, 125.6, 120.7, 109.7, 80.6, 60.5, 55.4, 41.0, 39.5, 28.5, 21.6, 21.3,
3
3
4
5
.
.
.
+
10.0, 9.8. HRMS (EI) calcd for C17H24O4 [M+H] : 293.1753; found, 293.1744.

5
760
J. Wei et al. / Tetrahedron Letters 51 (2010) 5757–5760
Dihydro-5-(3,4-dimethoxy-2-propylphenyl)-3,4-dimethyl-2-furanone 7c: yellow
oil; 1H NMR (CDCl
, 250 MHz) d 7.00 (d, J = 8.5 Hz, 1H), 6.79 (d, J = 8.7 Hz, 1H),
.78 (d, J = 5.4 Hz, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 2.75 (m, 1H), 2.55 (m, 1H), 2.31
2.49 (s, 3H), 2.49 (s, 3H), 1.50 (d, J = 6.9 Hz, 6H); 13C NMR (CDCl
175.2, 152.5, 149.2, 148.8, 135.3, 130.8, 123.3, 123.1, 120.6, 118.6, 116.7, 27.1,
3
, 250 MHz) d
3
+
5
16 3
20.5, 19.9, 12.0. HRMS (EI) calcd for C16H O [M+H] : 257.1177; found,
1
3
(
m, 1H), 1.34 (m, 6H), 1.23 (m, 3H), 0.65 (m, 3H); C NMR (CDCl
3
, 250 MHz) d
257.1176. 4-Hydroxy-7,8-dimethyl-5-propyl-3-naphtho[1,8-bc]furan-3-one 10c:
1
1
2
2
79.2, 151.2, 146.6, 134.0, 120.6, 109.8, 103.2, 77.3, 68.3, 60.4, 55.4, 34.3, 28.3,
yellow solid; mp 163–165 °C; H NMR (CDCl
(s, 1H), 7.35 (s, 1H), 6.12 (s, 1H), 5.38 (s, 1H), 3.02 (t, J = 7.6 Hz, 2H), 2.44 (s, 3H),
2.32 (s, 3H), 1.66 (m, 2H), 1.04 (t, J = 7.6 Hz, 3H); 13C NMR (CDCl
, 250 MHz) d
200.1, 157.0, 151.1, 142.8, 134.8, 130.8, 128.1, 121.0, 117.8, 117.2, 112.8, 28.5,
3
, 250 MHz) d 15.17 (s, 1H), 11.24
+
6.1, 24.2, 14.5, 12.9. HRMS (EI) calcd for C17
93.1751.
24 4
H O [M+H] : 293.1753; found,
3
2
2
0. Edwards, J. D.; Cashaw, J. L. J. Org. Chem. 1955, 20, 847–849.
1. Deck, L. M.; Brazwell, E. M.; Vander Jagt, D. L.; Royer, R. E. Org. Prep. Proced. Int.
+
23.3, 21.1, 14.6, 12.6. HRMS (EI) calcd for C16
18 4
H O [M+H] : 257.1177; found,
1
990, 22, 495–500.
257.1284.
2
2
2
2
2
2. Edwards, J. D., Jr.; Cashaw, J. L. J. Am. Chem. Soc. 1956, 78, 3821–3824.
3. Chin, C.; Tran, D. D.; Shia, K.; Liu, H. Synlett 2005, 417–420.
4. Konishi, H.; Aritomi, K.; Okano, T.; Kiji, J. Bull. Chem. Soc. Jpn. 1989, 62, 591–593.
5. Curley, R. W., Jr.; Ticoras, C. J. Synth. Commun. 1986, 16, 627–631.
6. Meyers, A. I.; Roth, G. P.; Hoyer, D.; Barner, B. A.; Laucher, D. J. Am. Chem. Soc.
36. Moazzam, M.; Sana, S.; Rajanna, K. C. 2002, 32, 1351–1356.
37. Meltzer, P. C.; Bickford, H. P.; Lambert, G. J. J. Org. Chem. 1985, 50, 3121–3124.
38. Edwards, J. D., Jr. J. Am. Chem. Soc. 1958, 80, 3798–3799.
39. Smith, E. S. J. Org. Chem. 1972, 37, 3972–3973.
40. Banerjee, A. K.; Poon, P. S.; Laya, M. S. Russ. J. Gen. Chem. 2003, 73, 1815–1820.
1
988, 110, 4611–4624.
41. Data for aldehyde 11: 1,6,7-trihydroxy-5-isopropyl-3-methyl-2-naphthaldehyde:
1
2
2
2
7. Venuti, M. C. J. Org. Chem. 1981, 46, 3124–3127.
yellow solid; mp 160–161 °C; H NMR (acetone-d
6
, 500 Hz) d 13.69 (s, 1H),
8. Huang, J.; Su, T.; Watanabe, K. A. J. Org. Chem. 1991, 56, 4811–4815.
10.24 (s, 1H), 7.64 (s, 1H), 7.33 (s, 1H), 3.83 (m, 1H), 2.67 (s, 3H), 1.45 (d,
J = 7.3 Hz, 6H); 13C NMR (acetone-d
, 500 Hz) d 195.2, 162.7, 149.0, 144.6,
133.2, 132.1, 126.0, 118.3, 115.3, 112.1, 104.3, 26.8, 20.3, 18.5. HRMS (EI) calcd
9. Data for naphthalenols 9: 5-isopropyl-3-methyl-1,6,7-naphthalenetriol 9a: red
6
oil; 1H NMR (CDCl
, 250 MHz) H NMR: d 7.41 (s, 1H), 7.37 (s, 1H), 6.48 (s, 1H),
1
3
+
5
.92 (br s, 2H), 5.40 (br s, 1H), 3.84 (m, 1H), 2.33 (s, 3H), 1.44 (d, J = 7.2 Hz, 6H);
16 4
for C15H O [M+H] : 261.1127; found, 261.1127.
13
C NMR (CDCl
08.5, 102.0, 95.0, 19.8, 13.7, 7.9. HRMS (EI) calcd for C14
33.1177; found, 233.1122. 5-Isopropyl-3,4-dimethyl-1,6,7-naphthalenetriol 9b:
3
, 250 MHz) d 143.1, 136.7, 135.4, 126.2, 122.7, 118.7, 110.9,
42. Data for compound 13b: 1-isopropyl-2,3,5-trimethoxy-6,7-dimethyl-1-
+
1
1
2
H
16
O
3
[M+H] :
naphthalene: oil; H NMR (CDCl
3
, 500 Hz) d 7.69 (s, 1H), 7.31 (s, 1H), 3.98 (s,
3H), 3.88 (s, 3H), 3.87 (m, 1H), 3.86 (s, 3H), 2.42 (s, 3H), 2.34 (s, 3H), 1.50 (d,
1
13
light grey solid; mp 194–195 °C; H NMR: (acetone-d
6
, 250 MHz) d 8.87 (br s,
J = 7.2 Hz, 3H), 1.49 (s, 3H); C NMR (CDCl
3
, 500 Hz) d 152.9, 151.8, 147.0,
1
H), 7.48 (s, 1H), 7.41 (s, 1H), 7.37 (br s, 1H), 7.15 (br s, 1H), 3.84 (m, 1H), 2.36
135.0, 133.4, 127.1, 124.8, 124.4, 120.0, 99.8, 61.0, 60.7, 55.4, 26.8, 22.2, 21.1,
12.4. HRMS (EI) calcd for C18H O [M+H] : 289.1803; found, 289.1730.
24 3
1
3
+
(
s, 3H), 2.26 (s, 3H), 1.46 (d, J = 7.2 Hz, 6H); C NMR: (methanol-d
4
, 250 MHz) d
1
2
49.2, 145.2, 144.7, 133.3, 128.2, 125.7, 121.5, 116.8, 116.5, 102.8, 27.8, 21.5,
43. Dallacker, V. F.; Leuther, P.; Westerop, K. W. Chemiker-Zeit 1989, 113, 97–102.
44. Data for ester 15a: methyl 4-isopropyl-2,3,8-trimethoxy-6-methyl-1-naphthalene-
+
18 3
1.3, 12.2. HRMS (EI) calcd for C15H O [M+H] : 247.1334; found, 247.1332.
3,4-Dimethyl-5-propyl-1,6,7-naphthalenetriol 9c: light grey solid; mp 168–
carboxylate: colorless oil; 1H NMR (CDCl
3
, 500 Hz) d 7.53 (s, 1H), 6.65 (s, 1H),
4.00 (s, 3H), 3.94 (s, 3H), 3.93 (s, 3H), 3.92 (m, 1H), 3.91 (s, 3H), 2.50 (s, 3H),
1.49 (d, J = 7.2 Hz, 6H); 13C NMR (CDCl
, 500 Hz) d 169.2, 154.4, 150.1, 148.3,
136.6, 134.8, 131.1, 121.3, 117.6, 116.1, 107.0, 61.4, 60.6, 56.3, 52.0, 27.0, 22.4,
1
1
1
2
1
70 °C; H NMR: (acetone-d
6
, 250 MHz) d 9.29 (s, 1H), 7.79 (s, 1H), 7.45 (s,
H), 7.44 (s, 1H), 7.19 (s, 1H), 2.96 (m, 2H), 2.34 (s, 3H), 2.24 (s, 3H), 1.63 (m,
H), 1.00 (t, J = 7.4 Hz, 3H); C NMR: (acetone-d
3
1
3
6
, 250 MHz) d 148.9, 144.0,
+
43.3, 132.7, 127.8, 120.1, 120.0, 115.4, 115.2, 102.5, 27.4, 23.2, 20.9, 14.1, 11.8.
24 5
22.0. HRMS (EI) calcd for C19H O [M+Na] : 355.1624; found, 355.1615.
+
HRMS (EI) calcd for C15
H
18
O
3
[M+H] : 247.1334; found, 247.1334.
45. Data for bromide 15c: methyl 7-bromo-2,3,8-trimethoxy-6-methyl-4-isopropyl-1-
1
3
3
3
0. Rieche, A.; Gross, H.; Hoft, E. Chem. Ber. 1960, 93, 88–94.
naphthalenecarboxylate: white solid; mp 98–100 °C; H NMR: d 7.77 (s, 1H),
1. Schuda, P. F.; Price, W. A. J. Org. Chem. 1987, 52, 1972–1979.
3.96 (s, 3H), 3.90 (s, 6H), 3.82 (s, 3H), 3.81 (m, 1H), 2.54 (s, 3H), 1.45 (d,
2. Data
naphthaldehyde 3a: yellow solid; mp 158–160 °C (lit. 159–163 °C); H NMR
CDCl , 250 MHz) d 15.10 (s, 1H), 11.20 (s, 1H), 7.53 (s, 1H), 6.69 (s, 1H), 6.33 (s,
H), 5.71 (s, 1H), 3.85 (m, 1H), 2.43 (s, 3H), 1.50 (d, J = 6.9 Hz, 6H); C NMR
CDCl , 250 MHz): d 199.3, 155.6, 151.6, 142.8, 134.2, 133.9, 129.5, 116.9,
for
hemigossypols
3:
2,3,8-trihydroxy-4-isopropyl-6-methyl-1-
J = 7.2 Hz, 6H); 13C NMR: d 168.4, 152.4, 150.4, 149.6, 137.1, 135.4, 129.8,
1
5
1
122.2, 121.2, 120.9, 116.4, 61.9, 61.5, 60.8, 52.3, 27.1, 24.2, 22.0. HRMS (EI)
+
(
3
calcd for C19
H
23BrO
5
[M+H] : 411.0807; found, 411.0740.
13
1
46. Data for lactones 4: 3,4-dihydroxy-4-isopropyl-6-methyl-1,8-naphtholactone 4a:
1
(
3
white solid; mp 220–222 °C; H NMR (CDCl
3
, 500 Hz) d 8.70 (br s, 1H), 7.51 (s,
+
1
14.4, 113.2, 111.6, 28.0, 21.6, 20.3. HRMS (EI) calcd for C15
16 4
H O [M+H] :
1H), 6.92 (s, 1H), 6.08 (s, 1H), 3.93 (m, 1H), 2.55 (s, 3H), 1.49 (d, J = 7.2 Hz, 6H);
13
2
61.1127; found, 261.1172. 2,3,8-Trihydroxy-4-isopropyl-6,7-dimethyl-1-
C NMR: (acetone-d
6
, 500 Hz) d 166.1, 149.3, 148.0, 147.8, 136.3, 135.7, 124.4,
1
naphthaldehyde 3b: yellow solid; mp 160–162 °C; H NMR (CDCl
3
, 250 MHz)
122.3, 117.7, 106.1, 100.9, 28.1, 22.9, 21.0. HRMS (EI) calcd for C15H O
14 4
+
d 15.21 (s, 1H), 11.23 (s, 1H), 7.57 (s, 1H), 6.29 (s, 1H), 5.42 (s, 1H), 3.85 (m, 1H),
[M+H] : 259.0970; found, 259.0970. 7-Bromo-2,3-dihydroxy-4-isopropyl-6-
1
3
1
2
1
2
2
.45 (s, 3H), 2.33 (s, 3H), 1.50 (d, J = 6.9 Hz, 6H); C NMR (CDCl
3
, 250 MHz) d
methyl-1,8-naphtho-lactone 4c: white solid; mp 254–255 °C;
(acetone-d 500 Hz) 7.78 (d, J = 1.0 Hz, 1H), 3.89 (m, 1H), 2.57 (d,
J = 1.0 Hz, 3H), 1.49 (d, J = 7.2 Hz, 6H); C NMR (acetone-d
148.3, 147.6, 147.5, 136.6, 135.5, 123.4, 123.2, 119.8, 101.2, 100.0, 28.4, 23.4,
H NMR
99.2, 155.9, 149.5, 142.1, 134.1, 133.3, 126.9, 117.8, 117.4, 115.1, 113.4, 27.7,
6
,
d
+
13
0.0, 20.3, 11.8. HRMS (EI) calcd for C16
H
18
O
4
[M+H] : 275.1283; found,
6
, 500 Hz) d 164.7,
75.1328. 2,3,8-Trihydroxy-6,7-dimethyl-4-propyl-1-naphthaldehyde 3c: yellow
1
+
solid; mp 194–195 °C; H NMR (CDCl
3
, 250 MHz) d 8.47 (s, 1H), 7.29 (s, 1H),
4
21.0. HRMS (EI) calcd for C15H13BrO [M+H] : 337.0075; found, 337.0088.
7
1
1
.05 (br s, 1H), 2.79 (t, J = 7.4 Hz, 2H), 2.47 (s, 3H), 2.44 (s, 3H), 1.70 (m, 2H),
47. Lohaus, G. Chem. Ber. 1967, 100, 2719–2723.
.03 (t, J = 7.4 Hz, 3H); 1 C NMR (CDCl
3
48. Data for compounds 16 and 17: 4-isopropyl-2,3-dimethoxy-6,7-dimethyl-1,8-
3
, 250 MHz) d 175.0, 152.4, 149.3, 149.0,
35.5, 126.5, 123.6, 122.6, 120.7, 118.6, 117.0, 27.7, 22.5, 19.9, 14.4, 12.0.
naphtholactone 16: oil; 1H NMR (CDCl
, 500 Hz) d 7.59 (s, 1H), 4.56 (s, 3H), 3.86
3
13
+
HRMS (EI) calcd for C16
H
18
O
4
[M+H] : 275.1283; found, 275.1288.
(s, 3H), 3.85 (m, 1H), 2.47 (s, 3H), 2.39 (s, 3H), 1.51 (d, J = 7.2 Hz, 6H); C NMR
(CDCl , 500 Hz) d 165.6, 155.0, 149.8, 146.7, 144.9, 136.3, 124.6, 122.1, 118.5,
116.1, 103.3, 62.5, 61.6, 27.7, 22.2, 20.9, 11.9. HRMS (EI) calcd for C18
3
3
3
3. Miller, R. F.; Adams, R. J. Am. Chem. Soc. 1937, 59, 1736–1738.
4. Jaroszewski, J. W.; Hansen, T. Chirality 1992, 4, 216–221.
5. Data for anhydrohemigossypols 10: 4-hydroxy-5-isopropyl-7-methyl-3-
3
20 4
H O
+
[M+H] : 301.1440; found, 301.1435. 5-Carboxamido-4-isopropyl-2,3-dimethoxy-
1
1
naphtho[1,8-bc]furan-3-one 10a: yellow oil; H NMR (CDCl
3
, 250 MHz) d 8.48
6,7-dimethyl-1,8-naphtholactone 17: solid; mp 259–260 °C; H NMR: (acetone-
(
s, 1H), 7.50 (s, 1H), 7.31 (s, 1H), 7.27 (s, 1H), 3.52 (m, 1H), 2.56 (s, 3H), 1.50 (d,
d , 500 Hz) d 4.50 (s, 3H), 4.22 (m, 1H), 3.94 (s, 3H), 2.44 (s, 3H), 2.37 (s, 3H),
6
13
13
J = 7.3 Hz, 6H); C NMR (CDCl
1
C
dimethyl-3-naphtho[1,8-bc]furan-3-one 10b: brown solid; mp 192–193 °C;
NMR (CDCl
3
, 250 MHz) d 175.3, 152.3, 149.1, 148.8, 135.2,
1.43 (d, J = 6.5 Hz, 3H), 1.33 (d, J = 6.5 Hz, 3H); C NMR (dimethylformamide-
, 500 MHz) d 173.4, 164.9, 155.5, 153.4, 146.4, 146.3, 134.2, 130.2, 124.2,
120.2, 116.3, 104.7, 62.6, 61.7, 28.8, 21.4, 21.3, 16.9, 12.2. HRMS (EI) calcd for
30.7, 123.2, 123.0, 120.4, 118.6, 116.7, 27.1, 19.8, 12.0. HRMS (EI) calcd for
d
7
+
15
H
14
O
3
[M+H] : 243.1021; found, 243.0976. 4-Hydroxy-5-isopropyl-7,8-
1
+
H
19 5
C H21NO [M+H] : 344.1498; found, 344.1498.
3
, 250 MHz) d 8.50 (s, 1H), 7.49 (s, 1H), 7.22 (s, 1H), 3.46 (m, 1H),