Synthesis and cytotoxicity of a salicylihalamide a analogue

Article abstract of DOI:10.1021/np070694q

The synthesis of a simple analogue of salicylihalamide A with a truncated lactone ring (±2) was achieved in 10 steps. Its cytotoxicity profile in the NCI 60-cell-line human tumor assay differed significantly from that of salicylihalamide A in both level a

Full text of DOI:10.1021/np070694q

898
J. Nat. Prod. 2008, 71, 898–901
Synthesis and Cytotoxicity of a Salicylihalamide A Analogue
Shaoshan Tang and Karen L. Erickson*
Gustaf H. Carlson School of Chemistry and Biochemistry, Clark UniVersity, 950 Main Street, Worcester, Massachusetts 01610
ReceiVed December 8, 2007
The synthesis of a simple analogue of salicylihalamide A with a truncated lactone ring ((2) was achieved in 10 steps.
Its cytotoxicity profile in the NCI 60-cell-line human tumor assay differed significantly from that of salicylihalamide A
in both level and specificity.
In 1997, the secondary metabolites salicylihalamides A (1a) and
B (1b) were first isolated from a marine sponge of the genus
Haliclona.1 These macrolides possess a novel combination of
structural moieties that include a 12-membered salicylate lactone
and a highly unsaturated enamide side chain, a feature that had not
been found previously in natural products.
Figure 1. Generic structure of the benzolactone enamides.
Salicylihalamide A displayed a unique differential cytotoxicity
profile in the NCI 60-cell-line human tumor assay, with the
melanoma cell lines showing the highest average sensitivity.
COMPARE pattern-recognition analyses of the NCI 60-cell mean
graph screening profile2 of 1a did not reveal any significant
correlations to the profiles of known antitumor compounds in NCI’s
standard agent database. Further investigation showed that salicy-
lihalamide A is a potent selective inhibitor of mammalian vacuolar
(H+)-ATPase, the first substance to demonstrate such selectivity.3
Discovery of the salicylihalamides was followed by the isolation
of a host of other natural products with the common traits of this
new benzolactone enamide class but isolated from such diverse
sources as bacteria, fungi, myxobacteria, and two different marine
animal phyla. Examples include the lobatamides, apicularen A,
oximidines I and II, CJ-12950, and CJ-1335,4 each with the highly
unsaturated enamide side chain, the salicylate moiety, and the
macrolactone ring, as illustrated in Figure 1 (Z represents a linker
of variable length, composition, and stereochemistry).3
The first total synthesis of salicylihalamide A was achieved by
De Brabander’s group5 and was soon followed by many other total
syntheses,4,6 as well as formal total syntheses4,7 and analogue
syntheses,4,8 paving the way for structure-activity studies. Neces-
sary elements for biological activity include the enamide side chain
with a free NH as well as a free phenolic OH group. Less clear is
the role of the macrolactone ring. To explore this question, we
undertook the synthesis of a simplified salicylihalamide analogue
with a truncated lactone ring, specifically a six-membered ring in
Figure 2. Retrosynthetic analysis for 2.
place of the 12-membered lactone of the parent compounds.
A convergent process linking the enamide side chain to the
salicylate lactone can be envisioned in several ways, as illustrated
in Figure 2. In pathway a the bond between the amide carbonyl of
2 and its R-carbon is broken to obtain an isocyanate and a
hexadienyl halide, an approach similiar to that reported in the first
total synthesis of salicylihalamide A.5 In pathway b the vinyl C-N
bond is disconnected to heptadienoic amide 3 and vinyl iodide 4.
This same bond is also ultimately disconnected in pathway c, giving
the same vinyl iodide (4) as pathway b. Here the nitrogen is
introduced via the hydroxylactam derived from the reduction of
* Corresponding author. E-mail: kerickson@clarku.edu.
10.1021/np070694q CCC: $40.75
2008 American Chemical Society and American Society of Pharmacognosy
Published on Web 04/12/2008

Notes
Journal of Natural Products, 2008, Vol. 71, No. 5 899
Scheme 2. Synthesis of Dienamide 3
Scheme 1. Synthesis of Salicylate Vinyl Iodide 4
8 was achieved with OsO4/NaIO4 in 2,6-lutidine.12 The resulting
lactone aldehyde (9) was then subjected to Takai’s stereoselective
one carbon chain elongation reaction13 followed by demethylation
of the phenolic group, affording 4.
maleimide, a method introduced by Coleman9 for constructing
enamide groups.
The synthesis of (2Z,4Z)-hepta-2,4-dienamide (3) is depicted in
Scheme 2 and parallels the protocol developed by Fu¨rstner et al.14
and Maier et al.15 Propionaldehyde was first brominated to give
gem-dibromide 11.16 Elimination with n-butyllithium generated the
terminal acetylide anion (12), which then underwent a Negishi
coupling reaction17 with methyl 3-iodo-(Z)-2-propenoate (13)18 to
give enyne ester 14. Classical Lindlar reduction afforded the desired
Z,Z-diene ester 15. Finally, aminolysis of 15 converted it to amide
3, the synthon needed for coupling with salicylate vinyl iodide 4.
In our work, all three pathways were investigated with a as the
initial choice. However, difficulties were encountered in the
synthesis of 1,3-(Z,Z)-hexadienyl bromide. Hydrogenation of its
precursor, 1-bromo-(3Z)-hexen-1-yne, consistently gave very low
yields of product. This, together with the inability to successfully
couple the hexadienyl bromide to the lactone isocyanate, terminated
work on this pathway.
In pathway c the coupling reaction of vinyl iodide lactone 4 with
the tert-butyl dimethylsilyl ether of the hydroxylactam was
problematic. Despite the fact that model compounds gave acceptable
yields of coupled product, 4 did not under a variety of reaction
conditions. More importantly, the subsequent Wittig reaction to
attach the terminal propenyl group was completely unsuccessful.
Thus, this pathway was also abandoned in favor of pathway b.
Scheme 1 illustrates the synthesis of salicylate vinyl iodide 4.
Allylation of lithium o-anisate represents the most direct route to
6-allyl-2-methoxybenzoic acid (6).10 Although the yields in this
reaction are typically poor, in dilute solution yields of 40-50%
were consistently obtained, and with rapid introduction of the
lithium reagent, one run actually proceeded in >90% yield.
Oxidative cleavage of the double bond of 6 with osmium
tetraoxide/sodium periodate afforded aldehyde 7. Although origi-
nally extracted into the ether layer during the reaction workup, once
concentrated, aldehyde 7 did not redissolve in common organic
solvents. This observation may be explained by a dimerization/
polymerization equilibrium depicted in Figure 3.11 The existence
of the cyclic pseudoacid form was evident from the proton NMR,
where the methine H was found as a multiplet at δ 5.8, and the
methylene protons at δ 3.00 (dd, J ) 16.2, 5.7 Hz) and 3.22 (dd,
J ) 16.2, 6.6 Hz).
The copper(I)-mediated cross-coupling reaction of vinyl halides
and amides to generate enamides19 was first reported by Ogawa.20
Porco’s group rejuvenated this reaction in their synthetic work on
the salicylate macrolides.21 Liebeskind’s copper(I) thiophencar-
boxylate (CuTc)22 was found to be effective in promoting coupling
between vinyl iodides and amides to afford enamides with good
stereoselectivity. The reaction had to be performed in polar aprotic
solvents in the presence of a base, either Cs2CO3 or Rb2CO3.
Following Porco’s work, this methodology found its way into
many natural product syntheses including the benzolactone
enamides,14,23 although there have been problems and failures.24
Other studies have been done in attempts to improve the reaction.25
In our case, the coupling of 3 and 4, or the tert-butyldimethylsilyl
derivative of 4, employing Liebeskind’s CuTc and Cs2CO3, was
totally unsuccessful. The bases Rb2CO3, K3PO4, and K2CO3 were
effective, but none were superior to the others and yields were
consistently very low (around 10%), although model compounds
gave modest yields (45-56%). Various reaction conditions were
investigated with no significant improvement, leaving the final step
in the synthesis of analogue 2 one of very poor conversion.
In the National Cancer Institute’s 60-cell-line assay, 2 displayed
a cytotoxicity pattern distinctly different from salicylihalamide A.
Analogue 2 showed only modest activity, with the highest level
displayed in the leukemia SR cell line (GI50 ) 2 µM). Melanoma
line SK-Mel-5 displayed a GI50 of 27 µM, and breast cell lines
MCF7 and MDA-MB-435 had GI50 values of 49 and 11 µM,
respectively. In comparison, salicylihalamide A showed high
selectivity for the melanoma cell lines (range of differential
sensitivity g103) with an average GI50 in these lines of 7 ( 2 nM.1
Obviously, features apparently important for cytotoxicity in sali-
cylihalamide A are missing in 2. In addition to smaller lactone ring
size, analogue 2 lacks the ring hydroxyl and methyl substituents
as well as its multiple bond. Moreover, 2 is not a single enantiomer.
Any one or combination of these differences could alter the level
and pattern of cytoxicity that is displayed by the parent molecule.
On their own, the salicylihalamide A structural features intact in 2
are insufficient for comparable activity.
Aldehyde 7 was converted to allyl lactone 8 in one step upon
treatment with allylmagnesium bromide, followed by acidification,
which triggered the lactonization. Cleavage of the double bond of
Figure 3. Pseudoacid forms of 7.

900 Journal of Natural Products, 2008, Vol. 71, No. 5
Notes
Experimental Section
mg, 39%) as a colorless syrup: IR νmax 3059, 3008, 2939, 2905, 2839,
1763, 1726, 1598, 1584, 1476, 1438, 1278, 1233, 1107, 1085, 1058,
948, 911, 801, 774, 729, 693 cm-1;1H NMR (CDCl3, 600 MHz) δ 2.41
(1H, m, H-8b), 2.49 (1H, m, H-8a), 2.80 (2H, m, H-10), 3.85 (3H, s,
OCH3), 4.36 (1H, m, H-9), 6.16 (1H, d, J ) 14.6 Hz, H-12), 6.53 (1H,
dt, J ) 14.4, 7.3 Hz, H-11), 6.73 (1H, d, J ) 7.3 Hz, H-6), 6.85 (1H,
d, J ) 8.2 Hz, H-4), 7.38 (1H, dd, J ) 7.3, 8.2 Hz, H-5); 13C NMR
(CDCl3) δ 162.0 (C-1), 161.0 (C-3), 141.2 (C-7), 140.0 (C-11), 134.6
(C-5), 119.2 (C-6), 113.3 (C-2), 110.9, (C-4), 78.8 (C-12), 75.7 (C-9),
56.1 (OCH3), 40.6 (C-10), 33.5 (C-8); HREIMS m/z 343.9896 (calcd
for C13H13O3I, 343.9904).
For general experimental procedures see the Supporting Informa-
tion.
2-Methoxy-6-(1-oxoethyl) Benzoic Acid (7). To a solution of 6 (2.13
g, 11 mmol) in THF (66 mL) and H2O (22 mL) was added OsO4 (56
mg, 2 mol%), followed by NaIO4 (7.31 g, 33 mmol) in 4 portions over
30 min. The mixture was stirred at rt for 1.5 h and then filtered to
remove the precipitate, which was washed with EtOAc. The aqueous
layer was separated and extracted with EtOAc (3×). The organic
extracts were combined, washed with brine, and dried with Na2SO4.
The solvent was removed in Vacuo, and the residue was mixed with
CH2Cl2. The product, an insoluble white solid, was removed by filtration
and washed with more CH2Cl2. The CH2Cl2 filtrate was concentrated
and subjected to vacuum liquid chromatography (VLC) on silica gel
eluting with EtOAc to obtain additional product (1.79 g total, 83%):
IR νmax 3363, 3088, 3015, 2969, 2949, 2848, 1699, 1654, 1599, 1585,
Salicylate Vinyl Iodide 4. To a solution of methyl ether 10 (76
mg, 0.22 mmol) in 15 mL of CH2Cl2 at -70 °C (2-propanol/dry ice
bath) was added BBr3 (680 µL, 1.0 M in CH2Cl2), and the reaction
mixture was stirred for 2 h then brought to rt, added to 50 mL of H2O,
and extracted with CH2Cl2 (3×). The combined organic layers were
washed with brine and dried over Na2SO4. The product, a colorless
solid, was obtained in 66% yield as a mixture of stereoisomers, which
were separated by preparative TLC (35% EtOAc/petroleum ether) to
afford vinyl iodide 4: E-isomer, IR νmax 3021, 3055, 2916, 1674, 1617,
1477, 1278, 1241, 1081, 1038, 1003, 929, 792, 670 cm-1; H NMR
1
(acetone-d6, 600 MHz) δ 3.00 (dd, 1H, J ) 16.2, 5.7 Hz, H-8b), 3.22
(1H, dd, J ) 16.2, 6.6 Hz, H-8a), 3.87 (3H, s, OCH3), 5.75 (1H, m,
H-9), 6.50 (1H, d, J ) 5.6 Hz, OH), 6.92 (1H, d, J ) 7.4 Hz, H-6),
7.05 (1H, d, J ) 8.6 Hz, H-4), 7.51 (1H, dd, J ) 7.4, 8.6 Hz, H-5);
13C NMR (acetone-d6) δ 161.7 (C-1), 160.7 (C-3), 140.4 (C-7), 135.2
(C-5), 121.1 (C-6), 115.2 (C-2), 112.0 (C-4), 95.6 (C-9), 56.3 (OCH3),
36.4 (C-8); HREIMS m/z 194.0568 (calcd for C10H10O4, 194.0574).
Allyl Lactone 8. To a solution of 1.70 g (8.8 mmol) of aldehyde 7
in 40 mL of dry THF cooled in an ice bath was added allyl magnesium
bromide (22 mL, 1.0 M in ether). The addition was finished in 20 min,
and the reaction mixture was stirred at rt for 24 h. HCl (10%, 17 mL)
was added dropwise to the reaction mixture cooled in an ice bath.
Stirring was continued for another 24 h. The organic phase was
separated, and the aqueous phase was extracted with EtOAc (3×). The
organic extracts were combined, washed with brine, and dried over
MgSO4. After the solvent was removed, the crude product was purified
by silica gel VLC eluting with 50% EtOAc/petroleum ether to afford
lactone 8 (1.82 g, 95%) as a yellow oil: IR νmax 3076, 3009, 2941,
2841, 1728, 1643, 1599, 1585, 1477, 1456, 1439, 1277, 1233, 1086,
1
1462, 1229, 1207, 1163, 1115, 1039, 949, 807, 657 cm-1; H NMR
(CDCl3, 600 MHz) δ 2.58 (2H, m, H-8), 2.93 (2H, m, H-10), 4.63
(1H, m, H-9), 6.29 (1H, d, J ) 14.5 Hz, H-12), 6.64 (1H, dt, J ) 14.5,
7.4 Hz, H-11), 6.70 (1H, d, J ) 7.4 Hz, H-6), 6.89 (1H, d, J ) 8.6 Hz,
H-4), 7.42 (1H, dd, J ) 8.2, 7.6 Hz, H-5), 10.92 (1H, s, OH); 13C
NMR (CDCl3) δ 169.5 (C-1), 162.3 (C-3), 139.5 (C-11), 138.9 (C-7),
136.4 (C-5), 118.1 (C-6), 116.5 (C-4), 108.3 (C-2), 79.5 (C-12), 77.7
(C-9), 41.0 (C-10), 32.3 (C-8); Z-isomer: 1H NMR (CDCl3, 200 MHz)
δ 2.71 (2H, t, J ) 6.3 Hz, H-8)), 2.98 (2H, m, H-10), 4.72 (1H, td, J
) 10.6, 6.3 Hz, H-9), 6.46 (2H, m, H-11, H-12), 6.71 (1H, d, J ) 6.6
Hz, H-6), 6.90 (1H, d, J ) 8.6 Hz, H-4), 7.42 (1H, dd, J ) 8.2, 7.8
Hz, H-5), 10.93 (1H, (s, OH); 13C NMR (CDCl3) δ 169.6 (C-1), 162.3
(C-3), 139.1 (C-7), 136.4 (C-5), 135.2 (C-11), 118.2 (C-6), 116.5 (C-
4), 109.9 (C-2), 86.9 (C-12), 77.9 (C-9), 40.0 (C-10), 32.5 (C-8);
HREIMS m/z 329.9753 (calcd for C12H11O3I, 329.9747).
Salicylihalamide Analogue 2. A solution of 4 (39 mg, 0.12 mmol)
in 2 mL of dioxane was carefully purged with argon for 30 min. The
flask was covered with aluminum foil, and CuTc (14 mg, 0.07 mmol),
DMEDA (15 mL, 0.14 mmol), diene amide 3 (23 mg, 0.18 mmol),
and K3PO4 (51 mg, 0.24 mmol) were introduced. The solution was
degassed for another 15 min before the temperature was raised to 90
°C, and stirring was continued for 28 h. The slurry was cooled to rt,
diluted with EtOAc, and washed with pH 7 buffer (3×). The aqueous
layer was extracted with EtOAc (3×). The organic layers were
combined, dried with Na2SO4, and concentrated. The crude sample was
subjected to preparative TLC (50% EtOAc/petroleum ether to give 2
(2 mg, 5%): 1H NMR (MeOH-d4, 600 MHz) δ 1.03 (3H t, J ) 7.6 Hz,
H-19), 2.30 (2H, quintet, J ) 7.6 Hz, H-18), 2.56 (2H, m, H-8), 2.99
(2H, m, H-10), 4.63 (1H, m, H-9), 5.37 (1H, dt, J ) 14.7, 7.0 Hz,
H-11), 5.70 (1H, d, J ) 11.7 Hz, H-14), 5.84 (1H, m, H-17), 6.79
(1H, d, J ) 7.6 Hz, H-6), 6.84 (1H, d, J ) 8.2 Hz, H-4), 6.88 (1H, d,
J ) 14.1 Hz, H-12), 6.90 (1H, t, J ) 11.7 Hz, H-15), 7.31 (1H, t, J )
11.4 Hz, H-16), 7.45 (1H, dd, J ) 8.2, 7.6 Hz, H-5); 13C NMR (MeOH-
d4) δ 171.4 (C-1), 165.9 (C-13), 163.2 (C-3), 142.8 (C-17), 141.5 (C-
7), 138.0 (C-15), 137.5 (C-5), 127.1 C-12), 125.3 (C-16), 120.2 (C-
14), 119.4 (C-6), 116.8 (C-4), 109.5 (C-2), 108.4 (C11), 81.1 (C-9),
36.4 (C-10), 33.0 (C-8), 21.5 (C-18), 14.4 (C-19); HRMS m/z 328.1541
(M + H) (calcd for C19H21O4N 328.1543).
1061, 802, 774, 699 cm-1; H NMR (CDCl3, 600 MHz) δ 2.43 (1H,
1
m, H-8b), 2.56 (1H, m, H-8a), 2.86 (2H, m, H-10), 3.93 (3H, s, OCH3),
4.44 (1H, (m, H-9), 5.18 (2H, m, H-12), 5.90 (1H m, H-11), 6.80 (1H,
d, J ) 7.4 Hz, H-6), 6.92 (1H, d, J ) 8.6 Hz, H-4), 7.45 (1H, dd, J )
8.2, 7.8 Hz, H-5); 13C NMR (CDCl3) δ 162.6 (C-1), 161.1 (C-3), 141.8
(C-7), 134.5 (C-5), 132.5 C-11), 119.3 (C-6), 118.6 (C-12), 113.6 (C-
2), 110.9 (C-4), 76.9 (C-9), 56.1 (OCH3), 38.9 (C-10), 33.7 (C-8);
HREIMS m/z 218.0938 (calcd for C13H14O3, 218.0937).
Aldehyde 9. To a solution of allyl lactone 8 (749 mg, 3.43 mmol)
in 32 mL of dioxane/H2O (3:1) was added 2,6-lutidine (802 µL, 6.84
mmol), OsO4 (17 mg, 2 mol %), and NaIO4 (2.93 g, 13.72 mmol, in
portions). The suspension was stirred at rt for 1 h, then mixed with 60
mL of H2O and filtered. The filtrate was washed with CH2Cl2. The
aqueous layer was separated and extracted with CH2Cl2 (3×). The
combined organic layers were washed with brine and dried over
Na2SO4. The crude product was subjected to silica gel VLC eluting
with EtOAc to give product 9 (531 mg, 70%) as a yellow oil: IR νmax
3100, 3088, 2925, 2847, 2741, 1761, 1723, 1598, 1585, 1478, 1459,
1439, 1278, 1235, 1082, 1061, 804, 777, 696 cm-1; 1H NMR (CDCl3,
200 MHz) δ 2.73 (1H, dd, J ) 17.6, 5.9 Hz, H-8b), 2.88 (2H d, J )
7.0 Hz, H-10), 2.96 (1H, dd, J ) 17.6, 6.6 Hz, H-8a), 3.83 (3H, s,
OCH3), 4.84 (1H, quintet, J ) 7.0 Hz, H-9), 6.72 (1H d, J ) 7.4 Hz,
H-6), 6.84 (1H, d, J ) 8.6 Hz, H-4), 7.37 (1H, dd, J ) 7.4, 8.6 Hz,
H-5), 9.73 (1H, s, H-11); 13C NMR (CDCl3) δ 198.6 (C-11), 161.6
(C-1), 160.9 (C-3), 141.0 (C-7), 134.7 (C-5), 119.2 (C-6), 113.0 (C-
2), 111.0 (C-4), 72.2 (C-9), 56.0 (OCH3), 47.8 (C-10), 33.9 (C-8);
HREIMS m/z 220.0732 (calcd for C12H12O4, 220.0730).
Methyl Ether 10. Anhydrous CrCl2 (680 mg, 5.53 mmol) was
transferred under an argon atmosphere into a rb flask containing 5 mL
of THF. To the slurry was added a solution of aldehyde 9 (203 mg,
0.92 mmol) and iodoform (726 mg, 1.84 mmol) in 9 mL of THF via
syringe. The reaction mixture was stirred at rt for 1.5 h. The solution
was then mixed with 50 mL of ether and washed with 70 mL of H2O.
The organic layer was separated, and the aqueous layer was saturated
with NaCl and extracted with 30 mL of ether once. All the organic
layers were combined, then were washed with brine and dried over
MgSO4. After solvent removal, the crude product was subjected to VLC
on silica gel eluting with 50% EtOAc/petroleum ether to afford 10 (122
Acknowledgment. We thank The National Institutes of Health (R15
CA74361) for partial support of this research.
Supporting Information Available: General experimental proce-
dures, preparation of compounds 3, 6, and 11-15, and 1H and 13C NMR
spectra for all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
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