Efficient synthesis of tyrosine-derived marine sponge metabolites via acylation of amines with a coumarin

Article abstract of DOI:10.1021/jo050846r

Condensation of N-acetylglycine with aldehyde 15 in acetic anhydride gave acetamido coumarin 16. Hydrolysis to the enol coumarin 17 and reaction with hydroxylamine gave the oximino coumarin 18. Reaction of the oximino coumarin 18 with a range of nucleophi

Full text of DOI:10.1021/jo050846r

Efficient Synthesis of Tyrosine-Derived Marine Sponge
Metabolites via Acylation of Amines with a Coumarin
J. Jonathan Harburn, Nigam P. Rath, and Christopher D. Spilling*
Department of Chemistry and Biochemistry, University of MissourisSt. Louis, One University Boulevard,
St. Louis, Missouri 63121-4499
cspill@umsl.edu
Received April 26, 2005
Condensation of N-acetylglycine with aldehyde 15 in acetic anhydride gave acetamido coumarin
16. Hydrolysis to the enol coumarin 17 and reaction with hydroxylamine gave the oximino coumarin
18. Reaction of the oximino coumarin 18 with a range of nucleophiles gave the phenolic oximes in
excellent yield. The rates of acylation of histamine with the oximino coumarin 18 and methyl ester
9 were compared. Oxidative spirocyclization of three representative phenolic oximes with polymer-
supported (diacetoxyiodo) benzene gave the spiroisoxazolines.
Introduction
6c.9 Wasserman et al. showed that cyano ylides could be
employed in a very efficient preparation of the oximino
amides leading syntheses of verongamine 5a and aerothio-
nin 6a.10
In general, the metabolites can be considered as
derivatives of di-, tri-, and higher peptides containing one
or more oximino amide or spiroisoxazoline moiety. Much
Marine sponges of the order Verongida and related
organisms have provided a vast array of tyrosine 1
derived secondary metabolites.1,2 It was reported that the
metabolic pathway3 involves bromination of the tyrosine
1 aromatic ring and oxidation of the amine to an oxime
(2-5) (Scheme 1). The tyrosine oximes 2 are methylated
and coupled with amines to form oximino amides 54
which react further via an arene oxide5 to form spirocyclic
isoxazolines 6.6 The isoxazolines 6 can rearrange to give
the more stable phenolic oximes 7.7
These metabolites exhibit wide-ranging biological ac-
tivity and as a result have become targets for synthesis.8-12
In particular, new methods for the spirocyclization of
phenolic oximes have been reported,8 leading to syntheses
of aerothionin 6a, homoaerothionin 6b, and aerophobin-1
(6) For examples of spiroisoxazolines, see: (a) Cimino, G.; De Rosa,
S.; De Stefano, S.; Self, R.; Sodano, G. Tetrahedron Lett. 1983, 24, 3029.
(b) Fattorusso, E.; Minale, L.; Sodano, G.; Moody, K.; Thompson, R.
H. Chem. Commun. 1970, 752. (c) Moody, K.; Thomson, R. H.;
Fattorusso, E.; Minale, L.; Sodano, G. J. Chem. Soc., Perkin Trans. 1
1972, 18.
(7) For examples of phenolic oximino amides, see: Kobayashi, J.;
Honma, K.; Sasaki, T.; Tsuda, M. Chem. Pharm. Bull. 1995, 43, 403.
(8) (a) Murakata, M.; Yamada, K.; Hoshino, O. Heterocycles 1998,
47, 921. (b) Murakata, M.; Yamada, K.; Hoshino, O. Tetrahedron 1996,
52, 14713. (c) Murakata, M.; Yamada, K.; Hoshino, O. Chem. Commun.
1994, 443. (d) Kacan, M.; Koyuncu, D.; McKillop, A. J. Chem. Soc.,
Perkin Trans. 1 1993, 1771. (e) Noda, H.; Niwa, M.; Yamamura S.
Tetrahedron Lett. 1981, 22, 3247. (f) Forrester, A. R.; Thomson, R. H.;
Woo S.-O. J. Chem. Soc., Perkin Trans. 1 1975, 2340. (g) Forrester, A.
R.; Thomson, R. H.; Woo S.-O. J. Chem. Soc., Perkin Trans. 1 1975,
2348. (h) Okamoto, K. T.; Clardy, J. Tetrahedron Lett. 1987, 28, 4969.
(9) (a) Forrester, A. R.; Thomson, R. H.; Woo, S.-O. Liebigs Ann.
Chem. 1978, 66. (b) Nishiyama, S.; Yamamura, S. Tetrahedron Lett.
1983, 24, 3351. (c) Nishiyama, S.; Yamamura, S. Bull. Chem. Soc. Jpn.
1985, 58, 3453. (d) Murakata, M.; Masafumi, T.; Hoshino, O. J. Org.
Chem. 1997, 62, 4428.
(10) Wasserman, H. H.; Wang, J. J. Org. Chem. 1998, 63, 5581.
(11) (a) Hoshino, O.; Murakata, M.; Yamada, K. Bioorg. Med. Chem.
Lett. 1992, 2, 1561. (b) Goldstein K.; Fendert, T.; Proksch, P.;
Winterfeldt, E. Tetrahedron 2000, 56, 4173. (c) Hirotani, S.; Kaji, E.
Tetrahedron 1999, 55, 4255. (d) Nicolaou, K. C.; Hughes, R.; Pfeffer-
korn, J. A.; Barluenga, S.; Roecker, A. J. Chem.-Eur. J. 2001, 7, 4280.
(e) Nicolaou, K. C.; Hughes, R.; Pfefferkorn, J. A.; Barluenga, S.
Chem.-Eur. J. 2001, 7, 4296.
(1) Berquist, P. R.; Wells, R. J. Chemotaxonomy of the Porifera: The
Development and Current Status of the Field. In Marine Natural
Products: Chemical and Biological Perspectives; Scheuer, P. J., Ed.;
Academic Press: 1993, 5, 1-50.
(2) Faulkner, D. J. Nat. Prod. Rep. 1998, 113; Faulkner, D. J. Nat.
Prod. Rep. 1997, 259 and previous reports in this series.
(3) (a) Tymiak, A. A.; Rinehart, K. L., Jr. J. Am. Chem. Soc. 1981,
103, 6763. (b) De Rosa, M.; Minale, L.; Sodano, G. Comput. Biochem.
Physiol. 1973, 45B, 883. (c) Carney, J. R.; Rinehart, K. L. J. Nat. Prod.
1995, 58, 971.
(4) For examples of oximino amides, see: (a) Mierzwa, R.; King, A.;
Conover, M. A.; Tozzi, S.; Puar, M. S.; Patel, M.; Coval, S. J.; Pomponi,
S. A. J. Nat. Prod. 1994, 57, 175. (b) Rodriguez, A. D.; Akee, R. K.;
Scheuer, P. J. Tetrahedron Lett. 1987, 28, 4989.
(5) Roll, D. M.; Chang, C. W. J.; Scheuer, P. J.; Gray, G. A.; Shoolery,
J. N.; Matsumoto, G. K.; Van Duyne, G. D.; Clardy, J. J. Am. Chem.
Soc. 1985, 107, 2916.
10.1021/jo050846r CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/12/2005
6398
J. Org. Chem. 2005, 70, 6398-6403

Efficient Synthesis of Marine Sponge Metabolites
SCHEME 1. Biosynthesis of Tyrosine-Derived Secondary Metabolites
SCHEME 2
SCHEME 3
less than satisfactory results. In our hands, attempts to
couple the free acid 11, formed by hydrolysis of the
methyl ester 9, with amines using standard peptide
coupling reactions resulted in a decarboxylation leading
to formation of the nitrile 12. Hydrolytic deprotection of
the nitrile 12 led to the known13 phenol 13, which was
characterized by X-ray crystallography.14 Clearly, the
presence of the free oxime presents a problem in the
coupling reaction. Although, protection of the oxime was
an option,15 this would add additional deprotection steps
and thereby reducing the overall efficiency of the syn-
thesis. In a serendipitous development, an archived
sample of silylenol ether 1412b was examined by NMR
spectroscopy prior to further reaction. The 1H NMR
spectrum revealed that upon storage the silylenol ether
14 had cleanly converted to the enol coumarin 17,
presumably through deprotection and lactonization. It
was envisaged that an oxime 18, derived from coumarin
17, could serve as a self-protected active acylating agent.
However, more expeditious synthesis of coumarin 18 was
required.
of the structural variation exists in the amine component,
which is typically derived from metabolites of ornithine,
lysine, tryramine, cystamine, and histamine. The large
number and structure of the metabolites, and the poten-
tial for designing synthetic analogues with improved
biological activity, make these compounds ideal targets
for parallel synthesis. Indeed, using a similar rationale,
Nicolaou reported the formation of a combinatorial
library of antibacterial heterodisulfides based on the
homodimeric disulfide tyrosine-derived marine sponge
metabolite psammaplin A.11d,e,f Parallel synthesis of
amides would require an efficient method for the rapid
coupling of the phenolic oxime (and/or spirocyclic) moiety
to a large variety of amines. An ideal solution would be
a reactive acylating agent that required no protection of
the oxime or phenolic groups and hence no additional
deprotection steps.
In 1995 we communicated the results of our initial
studies on the oxidation, bromination, and decarboxyla-
tion of tyrosine esters12a and later reported the synthesis
of verongamine and purealidin N by the direct displace-
ment of methyl esters 8 and 9, respectively, with
histamine.12b However, although this direct amidation
reaction worked well with histamine, other amines,
particularly more the complex amines and diamines, gave
(12) (a) Boehlow, T. R.; Spilling, C. D. Nat. Prod. Lett. 1995, 7, 1.
(b) Boehlow, T. R.; Harburn, J. J.; Spilling, C. D. J. Org. Chem. 2001,
66, 3111.
(13) Anderson, R. J.; Faulkner, D. J. J. Am. Chem. Soc. 1975, 97,
936.
(14) Full details of the X-ray structure determination can be found
in the Supporting Information.
(15) Bailey, K. L.; Molinski, T. F. Tetrahedron Lett. 2002, 43, 9657.
J. Org. Chem, Vol. 70, No. 16, 2005 6399

Harburn et al.
TABLE 1.
Trivedi and Sethna had described16 a simple large-scale
method for the preparation of 3-hydroxycoumarins via
the condensation of the appropriate salicylaldehyde with
N-acetylglycine followed by acid-catalyzed hydrolysis.
Reaction of the dibromosalicylaldeyde 1512b with N-acetyl
glycine in acetic anhydride gave the acetamido coumarin
16 in yields ranging from 53 to 90%.16a Careful reaction
with an ethanolic solution of sulfuric acid led to the
selective hydrolysis of the enamide to give the enol 17.
Reaction of the enol 17 with 8.5 equiv of hydroxylamine
in refluxing 80% EtOH for 1-2 h yielded the oximino
coumarin 18. Prolonged reaction of enol 17 with an excess
of hydroxylamine lead to formation and isolation of the
hydroxamic acid 19. The enol 17 and the hydroxamic acid
19 were characterized by X-ray crystallography.14 The
oximino coumarin 18 was reacted with a variety of
nucleophiles (Table 1). Reaction with aqueous hydroxide
gave the corresponding carboxylic acid 20a in excellent
yield (Table 1, entry 2). Similarly, the addition of meth-
oxide to coumarin 18 gave the known methyl ester 20b
in high yield.12b However, since most of the natural
products of interest are amides, a series of amines were
investigated. For the volatile amines (entries 4-6), the
coumarin 18 was dissolved in the neat amine. After the
reaction was complete, the excess amine was evaporated
to give the amides in high yield and purity. The more
complex amines (entries 1 and 7) were reacted with 1
equiv of the coumarin in methanol solution at 60 °C to
give the corresponding amides in good to excellent yield.
Reaction of the diamines (entries 8 and 9) also proceeded
in methanol solution to give the diamide precursors to
aerothionin and homoaerothionin in good yield. However
between 2 and 4 equiv of the coumarin were used to
ensure complete reaction.
It was clear that the coumarin oxime 18 was a superior
acylating agent for amines than the methyl ester 9. To
get a quantitative measure, the relative reactions rates
of ester 9 and coumarin 18 with histamine were com-
pared. Coumarin 18 (1 equiv) and the methyl ester 9 (1
equiv) (in separate NMR tubes) were reacted with 3 equiv
of histamine in d4-MeOH solution at 60 °C. The reactions
1
were followed by H NMR spectroscopy. The peak for
aromatic hydrogen in each starting material was inte-
grated and compared to the integration of an internal
standard (0.1 equiv hexamethylbenzene). The coumarin
18 was consumed (Figure 1) approximately six times
faster than the methyl ester 9 under identical reaction
conditions.
We had previously reported12b that the oxime ester 20b
could be cyclized with NBS in DMF or with polymer-
supported (diacetoxyiodo)benzene (PSDIB) reagent17 in
acetonitrile to give the isoxazoline 21.12b Since, in our
hands, the isoxazoline 21 was sensitive to chromatogra-
phy, the excellent yield and purity provided by the
oxidative cyclization using the PSDIB proved it to be the
superior method. Two additional amide substrates 7d
(16) (a) Trivedi, K. N.; Sethna, S. J. Org. Chem. 1960, 25, 1817. (b)
Kokotos, G.; Tzougraki, C. J. Heterocycl. Chem. 1986, 23, 87. (c) Shaw,
K. N. F.; McMillan, A.; Armstrong, M. D. J. Org. Chem. 1956, 21, 601.
(17) (a) Togo, H.; Nogami, G.; Yokoyama, M. Synlett 1998, 534. (b)
Ley, S. V.; Thomas, A. W.; Finch, H. J. Chem. Soc., Perkin Trans. 1
1999, 669.
6400 J. Org. Chem., Vol. 70, No. 16, 2005

Efficient Synthesis of Marine Sponge Metabolites
dried in vacuo to give 16 as a tan crystalline solid (17.1 g,
53%): mp 291-292.5 °C (lit. 292-294 °C, DMSO/H2O);6c IR
1
(KBr) 3347, 1715, 1681 cm-1; H NMR (d6-DMSO, 100 °C) δ
9.43 (s, 1H), 8.49 (s, 1H), 8.01 (s, 1H), 3.91 (s, 3H), 2.18 (s,
3H); 13C NMR (d6 DMSO, 100 °C) δ 169.4, 156.0, 153.9, 146.4,
129.6, 124.0, 121.5, 118.1, 112.0, 104.9, 60.4, 23.3; HRMS (EI,
M+) calcd for C12H979Br81BrNO4 390.8898, found 390.8875.
Anal. Calcd for C12H9Br2NO4: C, 36.86; H, 2.32; N 3.58.
Found: C, 36.92; H, 2.29; N 3.57.
6,8-Dibromo-3-hydroxy-7-methoxy-coumarin (17). A
solution of 3-acetamido-6,8-dibromo-7-methoxycoumarin 16 (10
g, 25.7 mmol) in absolute EtOH (100 mL) and 6 N HCl (50
mL) was heated at reflux overnight. The reaction mixture was
concentrated in vacuo to give a yellow precipitate, which was
collected by filtration. The filtrate was washed successively
with copious amounts of H2O, hexanes, and cold Et2O (50 mL)
and dried in vacuo to give 17 as a pale-yellow crystalline solid
(8.02 g, 90%): mp 178-179 °C (CHCl3); IR (KBr) 3367, 1695,
1
1649 cm-1; H NMR (CDCl3) δ 7.59 (s, 1H), 6.94 (s, 1H), 6.33
(s, 1H), 3.94 (s, 3H); 13C NMR (CDCl3) δ 159.6, 154.7, 146.5,
140.4, 129.0, 119.0, 114.3, 113.1, 107.3, 61.3; HRMS (CI, M+)
calcd for C10H779Br81BrO4 350.8691, found 350.8699. Anal.
Calcd for C10H6Br2O4: C, 34.32; H, 1.73. Found: C, 34.25; H,
1.72.
FIGURE 1. A graph comparing the rate of the reaction of
the methyl ester 9 and coumarin 18 with histamine.
SCHEME 4
6,8-Dibromo-7-methoxy-3-hydroximino-3,4-dihydro-
coumarin (18). A solution of 6,8-dibromo-3-hydroxy-7-meth-
oxycoumarin 17 (1 g, 2.87 mmol), hydroxylamine hydrochloride
(1.69 g, 24.3 mmol), and NaOAc (2.35 g, 28.7 mmol) in aqueous
EtOH (80%, 50 mL) was heated at reflux until no starting
material remained (usually 1-2 h, thin-layer chromatography
(TLC), SiO2, EtOAc:CH2Cl2, 2:1). The reaction mixture was
concentrated in vacuo and the pale-yellow solid was collected
by filtration. The solid was washed with copious amounts of
H2O and CHCl3 and dried in vacuo. Further purification by
chromatography (SiO2, hexanes:EtOAc) gave 18 as a pale-
yellow solid (0.721 g, 69%): mp 193.5-195 °C; IR (KBr) 3354,
1
1718, 1526 cm-1; H NMR (d6-DMSO) δ 9.28 (s, 1H), 7.28 (s,
1H), 3.74 (s, 3H), 3.71 (s, 2H); 13C NMR (d6 DMSO) δ 163.0,
154.4, 154.1, 150.2, 134.6, 121.3, 108.4, 106.3, 60.1, 25.6;
HRMS (EI, M+) calcd for C10H779Br81BrNO4 364.8742, found
364.8725. If the reaction mixture is heated at reflux for longer
than 1-2 h, formation of increasing amounts of the hydrox-
amic acid 19 was observed (>5 h, TLC, SiO2, EtOAc:CH2Cl2,
2:1). The hydroxamic acid was separated from the coumarin
18 by column chromatography (SiO2, EtOAc:CH2Cl2, 1:1) to
and 7f were cyclized with PSDIB to give 22a and 22b,
respectively. The spirocyclization occurred rapidly, and
workup only involved filtration, thus removing the need
for chromatography.
give a beige solid, IR (ATR) 3471, 3318, 3234, 1647, 1618 cm-1
;
1H NMR (d6-acetone) δ 7.57 (s, 1H), 3.82 (s, 2H), 3.80 (s, 3H);
13C NMR (d6-acetone) δ 163.9, 155.3, 155.0, 151.5, 122.2, 109.2,
107.2, 61.0, 26.6; Anal. Calcd for C10H10Br2N2O5: C, 30.18; H,
2.53; N, 7.04. Found: C, 30.40; H, 2.51; N. 6.90.
In summary, whereas attempted coupling of R-oximi-
noacid 11 with amines using carbodiimides resulted in
decarboxylation to the corresponding nitrile 12, reaction
of the coumarin oxime 18 with a range of nucleophiles
proceeded smoothly to give phenolic oximes 7a-g and
20a-b. The rate of acylation with the coumarin oxime
18 was approximately six times faster than the methyl
ester 9 (with histamine). The phenolic oximes 7d and 7f
reacted with PSDIB to give spiroisoxazolines 22a and
22b, respectively. These reactions are potentially useful
in the parallel synthesis of a wide range of sponge
metabolite analogues.
3-(3,5-Dibromo-2-hydroxy-4-methoxyphenyl)-2(E)-(hy-
droximino)propanoic Acid (20a). KOH (0.154 g, 2.74 mmol)
was added to a solution of 6,8-dibromo-7-methoxy-3-oximino-
coumarin 18 (0.5 g, 1.37 mmol) in THF (15 mL) and H2O (5
mL). The mixture was stirred for 18 h, then the solvent was
removed in vacuo. The residue was dissolved in distilled H2O
(10 mL) and acidified to pH 1 with dilute HCl (0.1 M) at which
point a pale-tan precipitate formed. The mixture was extracted
with EtOAc (3 × 15 mL), and the combined extracts were
washed with saturated NaCl solution (2 × 25 mL) and H2O (2
× 25 mL), dried over anhydrous Na2SO4, and evaporated in
vacuo to give a pale-tan solid (0.512 g, 98%): mp 141-143 °C
1
(PhMe); IR (ATR) 3472, 3319, 3235,1689 cm-1; H NMR (d6-
DMSO) δ 10.74 (br. s, 3H), 7.42 (s, 1H), 3.95 (s, 2H), 3.83 (s,
3H); 13C NMR (d6-DMSO) δ 166.1, 154.0, 153.1, 150.0, 133.2,
121.9, 107.8, 106.8, 60.2, 25.4.
Methyl 3-(3,5-Dibromo-2-hydroxy-4-methoxy-phenyl)-
2(E)-(hydroximino)propanoate (20b). A solution of the
coumarin oxime 18 (0.10 g, 0.276 mmol) and NaOMe (0.07 mL,
25 wt %, 0.303 mmol) in MeOH (1 mL) was stirred until the
starting material had been consumed (TLC, SiO2, EtOAc:
hexanes:CH2Cl2, 5:5:1). The solvent was evaporated in vacuo.
The residue was dissolved in EtOAc (10 mL) and washed with
Experimental Section
3-Acetamido-6,8-dibromo-7-methoxy-coumarin (16). A
solution of 3,5-dibromo-2-hydroxy-4-methoxybenzaldehyde12b
15 (25.4 g, 82.5 mmol), acetylglycine (9.66 g, 82.5 mmol), and
anhydrous NaOAc (13.5 g, 165 mmol) in Ac2O (250 mL) was
heated at reflux overnight. The mixture was allowed to cool
to room temperature, and the crystalline solid which precipi-
tated was collected by filtration. The solid was successively
washed with copious amounts of H2O, CHCl3, and Et2O and
J. Org. Chem, Vol. 70, No. 16, 2005 6401

Harburn et al.
dilute HCl (0.1M, 2 × 10 mL) and saturated NaCl (10 mL),
dried over Na2SO4, and evaporated in vacuo to give a colorless
solid (0.105 g, 97%), mp 146-147 °C (lit. 148-149 °C).8a,12b
Spectroscopic data were identical with those previously re-
ported.
General Procedure for the Reaction of Volatile Amines
with Coumarin (18). 6,8-Dibromo-7-methoxy-3-oximino cou-
marin 18 (0.5 g, 1.37 mmol) and amine (13.7 mmol) were
heated at reflux until no starting material remained by TLC
(SiO2, hexanes:EtOAc:CH2Cl2, 5:5:1). The remaining amine
was evaporated in vacuo, and the residue was purified by
chromatography. Yields and characterization data given below.
60.6, 57.6, 45.9, 43.9, 37.0, 33.7, 29.1; HRMS [FAB (MH -
NMe2)+] calcd. for C21H2279Br281Br2N2O5 701.8825, found
701.8871.
Aerothionin Precussor (7f). A solution of coumarin oxime
18 (0.50 g, 1.37 mmol), NEt3 (0.02 mL, 0.069 mmol), and 1,4-
diaminobutane (0.033 g, 0.323 mmol) in MeOH (10 mL) was
heated at reflux until no starting material was visible by TLC
(SiO2, CHCl3:MeOH, 5:1) at which point the solvent was
evaporated in vacuo to give a yellow gum. Chromatography
(SiO2, hexanes/EtOAc then CH2Cl2 to CH3CN to MeOH) gave
a pale-yellow solid (0.384 g, 67%): mp 187-189.5 °C (Et2O/
CHCl3) (lit. 188.5-189.5);6c,10 IR (ATR) 3352, 3215, 3087, 1651
cm-1; 1H NMR (d6-acetone) δ 8.11 (br s, 2H), 7.61 (s, 2H), 3.83
(s, 4H), 3.82 (s, 6H), 3.40 (m, 4H), 2.80 (m, 4H); 13C NMR (d6-
acetone) δ 166.1, 154.4, 154.3, 150.9, 134.6, 121.4, 108.4, 106.2,
60.1, 39.6, 26.8, 25.4; HRMS (FAB, CsI:NBA, M + Cs+) calcd
for C24H2679Br281Br2N4O8Cs 950.7500, found 950.7509.
Homoaerothionin Precusor (7g). A solution of the cou-
marin oxime 18 (0.250 g, 0.685 mmol), NEt3 (0.01 mL, 0.069
mmol), and 1,5-diaminopentane (0.033 g, 0.323 mmol) in
MeOH (10 mL) was treated as above to give a pale-yellow gum
N-(2,2,2 Trifluoroethyl) 3-(3,5-dibromo-2-hydroxy-4-
methoxyphenyl)-2(E)-(hydroximino)propanamide (7b).
Tan crystalline solid (0.665 g, 99%): mp 139.5-141 °C; IR
1
(ATR) 3474, 3373, 3239, 1647 cm-1; H NMR (CDCl3) δ 8.91
(br. s, 1H, OH), 7.43 (s, 1H), 7.16 (t, 1H, J ) 6.2 Hz, 1H) 3.95
(m, 2H), 3.79 (s, 5H); 13C NMR (CDCl3) δ 165.6, 154.5, 153.0,
151.0, 134.3, 125.1 (q, JCF ) 277 Hz), 120.0, 108.9, 107.9, 61.0,
41.5 (q, JCF ) 35.5 Hz), 24.86; HRMS (FAB, CsI/NBA/PEG 600,
M + Cs+) calcd for C12H1179Br81BrN2O4Cs: 596.8072, found
596.8041. Anal. Calcd for C12H9Br2NO4: C, 31.06; H, 2.39; N
6.04. Found: C, 30.83; H, 2.37; N 5.92.
(0.191 g, 70%): IR (Diamond) 3350, 32.15, 3086, 1650 cm-1
;
1H NMR (CDCl3) δ 11.24, (br s, 4H), 8.05 (t, 2H, J ) 5.8 Hz),
7.59 (s, 2H), 3.81 (s, 4H), 3.80 (s, 6H), 3.36 (m, 4H), 2.06 (m,
4H), 1.40 (m, 2H); 13C NMR (CDCl3) δ 167.1, 155.4, 155.3,
152.0, 135.6, 122.5, 109.4, 107.2, 61.1, 40.8, 31.1, 26.4, 25.3;
HRMS (FAB NBA, M + H+) calcd. for C25H2979Br2N4O8
832.8681, found 832.8669.
N-Allyl 3-(3,5-dibromo-2-hydroxy-4-methoxyphenyl)-
2(E)-(hydroximino)propanamide (7c). Colorless needles
(95%): mp 198-199 °C (acetone), IR (KBr) 3346, 3192, 3089,
1620 cm-1; 1H NMR (d6-acetone) δ 11.51 (br. s, 1H), 10.74 (br.
s, 1H), 8.04 (br. s, 1H), 7.51 (s, 1H), 5.77 (ddd, 1H, J ) 5.5,
10.3, 17.2 Hz,), 5.03 (ddd, 1H, J ) 1.6, 3.0, 17.2 Hz), 4.95 (ddd,
1H, J ) 1.6, 3.0, 10.3 Hz), 3.85 (dt, 2H, J ) 1.6 Hz, 5.5 Hz),
3.70 (s, 2H), 3.67 (s, 3H); 13C NMR (rotomers) (d6-acetone) δ
166.58, 154.95, 154.81, 151.46, 135.2, 134.9, 122.0, 116.5,
108.9, 106.8, 60.7, 39.4, 26.5, 25.1; (CD3OD) δ 167.0, 155.1,
154.7, 151.7, 136.1, 134.9, 134.8, 123.0, 117.9, 109.0, 107.4,
60.9, 40.7, 27.7, 25.8; HRMS (FAB CsI/NBA/PEG 600, M +
Cs+) calcd for C13H1479Br81BrN2O4Cs 554.8355, found 554.8356.
Anal. Calcd for C13H14Br2N2O4: C, 37.15; H, 3.36. Found: C,
37.14; H, 3.33.
A Comparison of the Rate of Reaction of the Methyl
Ester 9 and Coumarin 18 with Histamine. In two separate
NMR tubes were placed 18 (0.05 g, 0.137 mmol) or 9 (0.06 g,
0.137 mmol), histamine (0.046 g, 0.411 mmol), internal
standard hexamethylbenzene (0.002 g, 0.0137 mmol), and CD3-
OD (1.5 mL). The NMR tubes were heated at 60 °C (water
bath temperature), and 1H NMR spectra were recorded at
regular intervals. The integrals were corrected to the internal
standard and plotted against time.
General Procedure for Oxidative Spirocyclization.
PSDIB17 (1.0 g, 3.5 mmol/g, 3.5 mmol) was stirred in acetoni-
trile (10 mL) and allowed to swell. A solution of the phenolic
oxime (0.05 g) in acetonitrile (1 mL) was added via syringe to
the swelled polymer, and the mixture was stirred for 1 h. The
polymer was removed by filtration, washing with additional
acetonitrile (3 × 25 mL), and then the solvent was evaporated
in vacuo. Yields and characterization data are given below.
N-Benzyl7,9-dibromo-8-methoxy-6-oxo-1-oxa-2-azaspiro-
[4,5]deca-2,7,9-triene-3-carbamide (22a). Pale-yellow gum
(0.049 g, 98%); IR (ATR) 3339, 3063, 3031, 1668 cm-1; 1H NMR
(CDCl3) δ 7.39 (m, 5H), 7.00 (t, 1H, J ) 5.7 Hz), 6.80, (s, 1H),
4.59 (m, 2H), 4.20 (s, 3H), 3.66 (d, 1H, J ) 18.0 Hz), 3.42 (d,
1H, J ) 18.0 Hz); 13C NMR (CDCl3) δ 189.6, 163.7, 158.6,
152.9, 137.4, 136.8, 129.3, 128.1, 120.8, 107.1, 87.2, 65.5, 45.4,
44.1; HRMS (EI, M - NOH+) calcd. for C17H1379Br81BrNO3
438.9243, found 438.9245.
N-Benzyl 3-(3,5-dibromo-2-hydroxy-4-methoxyphenyl)-
2(E)-(hydroximino)propanamide (7d). Colorless crystalline
solid (0.619 g, 93%); mp 143.5-145 °C (acetone); IR (ATR)
1
3353, 3212, 3089, 1614 cm-1; H NMR (CDCl3) δ 10.10 (br s,
1H, OH), 8.80 (br s, 1H, OH), 7.54 (s, 1H), 7.38 (m, 5H), 4.52
(s, 1H), 4.51 (s, 1H), 3.87 (s, 3H), 3.840 (s, 2H); 13C NMR
(CDCl3) δ 165.2, 154.5, 153.4, 151.3, 137.0, 134.5, 129.3, 128.3,
128.2, 120.4, 109.0, 107.6, 60.9, 44.4, 25.2; HRMS (EI, M+)
calcd for C17H1679Br81BrN2O4 471.9455, found 471.9455.
Purealidin N 7a. A solution of the coumarin oxime 18 (0.50
g, 1.37 mmol) and histamine (0.153 g, 1.37 mmol) in MeOH
(10 mL) was heated at reflux until no starting material was
visible by TLC (SiO2, CHCl3:MeOH, 5:1), at which point the
solvent was evaporated in vacuo to give a yellow gum.
Chromatography (SiO2, hexanes:EtOAc then CHCl3 to MeOH)
gave a pale-yellow hygroscopic solid (0.641 g, 98%). Physical
and spectroscopic data were identical those previously repor-
ted.12b
N-[3,5-Dibromo-4-(3-dimethylaminopropoxy)pheneth-
yl] 3-(3,5-dibromo-2-hydroxy-4-methoxyphenyl)-2(E)-(hy-
droximino)propanamide (7e). A solution of coumarin oxime
18 (0.250 g, 0.69 mmol), NEt3 (0.02 mL, 0.137 mmol), and 3,5-
dibromo-4-(3-dimethylaminopropoxy) phenethylamine (0.260
g, 0.69 mmol) in MeOH (10 mL) was heated at reflux until no
starting material was visible by TLC (SiO2, CHCl3:MeOH, 5:1),
at which point the solvent was evaporated in vacuo to give a
yellow gum. Chromatography (SiO2, CHCl3 to MeOH) gave a
yellow gum, which was titrated with acetone to give a colorless
solid (0.321 g, 63%): mp 131-132.5 °C (acetone); IR (ATR)
3334, 3214, 3111, 1625 cm-1; 1H NMR (CD3OD) δ 7.41 (s, 2H),
7.06 (s, 1H), 4.00 (t, 2H, J ) 6.1 Hz), 3.78 (s, 3H), 3.57 (s, 2H),
3.46 (t, 2H, J ) 7.0 Hz), 2.86 (t, 2H, J ) 7.0 Hz), 2.67 (m, 2H),
2.31 (s, 6H), 2.06 (m, 2H); 13C NMR (CD3OD) δ 169.8, 165.5,
155.9, 153.4, 138.5, 134.4, 132.5, 122.0, 119.3, 112.1, 99.4, 72.8,
Aerothionin Precursor (22b). Pale-yellow gum (0.047 g,
94%); IR (ATR) 3342, 3066, 3031, 1662 cm-1; 1H NMR (DMSO-
d6) δ 8.65 (t, J ) 5.7 Hz, 2H, 2 × NH), 7.24 (s, 2H), 4.06, (s,
6H, 2 × OCH3), 3.51 (br, 4H), 3.18 (br 4H), 1.48 (br, 4H); 13C
NMR (DMSO-d6) δ 190.5, 163.9, 158.9, 154.6, 139.6, 119.3,
108.4, 86.8, 62.7, 45.9, 39.4, 27.1; HRMS (FAB, NBA, M + H+)
calcd. for C24H2379Br281Br2N4O8 814.8204, found 814.8245.
Acknowledgment. We are grateful to the Missouri
Research Board for financial support of this project. We
are also grateful to the NSF, the US DoE, and the
University of Missouri Research Board for grants to
purchase the NMR spectrometers (CHE-9318696, CHE-
9974801, DE-FG02-92-CH10499) and X-ray diffracto-
meter (CHE-9309690) and mass spectrometer (CHE-
9708640) used in this work. We thank Mr. Joe Kramer
and Prof. R. E. K. Winter for mass spectra.
6402 J. Org. Chem., Vol. 70, No. 16, 2005

Efficient Synthesis of Marine Sponge Metabolites
Supporting Information Available: General experimen-
tal details, experimental for compounds 11, 12, and 13, 1H and
13C NMR spectra for compounds 11, 12, 13, 16, 17, 18, 20a,
20b, 7a, 7b, 7c, 7d, 7e, 7f, 7g, 22a, and 22b, X-ray crystal-
lographic data for compounds 13, 17, and 19, and stack plots
of the 1H NMR spectra for the reaction of 9 and 18 with
histamine. This material is provided free of charge via the
Internet at http://pubs.acs.org.
JO050846R
J. Org. Chem, Vol. 70, No. 16, 2005 6403