Iminophosphorane-based preparation of 2,5-disubstituted oxazole derivatives: Synthesis of the marine alkaloid almazole C

Article abstract of DOI:10.1055/s-2007-967995

A four-steps synthesis (32% overall yield) of marine alkaloid almazole C isolated from the red seaweed Haraldiophylum sp. is described. The key step, construction of the central 2,5-disubstituted oxazole ring is based on the aza-Wittig reaction of the imi

Full text of DOI:10.1055/s-2007-967995

324
LETTER
Iminophosphorane-Based Preparation of 2,5-Disubstituted Oxazole
Derivatives: Synthesis of the Marine Alkaloid Almazole C
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M. Fresneda,* Marta Castañeda, Mathias Blug, Pedro Molina*
Departamento de Química Orgánica, Facultad de Química, Universidad de Murcia, Campus de Espinardo, 30100 Murcia, Spain
Fax +34(968)364149; E-mail: fresneda@um.es; E-mail: pmolina@um.es
Received 19 July 2006
electrocyclization, intramolecular cycloaddition, or het-
Abstract: A four-steps synthesis (32% overall yield) of marine al-
erocumulene-mediated annelation have been used for the
kaloid almazole C isolated from the red seaweed Haraldiophylum
sp. is described. The key step, construction of the central 2,5-disub-
stituted oxazole ring is based on the aza-Wittig reaction of the imi-
preparation of a wide variety of nitrogen-containing
natural products.11
nophosphorane derived from the a-azidoacetyl indole and (S)-N-
In conjunction with our synthetic efforts on the synthesis
phthaloylphenylalanyl chloride.
of a number of nitrogen-containing alkaloids from marine
origin,12 we have devised a reliable synthesis of almazole
Key words: oxazoles, marine alkaloids, iminophosphoranes, in-
doles, aza-Wittig reaction
C, which is based on the iminophosphorane-based forma-
tion of the appropriately 2,5-disubstituted, central, five-
membered ring. The three-component reaction between
The oxazole heterocycle is a fundamental structural motif
an a-azidoketone, a tertiary phosphine and an acyl halide
found in many compounds such as natural products,1
has been employed for the preparation of the central
unnatural biologically active compounds,2 and molecular
sensors.3 Naturally occurring oxazoles are usually found
with a 2,4-substitution pattern, although 2,5-disubstituted
oxazole natural products are known. They comprise the
oxazole derivative ring.13 The reaction takes place
through an initially formed iminophosphorane which
undergoes acylation and further elimination of the corre-
sponding phosphine oxide to give an imidoyl chloride as
intermediate which gives the five-membered ring after
cyclization. Recently, two slight modifications of this
protocol have been applied successfully to the synthesis
of 2,5-disubstituted imidazole alkaloids from marine
origin.14
2,5-diaryloxazoles
halfordinol,4
balnoxin,5
and
annuloline6 and the 5-(3-indolyl)oxazoles pimprinine
alkaloids7 and martefragin A,8 which is a strong inhibitor
of lipid peroxidation.
In 1994, the 2,5-disubstituted oxadiazole alkaloid alma-
zole C (1, Figure 1), which showed antibacterial activity
against Gram-negative pathogens, was isolated from a red
seaweed of family Delesseriaceae of genus Haraldio-
phylum sp. on the north of Dakar.9 From the structural
point of view almazole C (1) represents slight variations
on 5-(3-indolyl)oxazole alkaloids that have been isolated
previously. As can be seen in Figure 1, the oxazole ring of
the almazole C (1) is substituted at 2-position by a N,N-
dimethylphenylalanine fragment.
We initially required an N-protected 3-acetylindole as
starting material and the protecting group of choice was
the MOM group. To this end N-methoxymethyl-3-azi-
doacetylindole (5) was prepared in a three-step sequence:
(a) N-protection of 3-acetylindole with chloromethyl-
methyl ether in DMF in the presence of NaH (89% yield),
(b) selective a-chlorination of 3-acetylindole 3 with
benzyltrimethyl-ammonium dichloroiodate15 to give the
a-chloroacetyl derivative 4 (90%), and (c) halogen–azide
exchange with sodium azide in acetone–water to afford
the a-azido ketone 5 (77%, Scheme 1).
N
O
The formation of the central oxazole ring was achieved
using the iminophosphorane methodology. Previous stud-
ies on the reactivity of a-azido ketones derived from the
indole ring revealed that the Staudinger reaction with
triphenylphosphine is very slow13b and in some cases
products derived from the double intermolecular aza-
H
NH
almazole C (1)
NMe2
Figure 1
Both inter- and intramolecular versions of the aza-Wittig Wittig reaction were isolated. For this reason the more re-
reaction have assumed increasing importance for the con- active n-tributylphoshine has been employed. Thus, the
struction of a wide variety of nitrogen-containing hetero- key intermediate 7 was prepared in 70% yield by reaction
cyclic ring systems.10 Several methodologies based on the of a-azido ketone 5 with n-tributylphosphine in THF at
intermolecular aza-Wittig reaction followed by either 0 °C and subsequent addition of (S)-N-phthaloylphenyl-
alanyl chloride16 (6) followed by treatment with Et3N.17
Attempts to improve the yield of compound 7 using the
SYNLETT 2007, No. 2, pp 0324–0326
Advanced online publication: 24.01.2007
0
1.
0
2.
2
0
0
7
triazaphosphadiene pathway18 (in this case the reaction is
DOI: 10.1055/s-2007-967995; Art ID: D21106ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of the Marine Alkaloid Almazole C
325
O
O
O
ii)
iii)
i)
90%
77%
Cl
89%
N
H
N
N
3
4
2
MOM
MOM
N
O
O
O
iv)
Cl
O
+
O
H
N
N
N3
70%
N
O
O
O
N
MOM
(S)
MOM
5
7
6
N
N
v)
vi)
O
O
H
NH2
H
NMe2
90%
90%
N
MOM
N
9
8
MOM
vii) 55%
N
viii) 53%
N
O
O
H
NMe2
N
N
H
10
MOM
almazole C (1)
Scheme 1 Total synthesis of amazole C1. Reagents and conditions: i) Nah, DMF, MOMCl, 1 h, r.t.; ii) Bn(CH3)3NCl2I, 5 d, r.t.; iii) NaN3,
acetone–H2O, reflux, 18 h; iv) n-Bu3P, Et3N, THF, 3 h, r.t.; v) N2H4·H2O, EtOH, 3 d, r.t.; vi) HCHO, H2/Pd (C), EtOH; vii) HCOOH, THF–
H2O, reflux, 30 h; viii) NaH, Mel, 3 d, r.t.
carried out with the acyl chloride present before the addi-
tion of the phosphine) failed.
References and Notes
(1) (a) Lewis, J. R. Nat. Prod. Rep. 2002, 19, 223. (b) Jin, Z.;
Li, Z.; Huang, R. Nat. Prod. Rep. 2002, 19, 454. (c) Jin, Z.
Nat. Prod. Rep. 2003, 20, 584. (d) Yeh, V. S. C.
The N-phthaloyl group of compound 7 was smoothly re-
moved with hydrazine in EtOH at room temperature to
give amine 8 in 90% yield. The best results to prepare the
N-dimethylated amine was realized by reductive amina-
tion with hydrogen in the presence of formaldehyde and
palladium as catalysis,19 to give compound 9 in 90% yield.
Also, another N-methylating agent was used: first the re-
ductive amination by Leuckart reaction was realized in the
presence of formaldehyde/formic acid in CH2Cl2 at room
temperature for four days to give N-dimethylated com-
pound 9 in 43% yield. When methyl iodide was used in
THF at reflux temperature for five days or in DMF in the
presence of NaH at room temperature for three days, vinyl
compound 10 was obtained in 21% and 53% yield, respec-
tively.
Tetrahedron 2004, 60, 11995. (e) Jin, Z. Nat. Prod. Rep.
2005, 22, 196. (f) Jin, Z. Nat. Prod. Rep. 2006, 23, 464.
(2) (a) Lipshutz, B. H. Chem. Rev. 1986, 86, 795. (b) Talley, J.
J.; Bertenshaw, S. R.; Brown, D. L.; Carter, J. S.; Graneto,
M. J.; Koboldt, C. M.; Masferrer, J. L.; Norman, B. H.;
Rogier, D. J. Jr.; Zweifel, B. S.; Seibert, K. Med. Res. Rev.
1999, 19, 199. (c) Wasserman, H. H.; McCarthy, K. E.;
Prowse, K. S. Chem. Rev. 1986, 86, 845.
(3) (a) Tarraga, A.; Molina, P.; Curiel, D.; Velasco, M. D.
Organometallics 2001, 20, 2145. (b) Tarraga, A.; Molina,
P.; Curiel, D.; Velasco, M. D. Tetrahedron 2001, 57, 6765.
(4) Crow, M. D.; Hodgkin, J. H. Tetrahedron Lett. 1963, 4, 85.
(5) Burque, B.; Parkins, H.; Talbot, A. M. Heterocycles 1979,
12, 349.
(6) Axerold, B.; Belzile, J. R. J. Org. Chem. 1958, 23, 919.
(7) (a) Bhate, D. S.; Hulyalker, R. K.; Menon, S. K. Experientia
1960, 16, 504. (b) Joshi, B. S.; Taylor, W. I.; Bathe, D. S.;
Karmarkar, S. S. Tetrahedron 1963, 19, 1473.
Compound 9 was converted into almazole C (1) by depro-
tection of the N-methoxymethyl substituent with formic
acid in THF at reflux temperature for 30 hours in 55%
yield.20 Compound 1 was identical in all aspects {IR, MS,
1H NMR, 13C NMR and [a]D20} with the natural product.1
(c) Noltenmeyer, M.; Sheldrick, G. M.; Hoppe, H.-U.;
Zeeck, A. J. Antibiot. 1982, 35, 549.
(8) (a) Takahashi, S.; Matsunaga, T.; Hasegawa, C.; Saito, H.;
Fujita, D.; Kiuchi, F.; Tsuda, Y. Chem. Pharm. Bull. 1998,
46, 1527. (b) Nishida, A.; Fuwa, M.; Fijikawa, Y.;
Nakahara, E.; Furuno, A.; Nakagawa, M. Tetrahedron Lett.
1998, 39, 5938.
(9) (a) Guella, G.; Mancini, I.; N’Diaye, I.; Pietra, F. Helv.
Chim. Acta 1994, 77, 1999. (b) N’Dieye, I.; Guella, G.;
Mancini, I.; Pietra, F. Tetrahedron Lett. 1996, 37, 3049.
Acknowledgment
We thank the Fundación Séneca (Comunidad Autónoma de la Re-
gión de Murcia) for financial support (project number 00582/PI/04)
and the Mathias Blug Erasmus Program studentship from the
University of Kaiserslautern.
Synlett 2007, No. 2, 324–326 © Thieme Stuttgart · New York

326
P. M. Fresneda et al.
LETTER
(10) (a) Gololobov, Y. G.; Kasukhin, L. Tetrahedron 1992, 48,
1353. (b) Eguchi, S.; Matsushita, K.; Yamashita, K. Org.
Prep. Proced. Int. 1992, 209. (c) Molina, P.; Vilaplana, M.
J. Synthesis 1994, 1197. (d) Wammhoff, H.; Richardt, G.;
Stölben, S. Adv. Heterocycl. Chem. 1999, 64, 159.
(e) Eguchi, S.; Okano, T.; Okawa, T. Rec. Res. Dev. Org.
Chem. 1997, 1, 337.
(11) (a) Fresneda, P. M.; Molina, P. Synlett 2004, 1. (b) Eguchi,
S. ARKIVOC 2005, (ii), 98.
(12) (a) Fresneda, P. M.; Molina, P.; Delgado, S.; Bleda, J. A.
Tetrahedron Lett. 2000, 41, 4777. (b) Molina, P.; Fresneda,
P. M.; Delgado, S. J. Org. Chem. 2003, 68, 489.
(c) Fresneda, P. M.; Delgado, S.; Francesch, A.;
Manzanares, I.; Cuevas, C.; Molina, P. J. Med. Chem. 2006,
49, 1217.
(13) (a) Zbiral, E.; Bauer, E.; Stroh, J. Monatsh. Chem. 1971,
102, 168. (b) Molina, P.; Fresneda, P. M.; Almendros, P.
Synthesis 1993, 54. (c) Molina, P.; Fresneda, P. M.;
Almendros, P. Heterocycles 1993, 36, 2255.
(14) (a) Fresneda, P. M.; Molina, P.; Sanz, M. A. Synlett 2001,
218. (b) Fresneda, P. M.; Molina, P.; Sanz, M. A. Synlett
2000, 1190.
(15) Croce, D. P.; Ferraccioli, R.; Ritieni, A. Synthesis 1990, 212.
(16) Sheehan, J. C.; Chapman, D. W.; Roth, R. W. J. Am. Chem.
Soc. 1952, 74, 3822.
7.41 (d, 1 H, J = 8.1 Hz, H-7), 7.59 (dd, 2 H, J = 5.4, 3.0 Hz,
2 Hm¢’), 7.68 (d, 1 H, J = 7.8 Hz, H-4), 7.71 (dd, 2 H,
J = 5.4, 3.0 Hz, 2 Ho¢). 13C NMR (75 MHz, CDCl3): d = 35.6
(CH2), 49.3 (CH), 56.0 (OCH3), 77.6 (OCH2), 105.3 (C-3),
110.4 (C-7), 120.1 (C-4), 120.6 (C-4¢), 121.4 (C-7), 121.4
(C-5), 123.2 (C-6), 123.4 (Co¢), 125.2 (C-3a), 125.6 (C-2),
126.9 (Cp), 128.6 (Cm), 129.0 (Co), 131.6 (C-i¢), 134.0
(Cm¢), 136.5 (C-7a), 136.6 (Ci), 147.9 (C-5¢), 158.4 (C-2¢),
167.4 (CO). MS (FAB positive): m/z (%) = 478 (100) [M +
1], 477 (75) [M+], 326 (29) [M+ – Bn], 331 ]M+ –
phthalimido]. Anal. Calcd for C29H23N3O4: C, 72.94; H,
4.85; N, 8.80. Found: C, 72.86; H, 4.80; N, 8.85.
(18) Shalev, D. E.; Chiacchiera, S. M.; Radkowsky, A. E.;
Kosower, E. M. J. Org. Chem. 1996, 61, 1689.
(19) Aurelio, L.; Brownlee, T. C.; Hughes, A. B. Chem. Rev.
2004, 104, 5823; and references cited therein.
(20) Almazole C (1).
To a suspension of 7 (0.32 g, 0.68 mmol) in EtOH (20 mL),
hydrazine monohydrate (0.14 mL, 2.68 mmol) was added at
0 °C. The reaction mixture was stirred for 36 h at r.t. The
precipitated solid was separated by filtration, slurried with
CH2Cl2 and filtered. The filtrate was dried (MgSO4) and the
solvent removed under reduce pressure to give (S)-1-{5-[N-
(Methoxymethyl)-1H-indol-3-yl]oxazol-2-yl}-2-phenyl-
ethanamine (8, 0.21 g, 90% yield). A mixture of the amine 8
(0.4 g, 1,16 mmol), formaldehyde 37% (0.86 mL, 9.54
mmol) and 10% Pd on charcoal (0.24 g, 2.3 mmol) in
EtOH (25 mL) was stirred at r.t. under nitrogen for 17 h.
The reaction mixture was filtered under celite and the
solvent removed under reduce pressure to give (S)-1-{5-
[1-(methoxymethyl)-1H-indol-3-yl]oxazol-2-yl}-N,N-
dimethyl-2-phenylethanamine (9, 0.388g, 90% yield). A
mixture of N-methoxymethyl almazole C (9, 0.3 g, 0.8
mmol), 85% formic acid (40 mL), THF (25 mL), and H2O
(5 mL) was heated at reflux temperature for 30 h. After
cooling the solvents were removed under reduced pressure.
The residue was purified by chromatography on a silica-
amine gel column using Et2O–EtOAc (9:1) as eluent to give
1 (0.146 g, 55% yield); spectroscopic and optical properties
{[a]D20 +141 (c 0.1, MeOH)} were identical to natural
almazole C.
(17) 2-[(S)-1-{5-[N-(Methoxymethyl)-1H-indol-3-yl]oxazol-2-
yl}-2-phenylethyl]isoindoline-1,3-dione (7).
To a solution of 3-(a-azidoacetyl) indole 5 (0.2 g, 0.82
mmol) in dry THF (32 mL), n-tributylphosphine (0.3 mL,
1.23 mmol) was added dropwise at 0 °C under N2. Then, a
solution of (S)-N-phthaloylphenylalanyl chloride 6 (0.26 g,
0.82 mmol) in the same solvent (20 mL) was added. The
resultant mixture was stirred at r.t. for 1 h, and then dry Et3N
(0.17 mL, 1.23 mmol) was added and stirred for 2 h. The
resultant solution was concentrated to dryness under reduced
pressure and the residue was chromatographed on a silica gel
column using CH2Cl2–EtOAc (8:2) as eluent to give 7 (0.27
g, 70% yield). Mp 157–160 °C 1H NMR (300 MHz, CDCl3):
d = 3.17 (s, 3 H, OCH3), 3.79 (m, 2 H, CH2), 5.37 (s, 2 H,
OCH2), 5.78 (dd, 1 H, J = 10.2, 6.3 Hz, CH), 7.08–7.22 (m,
8 H, H-5, H-6, H-4¢, 2 Ho, 2 Hm and Hp), 7.37 (s, 1 H, H-2),
Synlett 2007, No. 2, 324–326 © Thieme Stuttgart · New York

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