The synthesis of (-)-isodomoic acid C

Article abstract of DOI:10.1021/ja042415g

The neuroactive algal metabolite (-)-isodomoic acid C, a kainoid amino acid, has been synthesized for the first time. Asymmetric dearomatizing cyclization of an aromatic amide using a chiral lithium amide base generates a bicyclic enone containing a pyrro

Full text of DOI:10.1021/ja042415g

Published on Web 02/05/2005
The Synthesis of (-)-Isodomoic Acid C
Jonathan Clayden,*,† Faye E. Knowles,† and Ian R. Baldwin‡
School of Chemistry, UniVersity of Manchester, Oxford Road, Manchester M13 9PL, U.K., and
GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, SteVenage, Herts. SG1 2NY, U.K.
Received December 17, 2004; E-mail: j.p.clayden@manchester.ac.uk
Scheme 1. Asymmetric Dearomatizing Cyclizationa
Isodomoic acid C 11 is a member of a 10-strong family2 of
isomers of domoic acid 2,3 all of which are cyclic kainoid amino
acids4 isolable from the marine organisms Nitzschia pungens and
Chondria armata. Domoic acid has powerful neuroexcitatory
properties,5 and isodomoic acids are insecticidal.1 Domoic acid and
the isodomoic acids have, on occasion, been found in the edible
parts of the mussel, Mytilus edulis,2d posing a threat to both humans
and marine mammals and birds.6 The syndrome known as amnesic
shellfish poisoning has been ascribed to ingestion of shellfish con-
taining domoic and isodomoic acids,7 and there have been numerous
recent developments in methods for analysis of domoic acid.8
a Reagents: (i) p-MeOC6H4COCl, Et3N, CH2Cl2, 0 °C; (ii) NaH, DMF,
BnBr; (iii) 6, THF, -78 to 20 °C; (iv) HCl, H2O; (v) recryst (EtOAc).
of a mixed cuprate formed from the protected iodo alcohol 8,
yielding ketone 9 in 79% yield as a single diastereoisomer. Although
inconsequential for the synthesis overall, we assume that 9 forms
with the stereochemistry shown, by virtue of exo attack of the
cuprate on the bicyclic system. Removal of the cumyl protecting
group with formic acid17 led additionally to desilylation and formyl-
ation of the primary hydroxyl group. Reprotection of the secondary
lactam as an N-Boc derivative yielded 10 in 81% yield from 9.
The benzyl group of 5 is essential for clean cyclization; few
alternative cyclizing groups are as effective.13b However, the
resulting phenyl substituent requires conversion to the C2 carboxyl
group of the target, and the vigorously oxidizing conditions required
for such a reaction18 leave little room for manoeuvre chemo-
selectively. Ketone 10 is one of few compounds in the synthetic
sequence in which chemoselective oxidation of Ph is feasible, and
treatment of 10 with sodium periodate in the presence of catalytic
ruthenium(III) chloride yielded, after methylation with trimethyl-
silyldiazomethane, ester 11. Reprotection of the primary hydroxyl
group with TBDPS gave 12.
The way was now clear for cleavage of the six-membered ring
of 12, whose cis fusion with the lactam ring will generate the
necessary syn relationship between the C3 and C4 substituents of
isodomoic acid C. Following the precedent13 that similar 6,5-fused
systems undergo surprisingly regioselective Baeyer-Villiger oxida-
tion,19 we treated ketone 12 with m-CPBA. As we had hoped,
lactone 13 was formed quantitatively as a single regioisomer.
Careful methanolysis of lactone 13 by slow addition of sodium
methoxide avoided epimerization of the hard-earned cis stereo-
chemistry and returned the hydroxyester 14 as the C3,C4-cis
stereoisomer.
Domoic acid has been synthesized on one occasion,3b and only
one of the family of isodomoic acids, isodomoic acid G, has so far
been made,9 though domoic acid has been isomerized photochemi-
cally to a mixture of the isodomoic acids;2b moreover, Baldwin10
has successfully synthesized a series of non-natural domoic acid
analogues.11 In this paper, we describe the first total synthesis of
(-)-isodomoic acid C 1 in 15 steps from a simple aromatic amide
5. The key step in our strategy is the asymmetric dearomatizing
cyclization of this N-benzyl benzamide 5,12 a reaction we have
employed in the synthesis of the structurally related (-)-kainic acid
3.13 This work had shown that the stereochemistry of the bicyclic
product 7 of the cyclization was correct for the biologically active
kainoids,4 and that chemoselective Ru(VIII) oxidation of the aryl
ring and regioselective Baeyer-Villiger oxidation of the cyclo-
hexanone ring accomplished two of the key transformations required
for the conversion of 7 into a target kainoid.
To employ this cyclization in the synthesis of isodomoic acid
C, we made amide 5 from cumylamine14 4 on a 10-20 g scale and
cyclized it in 2.5 g batches. Treatment of 5 in THF at -78 °C with
N-lithioamine 615 by our published method13a promoted asymmetric
deprotonation and cyclization to an enol ether which was hydro-
lyzed16 in situ to yield enone 7 (Scheme 1) in 86% ee (by HPLC).
Recrystallization of 7 from ethyl acetate improved the enantiomeric
excess to >99%.
Elimination of water from 14 to give the unsaturated compound
15 was achieved via oxidation of the corresponding selenide using
the method of Grieco.20 Despite the presence of four carbonyl
groups in 15, we found that the slow addition of DIBAL to 15 in
THF allowed the selective reduction of the amide carbonyl group,
and treatment of the product with triethylsilane and boron trifluoride
gave the N-Boc pyrrolidine 16.
The reactivity of enone 7 allowed us to introduce a precursor to
the required side chain of isodomoic acid C by conjugate addition
Elaboration to the isodomoic acid C side chain was achieved by
fluoride-promoted deprotection of the silylated hydroxyl group,
† University of Manchester.
‡ GlaxoSmithKline.
9
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J. AM. CHEM. SOC. 2005, 127, 2412-2413
10.1021/ja042415g CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Synthesis of (-)-Isodomoic Acid Ca
key intermediates and spectroscopic comparison of natural and synthetic
(-)-isodomoic acid C. This material is available free of charge via the
Internet at http://pubs.acs.org.
References
(1) Maeda, M.; Kodama, T.; Tanaka, T.; Yoshizumi, H.; Takemoto, T.;
Nomoto, K.; Fujita, T. Chem. Pharm. Bull. 1986, 34, 4892-4895.
(2) For isodomoic acids A-D, see ref 1. (b) For isodomoic acids E and F,
see: Wright, J. L. C.; Falk, M.; McInnes, A. G.; Walter, J. A. Can. J.
Chem. 1990, 68, 22-25. (c) For isodomoic acids G and H, see: Zaman,
L.; Arakawa, O.; Shimosu, A.; Onoue, Y.; Nishio, S.; Nishimura, K.;
Nomoto, K.; Fujita, T. Toxicon 1997, 35, 205-212. (d) For C-5′-epi-
Domoic acid, see: Walter, J. A.; Falk, M.; Wright, J. L. C. Can. J. Chem.
1994, 72, 430-436.
(3) For domoic acid, see: (a) Takemoto, T.; Daigo, K. Chem. Pharm. Bull.
1958, 6, 578-580. (b) Ohfune, Y.; Tomita, M. J. Am. Chem. Soc. 1982,
104, 3511-3513.
(4) For review articles covering kainoids, see: (a) Parsons, A. F. Tetrahedron
1996, 52, 4149-4174. (b) Moloney, M. G. Nat. Prod. Rep. 1998, 15,
205-219. (c) Moloney, M. G. Nat. Prod. Rep. 1999, 16, 485-498.
(5) Biscoe, T. J.; Evans, R. H.; Headley, P. M.; Martin, M. R.; Watkins, J.
C. Br. J. Pharmacol. 1976, 58, 373-382.
(6) Mestel, R. New Scientist 1995, 147, 6.
(7) Todd, E. C. D. J. Food Prot. 1993, 56, 69-83. (b) Costa, P. R.; Rosa,
R.; Sampayo, M. A. M. Mar. Biol. 2004, 144, 971-976. (c) Jeffery, B.;
Barlow, T.; Moizer, K.; Paul, S.; Boyle, C. Food Chem. Toxicol. 2004,
42, 545-557. (d) Costa, L. G.; Guizzetti, M.; Costa-Mallen, P.; Vitalone,
A.; Tita, B. Diet-Brain Connect. 2002, 197-213. (e) Mos, L. EnViron.
Toxicol. Pharmacol. 2001, 9, 79-85. (f) Doble, A. Food Sci. Technol.
2000, 103, 359-372. (g) Nijjar, M. S.; Nijjar, S. S. Food Sci. Technol.
2000, 103, 325-358.
(8) Micheli, L.; Radoi, A.; Guarrina, R.; Massaud, R.; Bala, C.; Moscone,
D.; Palleschi, G. Biosens. Bioelectron. 2004, 20, 190-196. (b) Martins,
J. M. L.; Gago-Martinez, A.; Dabek-Zlotorzynska, E.; Aranda-Rodriguez,
R.; Lawrence, J. F. J. Sep. Sci. 2002, 25, 342-344. (c) Furey, A.; Lehane,
M.; Gillman, M.; Fernandez-Puente, P.; James, K. J. J. Chromatogr., A
2001, 938, 167-174. (d) Garthwaite, I.; Ross, K. M.; Miles, C. O.; Briggs,
L. R.; Towers, N. R.; Borrell, T.; Busby, P. J. AOAC Int. 2001, 84, 1643-
1648. (e) Pineiro, N.; Vaquero, E.; Leao, J. M.; Gago-Martinez, A.;
Vazquez, J. A. R. Chromatographia 2001, 53, S231-S235. (f) James, K.
J.; Gillman, M.; Lehane, M.; Gago-Martinez, A. J. Chromatogr., A 2000,
871, 1-6. (g) Sun, T.; Wong, W. H. J. Agric. Food Chem. 1999, 47,
4678-4681. (h) Kawatsu, K.; Hamano, Y.; Noguchi, T. Toxicon 1999,
37, 1579-1589. (i) Rhodes, L.; Scholin, C.; Garthwaite, I. Nat. Toxins
1998, 6, 105-111. (j) Garthwaite, I.; Ross, K. M.; Miles, C. O.; Hansen,
R. P.; Foster, D.; Wilkins, A. L.; Towers, N. R. Nat. Toxins 1998, 6,
93-104. (k) Kotaki, Y.; Koike, K.; Sato, S.; Ogata, T.; Fukuyo, Y.;
Kodama, M. Toxicon 1999, 37, 677-682.
a Reagents: (i) t-BuLi, -78 °C, Et2O; (ii) MeLi, CuCN, Et2O, -78 to
25 °C; (iii) 7, -78 °C; (iv) HCO2H, reflux, 30 min; (v) Boc2O, Et3N,
DMAP, CH2Cl2, 25 °C, 18 h; (vi) NaIO4, RuCl3, H2O, MeCN, EtOAc, 18
h; (vii) Me3SiCHN2, toluene, MeOH, 20 °C, 5 min; (viii) NaOMe, MeOH,
-78 °C, 1 h; (ix) t-BuPh2SiCl, imid, CH2Cl2, 20 °C, 18 h; (x) m-CPBA
(70%), CH2Cl2, 25 °C, 72 h; (xi) o-NO2C6H4SeCN, Bu3P, THF, 20 °C, 2
h; (xii) H2O2, py, -40 to 25 °C, 12 h; (xiii) i-Bu2AlH, PhMe, THF, -78
°C, 1 h; (xiv) Et3SiH, BF3/OEt2, -78 °C, 2.5 h; (xv) Bu4NF, THF, 25 °C,
2 h; (xvi) Dess-Martin, CH2Cl2, 25 °C, 30 min; (xvii) 18, DBU, LiCl,
MeCN, 25 °C, 1 h; (xviii) LiOH, H2O, THF, 25 °C, 12 h; (xix) CF3CO2H,
CH2Cl2, ∆, 2 h.
(9) Ni, Y.; Amarasinghe, K. K. D.; Ksebati, B.; Montgomery, J. Org. Lett.
2003, 5, 3771-3774.
(10) Baldwin, J. E.; Moloney, M. G.; Parsons, A. F. Tetrahedron 1991, 47,
155-172.
(11) A review of the chemistry of the domoic acid family is in preparation:
Clayden, J.; Read, B.; Hebditch, K. E. Manuscript in preparation.
(12) Clayden, J.; Menet, C. J.; Mansfield, D. J. Chem. Commun. 2002, 38-
39.
(13) Clayden, J.; Menet, C. J.; Tchabanenko, K. Tetrahedron 2002, 58, 4727-
4733. (b) Clayden, J. Total Synthesis of Kainoids by Dearomatizing
Anionic Cyclization. In Strategies and Tactics in Organic Synthesis;
Harmata, M., Ed.; Academic Press: New York, 2004; Vol. 4.
(14) Balderman, D.; Kalir, A. Synthesis 1978, 24-26. (b) Clayden, J.; Menet,
C. J.; Mansfield, D. J. Org. Lett. 2000, 2, 4229-4232. (c) Metallinos, C.;
Nerdinger, S.; Snieckus, V. Org. Lett. 1999, 1, 1183-1186. (d) Metallinos,
C. Synlett 2002, 1556-1557.
(15) Hammerschmidt, F.; Hanninger, A. Chem. Ber. 1995, 128, 823.
(16) Clayden, J.; Tchabanenko, K.; Yasin, S. A.; Turnbull, M. D. Synlett 2001,
302-304.
(17) We now prefer formic acid to trifluoroacetic acid for the removal of cumyl
protecting groups (see ref 14b-d) from amide N.
(18) Carlsen, P. H.; Katsuki, T.; Mart´ın, V. S.; Sharpless, K. B. J. Org. Chem.
1981, 46, 3936-3938. (b) Matsuura, F.; Hamada, Y.; Shioiri, T.
Tetrahedron 1994, 50, 265-274. (c) Mander, L. N.; Williams, C. M.
Tetrahedron 2003, 59, 1105-1136.
(19) We presume that a subtle conformational effect is involved in this reaction;
comparable 6,5-fused cyclohexanones lacking a substituent â to the
carbonyl group (e.g., 10 lacking the RO(CH2)3 group) oxidize without
regioselectivity (see ref 13 and Clayden, J.; Tchabanenko, K. Chem.
Commun. 2000, 317-318). For leading references on stereoelectronic
control in the Baeyer-Villiger reaction, see: Crudden, C. M.; Chen, A.
C.; Calhoun, L. A. Angew. Chem., Int. Ed. 2000, 39, 2852-2855.
(20) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41, 1485-
1486.
Dess-Martin21 oxidation to aldehyde 17, and Horner-Wadsworth-
Emmons olefination. Under Masamune’s conditions,22 17 reacted
with ethyl 2-triethylphosphonopropionate 18 to yield a single
stereoisomer of the trisubstituted alkene 19. Deprotection by
treatment with lithium hydroxide followed by trifluoroacetic acid
yielded, after purification by ion exchange and reverse-phase HPLC,
the target natural product (-)-isodomoic acid C 1, [R]20 ) -30
D
( 10 (c ) 0.02, H2O) [lit.1 [R]20 ) -30 (c ) 0.015, H2O)].
D
1
Comparison of the H and 13C NMR spectra of the product with
those of authentic naturally derived isodomoic acid C23 indicated
an exact match.
Acknowledgment. We are grateful to the EPSRC for a
studentship, to GlaxoSmithKline for support, and to Drs. Michael
Quilliam, Patrick Holland, Chris Miles, Alistair Wilkins, and
Andrew Selwood for helpful discussions and for NMR spectra of
natural (-)-isodomoic acid C.
(21) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(22) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune,
S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1981, 25, 2183-2186.
(23) Spectra were very kindly provided by Prof. Alistair Wilkins of Waikato
University, Hamilton, New Zealand.
Supporting Information Available: Experimental procedures and
1
characterization of all new compounds. H and 13C NMR spectra of
JA042415G
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