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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
J Am Chem Soc. Author manuscript; available in PMC 2010 October 14.
Published in final edited form as:
PMCID: PMC2760019
NIHMSID: NIHMS146253

Total Syntheses of Isodomoic Acids G and H

Abstract

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The total syntheses of marine natural products belonging to the kainoid family, isodomoic acids G and H are described. The strategic connection involves a sequential silylcarbocyclization/silicon-based cross-coupling process. These total syntheses were achieved efficiently via a twelve and a thirteen step, longest-linear sequence, respectively. The key transformations include a diastereoselective rhodium-catalyzed carbonylative silylcarbocyclization reaction of a (L)-vinylglycine-derived 1,6-enyne, a desilylative iodination reaction, as well as an alkenyl-alkenyl silicon-based cross-coupling reaction. The mechanistic insight garnered during the investigation of the iododesilylation reaction enabled stereocontrolled introduction of the iodine with either inversion or retention of double bond configuration. The invertive desilylative iodination leads to the total synthesis of isodomoic acid H, while its congener, isodomoic acid G, was obtained via a retentive iododesilylation.

Isodomoic acids G (1) and H (2) were isolated in 1997 by Arakawa from red alga Chondria armata.1 They belong to the family of kainoid amino acids, that includes kainic acid, domoic acid, and isodomoic acids, a series of structurally related natural products bearing a 3-carboxymethylproline moiety and a side-chain on C(4). These compounds differ in the position and configuration of the double bond at C(4).2 Kainoid amino acids have long been recognized as neuroexcitatory agents, and their high potency makes them extremely valuable as research tools in neuroscience as well as medicinal chemistry.3 In fact, in 2000 the shortage of kainic acid threatened to hamper research projects in neurodegenerative diseases and a call for new supplies for isolation or synthesis was issued.4a Even now, the price of kainic acid remains extremely high and other kainoid derivatives are obtained in only minute quantities from natural sources.4b In response, many syntheses of kainic acid have been reported, whereas those of other kainoids have only been sparsely documented.2 Notably, however, Montgomery recently disclosed an elegant synthesis of isodomoic acid G that also unambiguously established its absolute configuration.5

Our interest in developing a new synthetic route to these natural products stems from the desire (1) to showcase the synthetic utility of the sequential silylcarbocyclization/silicon-based cross-coupling technology recently developed in these laboratories and (2) to potentially provide access to various analogues by a modular approach.6 We describe herein efficient, stereoselective total syntheses of 1 and 2 via a common intermediate.7

An obvious disconnection of 1 and 2 is the division into the substituted proline core and side-chain fragments at C(1′)–C(2′) (Scheme 1). The construction of the conjugated diene would involve the silicon-based cross-coupling reaction of silanol 38 with iodide 4 or 5, both of which would be derived from aldehyde 6 via a stereo-divergent iododesilylation. The proline moiety of 6 would be constructed via the carbonylative silylcarbocyclization of enyne 7.9,10

The synthesis began by the opening of known amino lactone 8,11 derived from (L)-methionine, using TMSI followed by an in situ esterification with SOCl2 and MeOH to afford iodinated amino ester 9 in 91% yield (Scheme 2). The conversion of iodide 9 to selenide 10 could be effected at room temperature with sodium phenylselenide in 88% yield whereas the direct opening of 8 with this reagent required elevated temperatures that delivered 10 in racemic form.12 The N-alkynylation of 10 was carried out under Mitsunobu conditions with 2-butyn-1-ol at approximately 0 °C, to produce 11 in 93% yield. Oxidative elimination of the selenide moiety was accomplished by the treatment of 11 with H2O2 at room temperature.13 As a result, the sensitive N-methylpropargyl (L)-vinylglycine ester 7 was isolated in a satisfying 95% yield.

Scheme 2
a Conditions: (a) 1. TMSI, 2. SOCl2, MeOH (91%); (b) NaBH4, Ph2Se2 (88%); (c) 2-butyn-1-ol, PPh3, DEAD (93%); (d) 30% H2O2 (95%).

The key carbonylative silylcarbocyclization of 7 was effected using Rh(acac)(CO)2 at 120 °C under CO (500 psi), to afford aldehyde 6 in 77% yield as an inseparable mixture of 2,3-trans- and 2,3-cis-diastereomers in an 8:1 ratio (Scheme 3). To proceed forward with a pure trans isomer, 6 was reduced by NaBH4 to afford alcohol trans-12 in which could be obtained free of the cis isomer in 85% yield. The conversion of 12 to a methyl ester through a CrO3-catalyzed oxidation14 and a subsequent methylation with diazomethane provided ester 13 in 81% yield. The iododesilylation of 13 using ICl proceeded smoothly in 1 h at room temperature with a complete inversion of double bond configuration to afford Z-alkenyl iodide 5 in 86% yield. This stereochemical outcome can be rationalized by the anchimeric participation of the C(7) carbonyl group.15 As 13 reacts with ICl, the iodonium ion in intermediate A can be captured by the C(7) carbonyl group, to form oxocarbenium ion B. A simple bond rotation orients the silyl group antiperiplanar to the oxocarbenium C–O bond (conformer B′), and attack of chloride on the silicon atom regenerates the double bond invertively to furnish iodide 5.

Scheme 3
a Conditions: (a) HSiMe2Ph, Rh(acac)(CO)2 (5 mol %), CO (500 psi), 120 °C (77%, trans/cis, 8:1); (b) NaBH4 (85%); (c) 1. CrO3, H5IO6, 2. CH2N2 (81%); (d) ICl (86%); (e) 3, Pd2(dba)3·CHCl3 (5 mol %), TBAF·8H2O (92%); (f) LiOH (quant.); ...

Optimization experiments for the key cross-coupling of 5 revealed that the hydration level of TBAF was critical to success, and TBAF·8H2O gave the optimal results. Gratifyingly, when 3 and 5 were combined in the presence of Pd2(dba)3·CHCl3 and TBAF·8H2O, full conversion was observed within 1 h, and the fully protected isodomoic acid H (14) was isolated in 92% yield. The final deprotection was accomplished by the quantitative saponification of the three methyl esters using LiOH,16 followed by the detosylation of the crude triacid 15 using sodium amalgam,17 to thus afford 59 mg (56%) of isodomoic acid H (2) whose spectroscopic properties matched those of the natural material.1

As discussed above, the invertive iododesilylation of 13 resulted from the anchimeric assistance of a proximal participating group. Conversely, by employing a substrate bearing a non-participating functional group at C(7), the iodination reaction would become retentive, thus enabling the synthesis of 1. To this end, 12 was protected as a triisopropylsilyl ether (16) (Scheme 4). Gratifyingly, exposure of 16 to ICl under previously developed conditions followed by an in situ deprotection using aqueous HF cleanly produced E-alkenyl iodide 17 in 73% yield. The synthesis of 1 was completed through the same sequence of oxidation (79%), cross-coupling (90%), and deprotection (60% for two steps) under conditions developed earlier to furnish 93 mg of 1, whose spectroscopic properties matched those of the natural and previously synthesized materials.1,5

Scheme 4
a Conditions: (a) TIPSCl, imidazole (91%); (b) 1. ICl, 2. HF (73%); (c) 1. CrO3, H5IO6, 2. CH2N2 (79%); (d) 3, Pd2(dba)3·CHCl3 (5 mol %), TBAF·8H2O (90%); (e) LiOH (quant.); (f) 20% Na/Hg, NaH2PO4 (60%).

In conclusion, the total syntheses of isodomoic acids G (1) and H (2) have been accomplished expediently through a unified strategy. The rhodium-catalyzed carbonylative silylcarbocyclization of 7 afforded the densely substituted pyrrolidine core. Importantly, the double bond configuration of 4 and 5 was controlled by judicious selection of the C(6) substituent. The fluoride-promoted cross-coupling uniting 4 and 5 with side-chain silanol 3 could be achieved under mild conditions by modulating the hydration level of the TBAF. This exercise serves to illustrate the flexibility of the silicon-based cross-coupling reaction as enabling strategies in the synthesis of sensitive natural products. Further illustrations will be reported in due course.

Supplementary Material

1_si_001

Acknowledgments

We are grateful to the National Institutes of Health for generous financial support (GM63167) and Johnson-Matthey for a gift of Pd2(dba)3. J.M.M. acknowledges the NIH for a postdoctoral fellowship.

Footnotes

Supporting Information Available: Full experimental procedures and characterization data for intermediates and synthetic natural product described. This material is available free of charge via the Internet at http://pubs.acs.org.

References

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