Total syntheses of isodomoic acids G and H

Article abstract of DOI:10.1021/ja9063475

(Chemical Equation Presented) 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 proces

Full text of DOI:10.1021/ja9063475

Published on Web 09/15/2009
Total Syntheses of Isodomoic Acids G and H
Scott E. Denmark,* Jack Hung-Chang Liu, and Joseck M. Muhuhi
Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois, Urbana, Illinois, 61801
Received July 28, 2009; E-mail: sdenmark@illinois.edu
Isodomoic acids G (1) and H (2) were isolated in 1997 by
moiety of 6 would be constructed via the carbonylative silyl-
Arakawa from red alga Chondria armata.1 They belong to the
family of kainoid amino acids, which 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
carbocyclization 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 ∼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 2a
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
laboratories6 and (2) to potentially provide access to various
analogues by a modular approach. We describe herein efficient,
stereoselective total syntheses of 1 and 2 via a common
intermediate.7
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%).
Scheme 1
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 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 diaz-
omethane 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 oxocarbe-
nium 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.
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 stereodivergent iododesilylation. The proline
Optimization experiments for the key cross-coupling of 5
revealed that the hydration level of TBAF was critical to success,
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10.1021/ja9063475 CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4a
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
Scheme 3a
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%).
Acknowledgment. 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.
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.
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As discussed above, the invertive iododesilylation of 13 resulted
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Conversely, by employing a substrate bearing a nonparticipating
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