Total synthesis of (±)-kainic acid: A photochemical C-H carbamoylation approach

Article abstract of DOI:10.1021/ol200772f

A novel photochemical C-H carbamoylation of an octahydroisoindole derivative with PhNCO has allowed the authors to provide a unique access to a highly functionalized proline motif from which total synthesis of (±)-kainic acid, a bioactive marine alkaloid, has been accomplished.

Full text of DOI:10.1021/ol200772f

ORGANIC
LETTERS
2011
Vol. 13, No. 10
2674–2677
Total Synthesis of (()-Kainic
Acid: A Photochemical CꢀH
Carbamoylation Approach
Takuma Kamon, Yayoi Irifune, Tetsuaki Tanaka, and Takehiko Yoshimitsu*
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita,
Osaka 565-0871, Japan
yoshimit@phs.osaka-u.ac.jp
Received March 23, 2011
ABSTRACT
A novel photochemical CꢀH carbamoylation of an octahydroisoindole derivative with PhNCO has allowed the authors to provide a unique access
to a highly functionalized proline motif from which total synthesis of (()-kainic acid, a bioactive marine alkaloid, has been accomplished.
The fact that kainoids exhibit neuroexcitatory effects
has stimulated significant efforts to establish chemical
access to this class of amino acids.1,2 Kainic acid (1), the
first member of this family, was isolated in 1953 from the
seaweed Digenea simplex.3 Thereafter, a number of struc-
turally related compounds have been identified in nature,
including domoic acid (2),4 acromelic acid (3),5 and iso-
domoic acid (4),6 all of which share a common trisubsti-
tuted proline motif having another carboxylic group and
an alkenyl substituent (Figure 1).
Intensive studies on the synthesis of kainoids have
culminated in elegant approaches that feature unique
synthetic strategies and methodologies.7 One of the key
issues in synthesizing kainoids is the stereoselective con-
struction of the highly functionalized 3,4-cis-disubstituted
proline motif. In this context, cis-fused 6-azabicyclo-
[4.3.0]nonanes (octahydroisoindole derivative) and their
congeners are attractive synthetic scaffolds that have been
successfully utilized for the construction of kainoid skele-
tons. Such bicyclic motifs are accessible by various means,
(1) For reviews on the biology of kainoids, see: (a) Monaghan, D. T.;
Bridges, R. J.; Cotman, C. W. Annu. Rev. Pharmacol. Toxicol. 1989, 29,
365–402. (b) Moloney, M. G. Nat. Prod. Rep 1998, 205–219. (c)
Moloney, M. G. Nat. Prod. Rep 1999, 16, 485–498. (d) Chamberlin,
R.; Bridges, R. In Drug Design for Neuroscience; Kozikowski, A. P., Ed.;
Raven Press: New York, 1993; pp 231ꢀ259. (e) McGeer, E. G.; Olney,
J. W.; McGeer, P. L. Kainic Acid as a Tool in Neurobiology; Raven Press:
New York, 1978.
(2) For reviews on syntheses of kainoids, see: (a) Parsons, A. F.
Tetrahedron 1996, 52, 4149–4174. (b) Moloney, M. G. Nat. Prod. Rep.
2002, 19, 597–616. (c) Clayden, J.; Read, B.; Hebditch, K. R. Tetra-
hedron 2005, 61, 5713–5724.
(3) Murakami, S.; Takemoto, T.; Shimizu, Z. J. Pharm. Soc. Jpn.
1953, 73, 1026–1028.
(4) Takemoto, T.; Daigo, K. Chem. Pharm. Bull. 1958, 6, 578–580.
(5) (a) Acromelic acids A and B: Konno, K.; Shirahama, H.; Matsumoto,
T. Tetrahedron Lett. 1983, 24, 939–942. (b) Acromelic acid C: Fushiya, S.;
Sato, S.; Kanazawa, T.; Kusano, G.; Nozoe, S. Tetrahedron Lett. 1990, 31,
3901–3904. (c) Acromelic acids D and E: Fushiya, S.; Sato, S.; Kera, Y.;
Nozoe, S. Heterocycles 1992, 34, 1277–1280.
Figure 1. Natural kainoids.
(6) Maeda, M.; Kodama, T.; Tanaka, T.; Yoshizumi, H.; Takemoto,
T.; Nomoto, K.; Fujita, T. Chem. Pharm. Bull. 1986, 34, 4892–4895.
r
10.1021/ol200772f
Published on Web 04/19/2011
2011 American Chemical Society

including the DielsꢀAlder reaction of proline derivatives with
dienes,7ii,8 the dearomatizing cyclization of N-benzyl benz-
amides,7w,aa and the stereoselective cyclization of ynone.7mm
In the present paper, we report the total synthesis of (()-kainic
acid (1), which features a novel photochemical CꢀH carba-
moylation of cis-fused azabicyclo[4.3.0]nonane derivative 5 to
establish a unique entry to the natural amino acid (Scheme 1).
Recently, we developed a means for the synthesis of amino
acid anilides from tertiary amines through Et3B-mediated
radical CꢀH carbamoylation reactions.9,10 This has enabled
us to devise a short access from tertiary amines to bioactive
amino acid derivatives, such as the local anesthetic mepiva-
caine. In this context, it occurred to us that the photolysis of
amines in the presence of a photosensitizer that enables
hydrogen transfer from nitrogen-substituted CꢀH bonds
would serve as a powerful alternative to the trialkylborane/
air system to promote CꢀH carbamoylation reactions.
Scheme 1. Present Approach to Kainic Acid (1) via Direct
Radical CꢀH Carbamoylation of Tertiary Amine 5
Inspired by pioneering studies of the photochemical trans-
formation of tertiary amines,11 we envisaged that a carba-
moylation reaction would proceed via a hypothetical hydro-
gen shuttle mediated by excited triplet ketones (Scheme 2). In
our hypothesis, a photochemically excited ketone would
generate corresponding R-amino alkyl radical ii through an
electron/proton transfer mechanism. Then, radical ii would
undergo addition to phenyl isocyanate to produce amidyl
radical iv, which, by hydrogen atom transfer from ketyl
radical iii, would eventually generate an anilide and ketone
i, leading to a catalytic cycle. Our hypothesis on this radical
cascade was evaluated for its relevance with cis-fused
azabicyclo[4.3.0]nonane 5, which was prepared in four steps
from the commercially available tetrahydromaleic anhydride
(Table 1).12 Evaluation of the reaction conditions led to the
discovery that, in the presence of a photosensitizer, cyclic
amine 5 underwent CꢀH carbamoylation with phenyl iso-
cyanate to afford anilide 6along with biscarbamoylated 9. As
far as we know, this is the first example of the intermolecular
addition of a photochemically generated R-amino alkyl
radical to phenyl isocyanate to furnish amino acid anilides.
It has been reported that PhNCO is decomposed by UV
irradiation (227 nm) to give phenylnitrene.13 However, in the
present case, most of the unreacted PhCNO could be recov-
ered as methyl phenylcarbamate after quenching the reaction
mixture with MeOH. The successful recovery of the un-
reacted isocyanate is probably attributable to circumvention
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Org. Lett., Vol. 13, No. 10, 2011
2675

Table 1. Photochemical CꢀH Carbamoylation of Tertiary
Amine 5
Scheme 2. Hypothetical Hydrogen Shuttle in Photochemical
CꢀH Carbamoylation Reaction
products (%)b
entrya
sensitizer
benzophenone
4,40-dimethoxybenzophenone
4,40-dimethoxybenzophenone
4,40-dimethoxybenzophenone
no
time (h)
6
9
of its decomposition by using a Pyrex reaction vessel that filters
short-wavelength light (<300 nm) as well as by the appro-
priate spectral energy distribution of a high-pressure Hg lamp
that has no spectral distribution around 230 nm. Benzophe-
none, a common sensitizer, was found to be less effective in
promoting the carbamoylation of 5 than 4,40-dimethoxy-
benzophenone (entries 1 and 2), supporting the superiority
of 4,40-dimethoxybenzophenone over benzophenone.11a,b,14
The prolonged reaction time increased the yield of desired
anilide 6, although the undesired production of biscarbamoy-
lated amine 9was also facilitated (entry 3). The reaction that was
performed with 2 g of amine 5 gave a yield comparable to those
obtained in smaller scale reactions (entry 2 vs 4). In the absence
of the sensitizer, no reaction essentially took place (entry 5).
With suitably functionalized anilide 6 in possession,
further synthetic manipulations were performed to yield
kainic acid (Scheme 3). Anilide 6 was treated with CAN in
aqueous MeCN at room temperature followed by protec-
tion of the resultant amine with CDI to furnish tetracyclic 10
in 65% overall yield. Then, acetonide 10 was hydrolyzed with
aqueous AcOH at 60 °C to give a diol, which, by treatment
with TBSCl and imidazole in DMF, afforded TBS ether 11
selectively in 86% yield (together with regioisomer 7% and
bis-ether 4%; for details, see Supporting Information). The
1H NMR analysis of the crude diol obtained by the acid
hydrolysis of 10 indicated that the hydroxyl group at C8 was
situated in an equatorial position, whereas the C7-hydroxyl
group was in an axial position.15 It is generally accepted that
an equatorial hydroxyl group is more reactive toward acyla-
tion reactions than a sterically demanding axial one.16 There-
fore, we assume that the observed preference in regioselectivity
of the silylation reaction was attributed to the conformational
factor associated with the rigid tricyclic skeleton.
1
2
3
4
5
3.5c
3.5c
8.5c
9d
20 (31) 7 (11)
37 (49) 13 (17)
44 (47) 28 (30)
39 (54) 8 (11)
not observede
15
a The mixture of 5 (1 equiv), PhNCO (1.5 equiv), and sensitizer
(0.2 equiv) in MeCN was degassed prior to the irradiation by a Hg high-
pressure lamp. b Yields in parentheses are based on recovered 5. c 150 mg
of 5 were used. d 2 g of 5 were used. e Determined by NMR analysis.
acid motif, as reported by the Clayden group.7w,17 Clayden and
co-workers have demonstrated that the β-substitution of a
pyroglutamate-fused cyclohexanone derivative causes severe
steric interaction with a hemiperoxyacetal moiety in the
BaeyerꢀVilliger oxidation, allowing regioselective oxygena-
tion of the bond between C7 and C8. We envisioned that a
quaternalization at the β-position of enone 14 with a silyl
substituent would enable a high degree of regiocontrol in the
BaeyerꢀVilliger oxidation because of the steric demand caused
by the hindered substituent, and allow facile desilylative olefina-
tion at a later stage to efficiently deliver the isopropenyl unit of
kainic acid. Thus, enone 13 was first converted into R,β-
unsaturated enone 14 through Me2CuLi-mediated methyla-
tion followed by silylation with TMSCl and Pd(OAc)2-
mediated oxidation of the resultant silyl enol ether.18 Then,
(15) The 1H NMR spectra of diol v showed similar coupling patterns
of the H(7) and H(8) protons in either CD3OD or CDCl3, indicating the
conformational rigidity of the tricyclic molecule in various solvents.
Furthermore, NOE was observed between the H(8) and H(9b) protons,
suggesting that the diol possesses the conformation indicated below.
Therefore, we currently assume that diol v in DMF has a similar
conformation to those in the above solvents and that the silylation of
diol v in DMF with TBSCl occurred regioselectively at the reactive
equatorial C8 hydroxyl group. For details, see Supporting Information.
Next, the dehydration of resultant 11 with Martin’s sulfuran
successfully produced alkene 12 in 83% yield. The TBS group
of 12 was removed by treatment with in situ generated
hydrochloric acid to provide an allylic alcohol, which, by
DessꢀMartin oxidation, afforded enone 13 in 96% yield over
2 steps. At this stage, it was reasonably assumed that methyla-
tion at the C6 position of 13 with Me2CuLi would provide a
β-methylated cyclohexanone, a relevant precursor of the kainic
(16) (a) Barton, D. H. R. Exper. 1950, 6, 316–320. (b) Eliel, E. L.;
Biros, F. J. J. Am. Chem. Soc. 1966, 88, 3334–3343.
(17) A nice approach employing the direct BaeyerꢀVilliger lactoni-
zation of a cyclohexenone derivative has also been reported. See ref
7mm.
(14) 4,4-Dimethoxybenzophenone was gradually consumed during
the long irradiation to give a complex mixture containing a pinacol
coupling product.
(18) (a) Toyooka, N.; Okumura, M.; Nemoto, H. J. Org. Chem. 2002,
67, 6078–6081. (b) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43,
1011–1013.
2676
Org. Lett., Vol. 13, No. 10, 2011

Scheme 3. Total Synthesis of (()-Kainic Acid (1)
Scheme 4. Rationale for Formation of 15a and 15b
Scheme 5. BaeyerꢀVilliger Oxidation of Ketone 16
In conclusion, we have accomplished the total synthesis
of (()-kainic acid (1), which features the novel photo-
chemical CꢀH carbamoylation reaction of octahydro-
isoindole derivative 5 with PhNCO. Further work is on-
going to explore the scope of the present radical CꢀH
carbamoylation method through its application to the
synthesis of various bioactive nitrogen-containing natural
products.
14 was subjected to 1,4-silylation with a silylcopper reagent19 to
produce 7 as a single detectable isomer whose stereochemistry
was established by NOE analysis.20 The next task was to
oxidize the silylated ketone with mCPBA, which led to the
production of desired seven-membered lactone 15a along with
silyl-migrated product 15b.21 Although the mechanism of the
formation of silyl lactone 15b is still unclear, it is likely that the
cationic stabilization of the β-carbon by the silyl group enabled
the unique migration (Scheme 4). The BaeyerꢀVilliger oxida-
tion of ketone 16 that lacks the silyl substituent gave a mixture
of regioisomeric lactones 17a and 17b in a ratio of ca. 3:2. This
result indicates the importance of quaternalization at the C6
position in achieving a high degree of regiocontrol (Scheme 5).
Then, the desilylative olefinations of 15a and 15b each with
Acknowledgment. This work was supported by a
Grant-in-Aid [KAKENHI No. 16790021] and a Grant-
in-Aid for Scientific Research on Innovative Areas [No.
22136006] from the Ministry of Education, Culture,
Sports, Science and Technology of Japan (MEXT).
Supporting Information Available. Experimental pro-
cedures, characterization data, and 1H/13C NMR spectra
of products. This material is available free of charge via
the Internet at http://pubs.acs.org.
(20) The relative stereochemistry of 7 was determined by an NOE
correlation that showed the proximity between the methyl substituent at
C6 and the proton at C9b.
HF Py in THF under heating conditions delivered olefin 8,
3
respectively, as a single product that possessed all the function-
alities necessary for accessing kainic acid (1). Hydrolysis of 8
with 3 N NaOH took place smoothly, giving rise to kainic acid
(1) as the sole product. The NMR spectra of synthesized 1
exactly matched those reported in the literature.7ff,ss
(19) Fleming, I.; Newton, T. W. J. Chem. Soc., Perkin Trans. 1 1984,
1805–1808.
(21) The stereochemistry of the newly created quaternary stereocen-
ter of 15b has yet to be determined.
Org. Lett., Vol. 13, No. 10, 2011
2677