Total synthesis of (-)-kaitocephalin based on a rh-catalyzed c-h amination

Article abstract of DOI:10.1021/ol300431n

A total synthesis of (-)-kaitocephalin, an ionotropic glutamate receptor antagonist, is accomplished in highly stereocontrolled manner via Overman rearrangement, rhodium-catalyzed benzylic C-H amination, pyrrolidine formation involving nucleophilic openin

Full text of DOI:10.1021/ol300431n

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1644–1647
Total Synthesis of (À)-Kaitocephalin
Based on a Rh-Catalyzed CÀH Amination
Keisuke Takahashi, Daisuke Yamaguchi, Jun Ishihara, and Susumi Hatakeyama*
Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki,
852-8521, Japan
susumi@nagasaki-u.ac.jp
Received February 21, 2012
ABSTRACT
A total synthesis of (À)-kaitocephalin, an ionotropic glutamate receptor antagonist, is accomplished in highly stereocontrolled manner via
Overman rearrangement, rhodium-catalyzed benzylic CÀH amination, pyrrolidine formation involving nucleophilic opening of a cyclic sulfamate,
and rhodium-catalyzed allylic CÀH amination as key steps.
In 1997, Shin-ya and co-workers isolated kaitocephalin
(1) from Eupenicillium shearii PF1191.1 This structurally
novel amino acid has attracted much attention due to its
potent antagonistic activity against ionotropic glutamate
receptors.1,2 Excessive stimulation of these receptors by
glutamic acid or other agonists causes a variety of neuro-
degenerative disorders including epilepsy, stroke, Parkin-
son’s disease, and Alzheimer’s disease.3 Since antagonists
of glutamate receptors are effective for the protection of
neuronal injury or death, kaitocephalin (1) has potential as
a promising lead compound for developing therapeutic
agents against various neuronal diseases. However, de-
tailed neurobiological studies and SAR studies have been
hampered at present by the fact that the fungus has not
produced a sufficient amount of kaitocephalin (1). Such
extremely low availability from natural sources as well
as the intriguing biological properties and structural
challenges has made kaitocephalin (1) and its analogues
attractive targets for synthesis. Thus, there have been a
number of the synthetic studies4,5 including total syntheses
achieved by four groups.6À9 In connection with our pro-
ject directed toward the synthesis of natural products
which selectively interact with ionotropic glutamate recep-
tors,4c,10 we became interested in the synthesis of
(4) Synthetic approaches to 1: (a) Loh, T.-P.; Chok, Y.-K.; Yin, Z.
Tetrahedron Lett. 2001, 42, 7893–7897. (b) Kudryavtsev, K. V.;
Nukolova, N. V.; Kokoreva, O. V.; Smolin, E. S. Russ. J. Org. Chem.
2006, 42, 412–422. (c) Takahashi, K.; Haraguchi, N.; Ishihara, J.;
Hatakeyama, S. Synlett 2008, 671–674.
(5) Total synthesis of 2-epimer of 1: Ma, D.; Yang., J. J. Am. Chem.
Soc. 2001, 123, 9706–9707.
(6) (a) Okue, M.; Kobayashi, H.; Shin-ya, K.; Furihata, K.;
Hayakawa, Y.; Seto, H.; Watanabe, H.; Kitahara, T. Tetrahedron Lett.
2002, 43, 857–860. (b) Watanabe, H.; Okue, M.; Kobayashi, H.;
Kitahara, T. Tetrahedron Lett. 2002, 43, 861–864. (c) Doi, F.; Watanabe,
H. 49th Symposium on the Chemistry of Natural Products, 2007
(Sapporo), pp 533À538.
(7) (a) Kawasaki, M.; Shinada, T.; Hamada, M.; Ohfune, Y. Org.
Lett. 2005, 7, 4165–4167. (b) Hamada, M.; Shinada, T.; Ohfune, Y. Org.
Lett. 2009, 11, 4664–4667.
(1) (a) Shin-Ya, K.; Kim, J.-S.; Furihata, K.; Hayakawa, Y.; Seto, H.
Tetrahedron Lett. 1997, 38, 7079–7082. (b) Kobayashi, H.; Shin-Ya, K.;
Furihata, K.; Hayakawa, Y.; Seto, H. Tetrahedron Lett. 2001, 42, 4021–
4023.
(8) Vasawani, R. G.; Chamberlin, R. J. Org. Chem. 2008, 73, 1661–
1681.
(2) Limon, A.; Reyes-Ruiz, J. M.; Vaswani, R. G.; Chamberlin,
A. R.; Miledi, R. ACS Chem. Neurosci. 2010, 1, 175–181. Kaitocephalin
inhibits NMDA and AMPA receptors but has only slight effects on KA
receptors.
(3) Bigge, C. E. Curr. Opin. Chem. Biol. 1999, 3, 441–447. (b) Mayer,
M. L. Current Opin. Neurobiol. 2005, 15, 282–288. (c) Dingledine, R.;
Borges, K.; Bowie, D.; Traynelis, S. F. Pharmcol. Rev. 1999, 51, 7–61. (d)
Madden, D. R. Nat. Rev. Neurosci. 2002, 3, 91–101.
(9) Yu, S.; Zhu, S.; Pan, X.; Yang, J.; Ma, D. Tetrahedron 2011, 67,
1673–1680.
(10) (a) Masaki, H.; Maeyama, J.; Kamada, K.; Esumi, T.; Iwabuchi,
Y.; Hatakeyama, S. J. Am. Chem. Soc. 2000, 122, 5216–5217. (b)
Takahashi, K.; Matsumura, T.; Ishihara, J.; Hatakeyama, S. Chem.
Commun. 2007, 4158–4160. (c) Takahashi, K.; Matsumura, T.; Corbin,
G. R. M.; Ishihara, J.; Hatakeyama, S. J. Org. Chem. 2006, 71, 4227–
4231.
r
10.1021/ol300431n
Published on Web 03/05/2012
2012 American Chemical Society

kaitocephalin (1). Herein, we report a novel stereo-
controlled synthesis of (À)-kaitocephalin (1) which features
two rhodium-catalyzed CÀH amination reactions for the
installation of both right-hand and left-hand sides of
amino acid functionalities.
Scheme 1 illustrates our retrosynthetic analysis of
kaitocephalin (1). We envisaged 2 as a precursor of 1 by
focusing on three carboxylic acids which could be available
byoxidative cleavageof a phenylgroupand a cyclopentene
ring simultaneously. We then postulated that this inter-
mediate could be accessed from 3 via rhodium-catalyzed
benzylic and allylic CÀH amination reactions followed by
an intramolecular nucleophilic attack of a nitrogen atom
on a sulfamate group, based on Du Bois’ protocol.11,12
overall yield. Alkenyl iodide 7 was then subjected to
Suzuki-Miyaura coupling18 with borane 8, in situ prepared
from
(R)-3-(tert-butyldimethylsilyloxy)-5-phenylpent-
1-ene19 and 9-BBN, to give allyl alcohol 9 in 84% yield.
At this stage, after conversion of 9 to trichloroacetimidate 10,
we examined its Overman rearrangement20 under various
Scheme 2. Preparation of Sulfamate 13
Scheme 1. Retrosynthetic Analysis of Kaitocephalin (1)
Our synthesis of 1 thus began with the enantio- and
stereoselective preparation of sulfamate 13 (Scheme 2).
Iodoenone 5,13 readily available from (1R,3S)-cyclopent-
4-ene-1,3-diol (4),14 was first converted to 7 via 6 by a five-
step sequence involving Luche reduction,15 Mitsunobu
reaction,16 saponification, protection as a p-methoxyben-
zyloxymethyl (PMBM) ether,17 and desilylation in 71%
conditions in order to introduce a nitrogen atom to the
quaternary center stereoselectively. As a result, we gratify-
ingly found that when a solution of 10 in xylene was heated
with K2CO3 at 170 °C for 20 min, the rearrangement
cleanly took place to afford trichloroacetamide 11 in
75% yield.21 It is important to note that when the reaction
was conducted at lower temperature (<140 °C), the yield
was dramatically diminished to 40% or less because
it required the longer reaction time resulting in appreci-
able decomposition of 10 or 11. Palladium-catalyzed
conditions22 were also found to be less effective in this
rearrangement and led to a complex mixture. The rear-
ranged product 11 thus obtained was then converted to
(11) (a) Espino, C. G.; Du Bois, J. Angew. Chem., Int. Ed. 2001, 40,
598–600. (b) Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am.
Chem. Soc. 2001, 123, 6935–6936. (c) Espino, C. G.; Fiori, K. W.; Kim,
M.; Du Bois, J. J. Am. Chem. Soc. 2004, 126, 15378–15379. (d) Fiori,
K. W.; Du Bois, J. J. Am. Che. Soc. 2007, 129, 562–568. (e) Zalatan,
D. N.; Du Bois, J. J. Am. Chem. Soc. 2009, 131, 7558–7559.
(12) For reviews, see: (a) Zalantan, D. N.; Du Bois, J. Top. Curr.
Chem. 2010, 292, 347–378. (b) Du Bois Org. Process Res. Dev. 2011, 15,
758–762.
(13) (a) Johnson, C. R.; Braun, M. P. J. Am. Chem. Soc. 1993, 115,
11014–11015. (b) Curran, T. T.; Hay, D. A.; Koegel, C. P.; Evans, J. C.
Tetrahedron 1997, 53, 1983–2004.
(14) Deardorff, D. R.; Windham, C. Q.; Craney, C. L. Organic
Syntheses; Wiley: New York, 1998; Collect. Vol. IX, pp 487À492.
(15) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226–2227.
(16) For a review, see: Hughes, D. L. Org. React. 1992, 42, 335–656.
(17) Kozikowski, A. P.; Wu, J.-P. Tetrahedron Lett. 1987, 28, 5125–
5128.
(19) (a) Uenishi, J.; Fujikura, Y.; Kawai, U. Org. Lett. 2011, 13,
2350–2353. (b) Reddy, D. K.; Shekhar, V.; Prabhakar, P.; Babu, B. C.;
Siddhardha, B.; Murthy, U. S. N.; Venkateswrlu, Y. Eur. J. Med. Chem.
2010, 45, 4657–4663.
(20) For a review, see: Overman, L. E. Acc. Chem. Res. 1980, 13, 218–
224.
(21) Nishikawa, T.; Asai, M.; Ohyabu, N.; Isobe, M. J. Org. Chem.
1998, 63, 188–192.
(18) For a review, see: Chemler, S. R.; Trauner, D.; Danishefsky, S. J.
Angew. Chem., Int. Ed. 2001, 40, 4544–4568.
(22) Schenck, T. G.; Bosnich, B. J. Am. Chem. Soc. 1985, 107, 2058–
2066.
Org. Lett., Vol. 14, No. 6, 2012
1645

Scheme 3. Preparation of Key Intermediate 17
Scheme 4. Synthesis of (À)-Kaitocephalin
cyclization occurred. The stereostructure of 15 was well
supported by the NOESY spectrum.
For another rhodium-catalyzed CÀH amination on the
cyclopentene ring, 15 was converted to carbamate 16 by
deprotection of the PMBM group with DDQ followed by
carbamoylation in 92% yield. Upon treatment of 16 with
11b
10 mol % Rh2(OAc)4, BAIB, and MgO in CH2Cl2 at
sulfamate 13 by desilylation followed by sulfamation in
72% yield.
room temperature, the desired allylic CÀH amination
proceeded to give cyclic carbamate 17 in 60% yield. This
reaction was markedly improved by employing 10 mol %
We next examined the assembly of the pyrrolidine core
starting with rhodium-catalyzed CÀH amination11 of 13
(Scheme 3). When sulfamate 13 was treated with 2 mol %
of Rh2(OAc)4, bis(acetoxy)iodobenzene (BAIB), and
MgO in CH2Cl2 at 40 °C according to the procedure11b
reported by Du Bois and co-workers, an oxidative CÀH
amination took place at the benzylic position regio- and
stereoselectively to give cyclic sulfamate 14 in 74% yield,
and no other isomers were detected. Although a pyrroli-
dine synthesis via intramolecular displacement of a cyclic
sulfamate with a nitrogen atom was unprecedented, we
were pleased to find very effective conditions for this
transformation. Thus, after selective tert-butoxycarbony-
lation of the sulfamate nitogen of 14, the resulting N-Boc
derivative was successively treated with NaH and water in
the same flask at 0 °C to instantaneously provide pyrroli-
dine 15 in 97% yield via stereoselective cyclization in SN2
fashion. When 5 M NaOH was used in place of NaHÀ
water, 15 was also obtained in good yield (89%) although
the cyclization became somewhat sluggish. Interestingly,
when NaH was used alone without addition of water, no
11d
of Rh2(esp)2 in benzene, and 17 was obtained in 86%
yield. It is important to add that all attempts to effect an
allylic CÀH amination prior to a benzylic CÀH amination
failed. For example, Rh2(OAc)4-catalyzed reaction of 18
did not give the corresponding cyclic carbamate and
ketone 19 was obtained in 20% yield instead.
The final stage of the synthesis of kaitocephalin (1)
involved fomation of the 3,5-dichloro-4-hydroxybenza-
mide moiety, oxidative cleavage of the phenyl group and
the cyclopentene ring generating three carboxylic acids,
and removal of all protecting groups (Scheme 4). Thus,
after removal of the Boc group of 17, the resulting amine
was subjected to amidation with 2023 under Schot-
tenÀBaumann conditions to give amide 21 in 97% yield.
At this point, we initially attempted the RuO4 oxidation24
of 21 using a catalytic amout of RuCl3 and NaIO4;
(23) Hirata, K. WO 2008/062740.
(24) (a) Carlsen, P. H. J.; Katsuki, T.; Martı
´
n, V. S.; Sharpless, K. B.
J. Org. Chem. 1981, 46, 3936–3938. (b) Matsuura, F.; Hamada, Y.;
Shioiri, T. Tetrahedron 1993, 49, 8211–8222. (c) Clayden, J.; Knowles,
F. E.; Baldwin, I. R. J. Am. Chem. Soc. 2005, 127, 2412–2413.
1646
Org. Lett., Vol. 14, No. 6, 2012

however, the desired triacid was not obtained at all. It
turned out that the cyclic carbamate moiety does not
survive under the oxidation conditions. After several dis-
couraging results, we found that N-Boc cyclic carbamate
22, derived from 21 in 91% yield, successfully underwent
RuO4-mediated oxidative cleavage to afford triacid 23.
Furthermore, we could unambiguously determine the
absolute structure of 22 by X-ray crystallographic
analysis.25 Finally, without purification, 23 was succes-
sively subjected to saponification and deprotection of the
N-Boc group to furnish (À)-kaitocephalin (1) in 24%
overall yield from 22 after Dowex 50WX4 treatment,
reversed-phase chromatography, and HPLC. The syn-
thetic substance was identical with an authentic sample
byspectroscopic (1H and 13C NMR) and chromatographic
(reversed-phase TLC and HPLC) comparisons.
readily available 5 in 21 steps and 4% overall yield. The
present work provides here a new methodology for the
stereoselective construction of substituted pyrrolidines
utilizing a rhodium-catalyzed CÀH amination.
Acknowledgment. This work was supported by a
Grant-in-Aid for Scientific Research (A) (22249001)
and Grant-in-Aid for Young Scientists (B) (23790015)
from JSPS and a Grant-in-Aid for Scientific Research
on Innovative Areas “Reaction Integration” (No. 2105)
(22106538) from MEXT. We thank Prof. Ohfune and
Prof. Shinada (Osaka City University) for providing us
with an authentic sample of kaitocephalin and valuable
information.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, we have accomplished the highly stereo-
controlled total synthesis of (À)-kaitocephalin (1) from
(25) The crystallographic data (CCDC 859724) can be obtained free
of charge from the Cambridge Crystallographic Data centre via www.
ccdc.cam.ac.uk/data_request/cif.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 6, 2012
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