Novel sequential sigmatropic rearrangements of allylic diols: Application to the total synthesis of ( - )-kainic acid

Article abstract of DOI:10.1021/ol1026602

Sequential sigmatropic rearrangements (Claisen/Claisen and Claisen/Overman) of enantiopure allylic diols are described. The reactions proceeded in complete diastereoselectivity without protecting group manipulations. The sequential Claisen/Overman rearrangement was successfully applied to the total synthesis of ( - )-kainic acid.

Full text of DOI:10.1021/ol1026602

ORGANIC
LETTERS
2010
Vol. 12, No. 24
5756-5759
Novel Sequential Sigmatropic
Rearrangements of Allylic Diols:
Application to the Total Synthesis of
(-)-Kainic Acid
Katsunori Kitamoto, Mana Sampei, Yasuaki Nakayama, Takaaki Sato,* and
Noritaka Chida*
Department of Applied Chemistry, Faculty of Science and Technology, Keio
UniVersity, 3-14-1, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
takaakis@applc.keio.ac.jp; chida@applc.keio.ac.jp
Received November 2, 2010
ABSTRACT
Sequential sigmatropic rearrangements (Claisen/Claisen and Claisen/Overman) of enantiopure allylic diols are described. The reactions proceeded
in complete diastereoselectivity without protecting group manipulations. The sequential Claisen/Overman rearrangement was successfully
applied to the total synthesis of (-)-kainic acid.
Chirality transfer through [3,3]-sigmatropic rearrangements
is one of the most reliable approaches for accessing enan-
tiopure multifunctional molecules.1 Stereochemical informa-
tion embedded in an optically pure allylic alcohol can be
transferred to newly generated carbon-carbon or carbon-
heteroatom bonds in a highly diastereoselective fashion.
Promising diastereoselectivity can be observed even in a
flexible acyclic system because of the organized six-
membered transition state.
enantiopure 1,2-allylic diols 1,2 which can be readily
prepared via a number of methods, such as Sharpless
asymmetric dihydroxylation3 and use of naturally occurring
monosaccarides and tartaric acid. The realization of two types
of novel sequential sigmatropic rearrangements is outlined
in Scheme 1. In the sequential Claisen/Claisen rearrangement
(1f2f3), the first rearrangement of allylic diol 1 would
generate 2,4,5 which would then spontaneously undergo the
second rearrangement to give bisamide 3. The reaction would
To maximize the potential utility of chirality transfer
through [3,3]-sigmatropic rearrangements, our laboratory has
been attracted to sequential sigmatropic rearrangements of
(2) For selected recent reviews on cascade, tandem, and domino reactions
including sigmatropic rearrangements, see: (a) Nicolaou, K. C.; Edmonds,
D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134–7186. (b)
Pellissier, H. Tetrahedron 2006, 62, 1619–1665. (c) Padwa, A.; Bur, S. K.
Tetrahedron 2007, 63, 5341–5378. (d) Poulin, J.; Grise´-Bard, C. M.;
Barriault, L. Chem. Soc. ReV. 2009, 38, 3092–3101. (e) Ilardi, E. A.; Stivala,
C. E.; Zakarian, A. Chem. Soc. ReV. 2009, 38, 3133–3148.
(3) Becker, H.; Soler, M. A.; Sharpless, K. B. Tetrahedron 1995, 51,
1345–1376.
(1) For selected reviews on chirality transfer through sigmatropic
rearrangemetnt, see: (a) Enders, D.; Knopp, M.; Schiffers, R. Tetrahedron:
Asymmetry 1996, 7, 1847–1882. (b) Nubbemeyer, U. Synthesis 2003, 961–
1008.
10.1021/ol1026602  2010 American Chemical Society
Published on Web 11/24/2010

quential methods would preclude protecting group manipula-
tion. In addition, the expected high diastereoselectivities
through the tight chairlike transition states would be an
attractive advantage in these sequential reactions.
Scheme 1
.
Two Types of Sequential Sigmatropic
Rearrangements
Our studies of the sequential Claisen/Claisen rearrange-
ment commenced with enantiopure E-allylic syn-diol 6a
derived from tartaric acid (Table 1). As we expected,
Table 1. Sequential Claisen/Claisen Rearrangements of Allylic
Diols 6a-ca
proceed in one pot and install two identical functional groups.
On the other hand, the sequential Claisen/Overman rear-
rangement (1f4f5) would introduce two different func-
tional groups.6 This transformation is more challenging
because it requires the suppression of the second competitive
Claisen rearrangement (4f2f3) following the first trans-
formation.7 If the single rearrangement of 1 can be com-
pletely controlled, however, a variety of sigmatropic rear-
rangements, including the Overman rearrangement (4f5),8,9
could be subsequently applied to the resultant allylic alcohol.
To synthesize 3 and 5 by classical sigmatropic rearrange-
ments, protection of the homoallylic alcohol in 1 is required
prior to the first rearrangement, with the second reaction
performed after deprotection. However, our proposed se-
entry
diol
time (d)
product
yield (%)
1
2
3
6a
6b
6c
2
2
2.5
7a
7b
7c
87
81
66
a Conditions: 55 µmol of 6, 20 equiv of MeC(OMe)2NMe2, t-BuPh (0.03
M), 180 °C in a sealed tube.
Eschenmoser’s conditions with excess MeC(OMe)2NMe2 at
180 °C in a sealed tube provided 7a in 87% yield (entry
1).10 The reaction proceeded diastereoselectively, with 7a
isolated as the sole product. High stereoselection was also
observed in the reaction of Z-allylic syn-diol 6b to give 7b
in 81% yield (entry 2). Because both enantiomers of the syn-
diols are readily available, all possible stereoisomers of 7
can be synthesized by choosing the appropriate combinations
of the diol stereochemistry and the olefin geometry. The
sequential rearrangement of the trisubstituted olefin 6c
enabled us to construct two contiguous stereocenters includ-
ing a highly congested quaternary carbon (entry 3).
Having successfully developed the sequential Claisen/
Claisen rearrangement, we turned our attention to the more
challenging Claisen/Overman version (Table 2). To circum-
vent the inherent problem of overreaction after the first
rearrangement (Scheme 1, 4f2f3), we envisioned the first
Claisen rearrangement via cyclic orthoamides.11 Addition of
1 equiv of MeC(OMe)2NMe2 to a solution of diol 6a and
o-xylene led to the formation of cyclic orthoamide 8a at room
temperature (entry 1). The resulting orthoamide 8a was then
heated to 160 °C in the same reaction vessel to furnish the
singly rearranged product 10a through N,O-ketene acetal 9a
in 16% yield, along with recovery of starting material 6a.
Although use of 2 equiv of MeC(OMe)2NMe2 increased
(4) For selected reviews on Claisen rearrangements, see: (a) Castro,
A. M. M. Chem. ReV. 2004, 104, 2939–3002. (b) Majumdar, K. C.; Alam,
S.; Chattopadhyay, B. Tetrahedron 2008, 64, 597–643.
(5) We reported the formal synthesis of (-)-morphine using the Claisen/
Claisen rearrangement of a cyclic allylic diol; see: (a) Tanimoto, H.; Saito,
R.; Chida, N. Tetrahedron Lett. 2008, 49, 358–362. For selected examples
of Claisen/Claisen rearrangements except for an aromatic version, see: (b)
Curran, D. P.; Suh, Y.-G. Carbohydr. Res. 1987, 171, 161–191.
(6) For selected examples of sequential reactions including Claisen
rearrangements, see: (a) Thomas, A. F. J. Am. Chem. Soc. 1969, 91, 3281–
3289. (b) Ziegler, F. E.; Piwinski, J. J. J. Am. Chem. Soc. 1979, 101, 1611–
1612. (c) Raucher, S.; Burks, J. E., Jr.; Hwang, K.-J.; Svedberg, D. P. J. Am.
Chem. Soc. 1981, 103, 1853–1855. (d) Mikami, K.; Taya, S.; Nakai, T.;
Fujita, Y. J. Org. Chem. 1981, 46, 5447–5449. (e) Mulzer, V. J.; Bock, H.;
Eck, W.; Buschmann, J.; Luger, P. Angew. Chem. 1991, 103, 450–452. (f)
Posner, G. H.; Carry, J.-C.; Crouch, R. D.; Johnson, N. J. Org. Chem. 1991,
56, 6987–6993. (g) Barriault, L.; Denissova, I. Org. Lett. 2002, 4, 1371–
1374. (h) Sauer, E. L. O.; Barriault, L. J. Am. Chem. Soc. 2004, 126, 8569–
8575. (i) Pelc, M. J.; Zakarian, A. Org. Lett. 2005, 7, 1629–1631. (j) Li,
X.; Ovaska, T. V. Org. Lett. 2007, 9, 3837–3840. (k) Ilardi, E. A.; Isaacman,
M. J.; Qin, Y.-C.; Shelly, S. A.; Zakarian, A. Tetrahedron 2009, 65, 3261–
3269.
(7) Curran reported the single Claisen rearrangement of an allylic bis-
ketenesilylacetal; see ref 5b.
(8) (a) Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597–599. For reviews
on Overman rearrangements, see: (b) Overman, L. E.; Carpenter, N. E. In
Organic Reactions; Overman, L. E., Ed.; Wiley: New York, NY, 2005;
Vol. 66, pp 1-107.
(9) We reported a sequential Overman/Overman rearrangement in the
total syntheses of biologically active compounds; see: (a) Momose, T.;
Hama, N.; Higashino, C.; Sato, H.; Chida, N. Tetrahedron Lett. 2008, 49,
1376–1379. (b) Hama, N.; Matsuda, T.; Sato, T.; Chida, N. Org. Lett. 2009,
11, 2687–2690. For selected examples of sequential reactions including
Overman rearrangements, see: (c) Villemin, D.; Hachemi, M. Synth.
Commun. 1996, 26, 1329–1334. (d) Banert, K.; Fendel, W.; Schlott, J.
Angew. Chem., Int. Ed. 1998, 37, 3289–3292. (e) Demay, S.; Kotschy, A.;
Knochel, P. Synthesis 2001, 863–866. (f) Singh, O. V.; Han, H. Org. Lett.
(10) Stereochemistries of 7a-c and 11a-c were established through
their cyclic derivatives and subsequent NOE experiments; see the Supporting
Information.
(11) Overman rearrangements through cyclic orthoamides were reported;
see: (a) Vyas, D. M.; Chiang, Y.; Doyle, T. W. J. Org. Chem. 1984, 49,
2037–2039. (b) Danishefsky, S.; Lee, J. Y. J. Am. Chem. Soc. 1989, 111,
4829–4837.
2004, 6, 3067–3070
.
Org. Lett., Vol. 12, No. 24, 2010
5757

To demonstrate the practical utility of the sequential
sigmatropic rearrangements, we applied this methodology
in the synthesis of (-)-kainic acid (17),14 which was isolated
from the Japanese marine alga Digenea simplex.15,16 Kainic
acid was originally used in anthelmintic and insecticide
preparations17 and recently has been applied to the study of
neuropharmacology because of its ability to cause responses
that mimic neuronal disorders, such as Alzheimer’s disease.18
A conspicuous feature of our approach to kainic acid is the
use of chirality transfer in acyclic compounds made possible
by taking advantage of the three secondary hydroxy groups
embedded in D-arabinose (Scheme 3). An SN2′ reaction
Table 2. Claisen Rearrangement of Allylic syn-Diols 6a-c
through Cyclic Orthoamides 8a-ca
yield (%)
entry diol MeC(OMe)2NMe2(equiv) additive
10
7
Scheme 3. Synthetic Plan toward (-)-Kainic Acid (17)
1
2
3
4
5
6a
6a
6a
6b
6c
1.0
2.0
2.0
2.0
2.0
none
none
MS4 Å
MS4 Å
MS4 Å
16
52
91
89
95
0
9
0
0
0
a Conditions: 140 µmol of 6, MeC(OMe)2NMe2, o-xylene (0.03 M), rt,
then MS4 Å (0 or 500 wt %), 160 °C in a sealed tube.
the yield, doubly rearranged product 7a was concomitant-
ly generated because of the presence of the excess
MeC(OMe)2NMe2 (entry 2). After an extensive survey of
methods to suppress the double rearrangement, we finally
found that the addition of 500 wt % MS4Å to orthoamide
8a prior to heating was critical for obtaining 10a in 91%
yield (entry 3).12 The developed procedure through the cyclic
orthoamide was reliable. The reaction of Z-allylic syn-diol
6b and trisubstituted olefin 6c gave allylic alcohols 10b and
10c in 89% and 95% yield, respectively (entries 4 and 5).
We then demonstrated the Overman rearrangement of the
resulting allylic alcohols 10a-c (Scheme 2). Allylic alcohols
(13f14) and sequential Claisen/Overman rearrangements
(15f16) could establish all of the chiral stereocenters (C2,
C3, C4) in kainic acid.
The synthesis of (-)-kainic acid (17) commenced with
selective MOM protection of 18, which was prepared from
(14) For selected reviews on the Kainoid family, 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. (d) Moloney, M. G. Nat. Prod. Rep. 2002, 19, 597–616.
Scheme 2. Overman Rearrangement of Allylic Alcohols 10a-c
(15) Murakami, S.; Takemoto, T.; Shimizu, Z. J. Pharm. Soc. Jpn. 1953,
73, 1026–1028
.
(16) For recent examples of the enantioselective total synthesis of kainic
acid, see: (a) Clayden, J.; Menet, C. J.; Tchabanenko, K. Tetrahedron 2002,
58, 4727–4733. (b) Martinez, M. M.; Hoppe, D. Org. Lett. 2004, 6, 3743–
3746. (c) Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2005, 127, 4763–
4776. (d) Scott, M. E.; Lautens, M. Org. Lett. 2005, 7, 3045–3047. (e)
Anderson, J. C.; O’Loughlin, J. M. A.; Tornos, J. A. Org. Biomol. Chem.
2005, 3, 2741–2749. (f) Morita, Y.; Tokuyama, H.; Fukuyama, T. Org.
Lett. 2005, 7, 4337–4340. (g) Poisson, J.-F.; Orellana, A.; Greene, A. E. J.
Org. Chem. 2005, 70, 10860–10863. (h) Pandey, S. K.; Orellana, A.; Greene,
A. E.; Poisson, J.-F. Org. Lett. 2006, 8, 5665–5668. (i) Sakaguchi, H.;
Tokuyama, H.; Fukuyama, T. Org. Lett. 2007, 9, 1635–1638. (j) Chalker,
J. M.; Yang, A.; Deng, K.; Cohen, T. Org. Lett. 2007, 9, 3825–3828. (k)
Jung, Y. C.; Yoon, C. H.; Turos, E.; Yoo, K. S.; Jung, K. W. J. Org. Chem.
2007, 72, 10114–10122. (l) Sakaguchi, H.; Tokuyama, H.; Fukuyama, T.
Org. Lett. 2008, 10, 1711–1714. (m) Tomooka, K.; Akiyama, T.; Man, P.;
Suzuki, M. Tetrahedron Lett. 2008, 49, 6327–6329. (n) Farwick, A.;
10a-c were transformed to trichloroimidates, which were
subsequently heated in the presence of K2CO3 to give
13
trichloroacetamide 11a-c in 73-81% yields over two
steps.10
Helmchen, G. Org. Lett. 2010, 12, 1108–1111
.
(12) We believe that MS4Å may selectively decompose the excess
MeC(OMe)2NMe2 in the presence of cyclic orthoamide 8a. In fact, when
MS4Å is added at the beginning of the reaction, the formation of the
orthoamide is suppressed.
(13) Nishikawa, T.; Asai, M.; Ohyabu, N.; Isobe, M. J. Org. Chem.
1998, 63, 188–192.
(17) Nitta, I.; Watase, H.; Tomiie, Y. Nature 1958, 181, 761–762.
(18) (a) MacGeer, E. G.; Olney, J. W.; MacGeer, P. L. Kainic Acid as
a Tool in Neurobiology; Raven: New York, 1978. (b) Goodenough, S.;
Schleusner, D.; Pietrzik, C.; Skutella, T.; Behl, C. Neuroscience 2005, 132,
581–589. (c) Abdul, H. M.; Sultana, R.; Keller, J. N.; Clair, D. K. S.;
Markesbery, W. R.; Butterfield, D. A. J. Neurochem. 2006, 96, 1322–1335.
5758
Org. Lett., Vol. 12, No. 24, 2010

Scheme 4. Total Synthesis of (-)-Kainic Acid (17) through the Sequential Claisen/Overman Rearrangement
D-arabinose by a known two-step sequence (Scheme 4).19
The remaining secondary alcohol was converted to the
mesylate. In the next SN2′ reaction of γ-mesyloxy R,ꢀ-enoate
19, we modified the original conditions reported by Ibuka
and Yamamoto to give 20 in 82% yield in a stereo- and
regioselective manner.20 E-Allylic anti-diol 21 was then
synthesized from ethyl ester 20 via a three-step sequence
involving LiAlH4 reduction, MPM protection, and removal
of the acetonide. The stage was now set for the crucial
sequential Claisen/Overman rearrangement. Both the Claisen
rearrangement of 21 and the subsequent Overman rearrange-
ment proceeded with complete diastereoselectivity, affording
trichloroacetamide 23. Thus, we successfully installed all
stereocenters present in kainic acid in the acyclic intermediate
through three chirality transfer reactions
With the key acyclic intermediate 23 in hand, we turned
our attention to the chemoselective oxidative cleavage of
trans-olefin 23. After removal of the MOM group, a hydroxy-
directed dihydroxylation under anhydrous conditions21 fol-
lowed by addition of Pb(OAc)4 gave aldehyde 24 without
touching the exomethylene group. Kraus-Pinnick oxidation
followed by methylation of the acid then provided methyl
ester 25 in 38% yield (3 steps). The pyrrolidine structure
was constructed by cleavage of the PMB group with CAN,
followed by a Mitsunobu reaction.22 Global deprotection with
KOH in t-BuOH/H2O at 120 °C accomplished the total
synthesis of (-)-kainic acid (17). Our sample was found to
be indistinguishable from the natural product on the basis
1
of H NMR, 13C NMR, HRMS, IR, MP, and its optical
rotaion.
In summary, we developed two novel sequential sigma-
tropic rearrangements of optically pure allylic diols. The
reactions proceed in high yields with complete diastereose-
lectivity. By choosing appropriate reaction conditions, two
identical functional groups (Claisen/Claisen) or two different
groups (Claisen/Overman) can be installed from the same
allylic diols without protecting group manipulation. In
particular, an orthoamide-type Claisen rearrangement devel-
oped in the Claisen/Overman sequence is very useful because
a variety of sigmatropic rearrangements can be employed in
the second rearrangement. As a demonstration of the
sequential Claisen/Overman rearrangement, we achieved the
total synthesis of (-)-kainic acid through three chirality
transfers, taking advantage of the secondary hydroxy groups
in D-arabinose.
Acknowledgment. Support from a Grant-in-Aid for
Scientific Research, B20350021 from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan is
gratefully acknowledged.
Supporting Information Available: Experimental pro-
1
cedures; copies of H NMR and 13C NMR spectra of new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(19) (a) Harcken, C.; Martin, S. F. Org. Lett. 2001, 3, 3591–3593. (b)
Jian, Y.-J.; Wu, Y. Org. Biomol. Chem. 2010, 8, 811–821.
(20) (a) Ibuka, T.; Tanaka, M.; Nishii, S.; Yamamoto, Y. J. Am. Chem.
Soc. 1989, 111, 4864–4872. (b) Habashita, H.; Kawasaki, T.; Takemoto,
Y.; Fujii, N.; Ibuka, T. J. Org. Chem. 1998, 63, 2392–2396.
(21) (a) Kon, K.; Isoe, S. Tetrahedron Lett. 1980, 21, 3399–3402. (b)
Smith, A. B., III; Boschelli, D. J. Org. Chem. 1983, 48, 1217–1226. (c)
Donohoe, T. J.; Garg, R.; Moore, P. R. Tetrahedron Lett. 1996, 37, 3407–
3410.
OL1026602
(22) For the Mitsunobu reaction of trichloroacetamides to synthesize
2-oxazolines, see: Roush, D. M.; Patel, M. M. Synth. Commun. 1985, 15,
675–679.
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