New stereoselective entry to azaspirocyclic nucleus of halichlorine and pinnaic acids by radical translocation/cyclization reaction

Article abstract of DOI:10.1021/ol034942v

(Matrix Presented) A stereoselective approach to the spirocyclic nucleus of halichlorine and pinnaic acids has been developed starting from a piperidine derivative. A key transformation in this sequence involves a cascade radical translocation/cyclization

Full text of DOI:10.1021/ol034942v

ORGANIC
LETTERS
2003
Vol. 5, No. 17
3017-3020
New Stereoselective Entry to
Azaspirocyclic Nucleus of Halichlorine
and Pinnaic Acids by Radical
Translocation/Cyclization Reaction
Kiyosei Takasu,* Hiroshi Ohsato, and Masataka Ihara*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences,
Tohoku UniVersity, Aobayama, Sendai 980-8578, Japan
mihara@mail.pharm.tohoku.ac.jp
Received May 29, 2003
ABSTRACT
A stereoselective approach to the spirocyclic nucleus of halichlorine and pinnaic acids has been developed starting from a piperidine derivative.
A key transformation in this sequence involves a cascade radical translocation/cyclization process.
Halichlorine (1)1 and pinnaic acids (2)2 are structurally related
new marine alkaloids isolated from the Japanese sponge
Halichondria okadai and the Okinawan bivalve Pinna
muricata, respectively. It has been found that halichlorine
significantly inhibits the induction of VCAM-1 (vascular cell
adhesion molecule-1), and alkaloids 2a and 2b show the
specific inhibition of cPLA2 (cytosolic phospholipase A2)
activity. Structurally, 1 and 2 possess unique tetra- and
bicyclic skeletons, respectively, involving the azaspiro[4.5]-
decane system. There have been several reports on synthetic
studies of these alkaloids,3,4 concentrating on stereoselective
construction of the azaspirocyclic core. Danishefsky and co-
workers have accomplished the total synthesis of optically
active 1 and 2a,3a and Arimoto’s group has recently reported
the total synthesis of racemic 2a.3d In both studies, the
construction of azaspirocycle was achieved by intramolecular
nucleophilic N-C bond formation reaction of cyclopenty-
lamines, which have already possessed the essential stere-
ochemical centers about the cyclopentane ring.
(1) Kuramoato, M.; Tong, C.; Yamada, K.; Chiba, T.; Hayashi, Y.;
Uemura, D. Tetrahedron Lett. 1996, 37, 3867-3870.
We envisioned that the azaspirocyclic framework would be
constructed from a simple piperidine derivative by utilizing
a cascade radical reaction, which involves radical translo-
cation and continuous radical cyclization reactions.5 In our
plan, an aryl radical would homolytically dissociate a C-H
bond, which is generally inactive or less active, by [1,5]-
radical translocation, and then the resulting R-aminyl radical
(2) Chou, T.; Kuramoto, M.; Otani, Y.; Shikano, M.; Yazawa, K.;
Uemura, D. Tetrahedron Lett. 1996, 37, 3871-3874. The proposed structure
in their report has been revised by Danishefsky’s goup. See ref 3c.
(3) (a) Trauner, D.; Schwarz, J. B.; Danishefsky, S. J. Angew. Chem.,
Int. Ed. 1999, 38, 3542-3544. (b) Carson, M. W.; Kim, G.; Hentemann,
M. F.; Trauner, D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40,
4450-4452. (c) Carson, M. W.; Kim, G.; Danishefsky, S. J. Angew. Chem.,
Int. Ed. 2001, 40, 4453-4456. (d) Hayakawa, I.; Arimoto, H.; Uemura, D.
Heterocycles 2003, 59, 441-444.
10.1021/ol034942v CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/01/2003

from 6 by the above cascade strategy. We have anticipated
that the rate and stereoselectivity in the radical reaction would
be controlled by the olefinic substituent (R′).
Scheme 1. Radical Translocation/Cyclization Strategy
Preparation of the radical precursors of 6a-e started with
the alkylation of glutalimide (7) with 2-bromobenzyl bromide
to provide benzylimide 8 (Scheme 3). Reduction of 8 with
Scheme 3a
would successively react with an intramolecular olefinic bond
(Scheme 1).6 Thus, this sequence would provide azaspiro-
cyclic structures having consecutive quaternary and tertiary
stereogenic centers from amine-containing monocyclic com-
pounds.
We here describe a novel approach toward the azaspiro-
[4.5]decane framework of halichlorine and pinnaic acids by
utilizing the cascade radical translocation and addition
reaction. Furthermore, we demonstrate the stereoselective
installation of substituents at C(5) and C(14) positions.
Retrosynthetically, the target alkaloids 1 and 2 could be
bisected into a spirocyclic subunit such as alcohol 3 and a
C(15)-C(21) chlorodienyl moiety7 (Scheme 2). A methyl
a
Reagents and conditions: (a) 2-bromobenzyl bromide, KOH,
DMF, rt. (b) (i) NaBH4, 2 N HCl, EtOH, rt; (ii) PhSO2H, CaCl2,
CH2Cl2, rt. (c) CH2dCH(CH2)3MgBr, ZnCl2‚Et2O, Et2O-CH2Cl2,
rt. (d) R′CHdCH2 (2 equiv), 10 (5 mol %), CH2Cl2, rt (reflux for
the preparation of 6d).
Scheme 2. Retrosynthetic Analysis of Halichlorine (1) and
Pinnaic Acids (2)
NaBH4 in the presence of a catalytic amount of HCl followed
by treatment with benzenesulfinic acid afforded sulfone 9
in good overall yield.8 The sulfone 9 was converted into
6-substituted piperidin-2-one 6a (R′ ) H) by Grignard
reaction in the presence of Lewis acidic ZnCl2. The
transformation of 6a into electron-deficient alkenes 6b-e
was accomplished by cross-metathesis reaction.9 Namely, 6a
was treated with 2 equiv of acrylate or acrolein and 5.0 mol
% Grubbs’ second-generation catalyst (10) to furnish the
corresponding activated alkenes 6b-e in medium to good
yield. In all the reactions, trans-alkenes were selectively
produced.
Next, the cascade radical translocation/cyclization reaction
of 6a-e was examined under the radical conditions. To a
refluxing solution of 6 in benzene was added a benzene
solution of Bu3SnH (2.0 equiv) and AIBN (0.5 equiv) by
using a syringe pump over a period of 18 h, and the mixture
was refluxed for additional 1 h. Conventional workup and
chromatographic purification furnished the desired spirolac-
tam 5 and its diastereomer epi-5. The results are summarized
in Table 1. Reaction of 6a possessing unactivated olefin
furnished a mixture of 5a and epi-5a (diastereomeric ratio
) 3:1) in 54% yield along with noncyclized debrominated
compound 11a (entry 1). Introduction of an ester function
into the olefinic substituent resulted in higher production of
spirocyclic compounds (entries 2-4), while the reaction of
substituent at C(14) position of 3 would be formed by
stereoselective methylation of tert-butyl ester 4. Diester 4
would arise from benzylamide 5, which could be constructed
(4) (a) Arimoto, H.; Asano, S.; Uemura, D. Tetrahedron Lett. 1999, 40,
3583-3586. (b) Trauner, D. Danishefsky, S. J. Tetrahedron Lett. 1999,
40, 6513-6516. (c) Lee, S.; Zhao, Z. Tetrahedron Lett. 1999, 40, 7921-
7924. (d) Clive, D. L.; Yeh, V. S. C. Tetrahedron Lett. 1999, 40, 8503-
8507. (e) Koviach, J. L.; Forsyth, C. J. Tetrahedron Lett. 1999, 40, 8529-
8532. (f) Shindo, M.; Fukuda, Y.; Shishido, K. Tetrahedron Lett. 2000,
41, 929-932. (g) Wright, D. L.; Schulte, J. P., II; Page, M. A. Org. Lett.
2000, 2, 1847-1850. (h) White, J. D.; Blakemore, P. R.; Korf, E. A.;
Yokochi, A. F. T. Org. Lett. 2001, 3, 413-415.
(5) For a review of radical translocation reactions, see: (a) Robertson,
J.; Pillai, J.; Lush, R. K. Chem. Soc. ReV. 2001, 30, 94-103. For examples
of radical translocation/cyclization reaction in synthesis, see: (b) Snieckus,
V.; Cuevas, J.-C.; Sloan, C. P.; Liu, H.; Curran, D. P. J. Am. Chem. Soc.
1990, 112, 896-898. (c) Curran, D. P.; Abraham, A. C.; Liu, H. J. Org.
Chem. 1991, 56, 4337-4339. (d) Sha, C.-K.; Hsu, C.-W.; Chen, Y.-T.;
Cheng, S.-Y. Tetrahedron Lett. 2000, 41, 9865-9869. (e) Sato, T.;
Yamazaki, T.; Nakanishi, Y.; Uenishi, J.; Ikeda, M. J. Chem. Soc., Perkin
Trans. 1 2002, 1438-1443. (f) Curran, D. P.; Liu, H. J. Chem. Soc., Perkin
Trans. 1 1994, 1377-1394.
(6) Hart, D. J.; Tsai, Y.-M. J. Am. Chem. Soc. 1984, 106, 8209-8217.
(7) Keen, S. P.; Weinreb, S. M. J. Org. Chem. 1998, 63, 6739-6741.
(8) Ley, S. V.; Lygo, B.; Sternfield, F.; Wonnacott, A. Tetrahedron 1986,
42, 4333-4342.
(9) Chatterjee, A. K.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 3783-
3784.
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Org. Lett., Vol. 5, No. 17, 2003

Scheme 4a
Table 1. Cascade Radical Reaction of 6 Leading to
Azaspirocycle 5a
% yield of
ratio of
entry
R′
(5 + epi-5)
5:epi-5
% yield of 11
1
2
3
4
5
H
54
88
71
78
75:25c
78:22c
56:44d
91:9d
7
0
nde
0
nde
CO2Me
CO2HFIPb
CO2 Bu
CHO
t
trace
a Reactions were performed using 2.0 equiv of Bu3SnH and 0.5 equiv
of AIBN in refluxing benzene for 19 h. b HFIP means 1,1,1,3,3,3-
hexafluoroisopropyl. c Ratios were determined by 1H NMR. d Ratios were
determined on the basis of isolated yields. e Not determined.
a Reagents and conditions: (a) cat. Pd(OH)2, H2, cat. HCl
t
(concd), BuOH, reflux. (b) Lawesson’s reagent, toluene, reflux.
R,â-unsaturated aldehyde 6e was unsuccessful (entry 5). The
best result was obtained in the case of tert-butyl ester 6d to
afford 5d in 71% yield with a high diastereoselectivity (entry
4; epi-5d was obtained in 7% yield). Spirolactam 5d, which
has the same relative configuration as the natural products,
could be easily separated from epi-5d by recrystallization,
and its stereochemistry was confirmed by NOESY experi-
ment. It is noteworthy that preparation of 5d could be
performed as a multigram-scale reaction. Although the
detailed reaction mechanism remains to be clarified, possible
conformations of the transition state can be drawn for an
explanation of the substrate-controlled selectivity observed
(Figure 1). In the cyclization step, there would be sterically
(c) (i) ethyl 2-bromoacetylacetate, NaHCO3, CH2Cl2, rt; (ii) NaOEt,
EtOH, 40 °C. (d) PtO2, H2, EtOH, rt. (e) (i) TFA, CH2Cl2, rt; (ii)
EDCl, CH2Cl2, rt. (f) (i) LiEt3BH, THF, 0 °C; (ii) TESCl, NEt3,
cat. DMAP, CH2Cl2, rt. (g) LDA, THF, -78 °C; then MeI, -78
°C. (h) Li(NH2)BH3, THF, 40 °C.
carbon atom chain at the C(5) position was accomplished
by Eschenmoser reaction.10 Namely, lactam 12 was converted
into thiolactam 13 (94% yield), and then coupling of 13 with
ethyl 2-bromoacetoacetate, followed by deacetylation, served
to generate vinylogous carbamate (E)-14 in 73% overall
yield. According to a method for stereoselective reduction
of a structurally analogous compound reported by Shishido’s
group,4f catalytic hydrogenation of 14 was successful in
exclusively giving piperidine 4, whose stereochemistry was
deduced by two-dimensional NMR results.
The next critical issue in the path towards halichlorine and
pinnaic acids is the stereoselective installation of methyl
group at the C(14) position. Initial experiments showed that
the C(14)-methylation of spirocyclic compounds such as 5d
was unsuccessful under a variety of conditions. We next
planned to utilize the stereochemical character (e.g., concave
vs convex selection) of a fused ring system, which would
be easily derived from 4. Tricyclic lactam 15 was prepared
by selective hydrolysis of 4 under acidic conditions and the
subsequent lactamization. The ester 15 was submitted to
reduction using Super-hydride at 0 °C followed by protection
by TESCl to give 16. Simple computer modeling by
Figure 1. Plausible transition states in the radical translocation/
cyclization reaction.
repulsive interaction between the R′ substituent and an axially
oriented proton on the piperidine ring.
The stereoselective transformation of 5d into the fully
functionalized spiro-system 3 is shown in Scheme 4. De-
benzylation of 5d with Pd(OH)2-H2 in acidic media
quantitatively furnished amide 12. Introduction of a two-
(10) (a) Roth, M.; Dubs, P.; Go¨tschi, E.; Eschenmoser, A. HelV. Chim.
Acta 1971, 54, 710-734. (b) Tanino, H.; Nakata, T.; Kaneko, T.; Kishi, Y.
J. Am. Chem. Soc. 1977, 99, 2818-2819.
Org. Lett., Vol. 5, No. 17, 2003
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molecular mechanics has encouraged us that the â-face at
the C(14) position of azatricyclo[7.3.0.01,5]dodecane 16
corresponds to the less bulky convex face. Exposure of
lithium enolate of 16 to methyl iodide at -78 °C gave rise
to 17 as a sole diastereomer in 85% yield. NOESY
experiment supported the introduction of the methyl group
from the desired direction, as expected.
With all the required configuration of stereogenic centers
except for the C(17) position in hand, we attempted cleavage
of the amide bond. It was found that treatment of lactam 17
with Li(NH2)BH3, prepared from BH3‚NH3 and BuLi,11 lead
to reductive cleavage of C-N bond to give 18 in 59% yield.
In summary, we have developed a novel concise route for
the synthesis of the azaspirocyclic core structure of hali-
chlorine and pinnaic acids possessing four of five stereogenic
centers in a highly stereoselective manner. The key cascade
radical translocation/cyclization reaction allows the creation
of the azaspiro[4.5]decane skeleton with creation of two
adjacent stereogenic centers from a readily available piperi-
dine derivative. The application of the cascade radical
reaction should provide stereocontrolled access to a wide
variety of spirocyclic compounds.12 Further studies toward
the total syntheses of the natural products will be reported
in due course.
Acknowledgment. This work was supported in part by
Fujisawa Pharmaceutical Company Award in Synthetic
Organic Chemistry, Japan, and Grants-in-Aid for Encourage-
ment of Young Scientists and for Scientific Research on
Priority Areas (A) “Exploitation of Multi Element Cyclic
Molecules” from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL034942V
(11) (a) Myers, A. G.; Yang, B. H.; Kopecky, D. J. Tetrahedron Lett.
1996, 37, 3623-3626. (b) Abe, H.; Aoyagi, S.; Kibayashi, C. J. Am. Chem.
Soc. 2000, 122, 4583-4592.
(12) We have proven that a variety of heteroatom-containing spirocycles
can be synthesized by our strategy. The efforts will be published elsewhere.
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