Short synthesis of (+)-cylindricine C by using a catalytic asymmetric Michael reaction with a two-center organocatalyst

Article abstract of DOI:10.1002/anie.200601722

(Chemical Equation Presented) Two for the price of one: The total synthesis of (+)-cylindricine C has been achieved in six steps using a catalytic asymmetric Michael reaction and tandem cyclization. A newly designed two-center organocatalyst gives good selectivity in this Michael reaction. TaDiAS = tartrate-derived diammonium salt.

Full text of DOI:10.1002/anie.200601722

Angewandte
Chemie
Cyclization
DOI: 10.1002/anie.200601722
Short Synthesis of (+)-Cylindricine C by Using a
Catalytic Asymmetric Michael Reaction with a
Two-Center Organocatalyst**
Scheme 1. Structure of the cylindricines.
construct a tricyclic ring system from 3 in a one-pot reaction
by using tandem cyclization through imine formation,the
Mannich reaction,and the aza-Michael reaction (Scheme 2).
The required compound 3 is a highly functionalized a-amino
Tomoyuki Shibuguchi, Hisashi Mihara,
Akiyoshi Kuramochi, Shun Sakuraba,
Takashi Ohshima, and Masakatsu Shibasaki*
Present syntheses of natural products and medicinally
relevant compounds require high efficiency in terms of
the number of synthetic steps. Tandem reactions that
combine several transformations in a single procedural
step are powerful tools for minimizing synthetic steps.[1]
In addition to time–cost benefits,they can allow
selective reactions of unstable species and side reactions
to be minimized by the rapid successive formation and
consumption of intermediates. Catalytic asymmetric
reactions have also enabled more efficient syntheses
of various highly versatile chiral compounds that allow
for the development of new or more practical retro-
synthetic analyses of complex natural products.[2] The
combination of tandem reactions and catalytic asym-
metric reactions leads to more efficient synthetic routes.
Herein,we report a short total synthesis of ( +)-
cylindricine C by a tandem cyclization and catalytic
asymmetric Michael reaction with a newly designed two-
center organocatalyst.
The cylindricines were isolated from the marine ascidian
Clavelina cylindrica by Blackman et al. between 1993 and
1995.[3] These structurally related compounds exhibit bioac-
tivity against a DNA-repair-deficient yeast strain[4] and also
inhibit the growth of murine leukemia and human solid-
tumor cell lines.[5] Their tricyclic ring system (see Scheme 1) is
comprised of a spirocyclic amine that makes them an
attractive target for total synthesis.[6]
Scheme 2. Retrosynthetic analysis of (+)-cylindricine C. Bn=benzyl.
acid derivative. Recently,we developed a two-center organo-
catalyst 6 (TaDiAS; tartrate-derived diammonium salt) that
efficiently catalyzes phase-transfer alkylation,[8a,b] Michael
reactions,[8a,b] and Mannich-type reactions of the glycine
Schiff base.[8c] We planned to synthesize 3 by using a catalytic
asymmetric Michael reaction[9,10] with TaDiAS.
First,we examined the catalytic asymmetric Michael
reaction of glycine Schiff base 4 to dienone 5,which was
prepared from pimelic acid in two steps (Table 1). Based on
our previous results,[8a,b] the reaction was performed with
10 mol% of (S,S)-6a (the best catalyst for the Michael
reaction to a,b-unsaturated esters). In contrast to the Michael
reaction to a,b-unsaturated esters,the addition of 4 to a,b-
unsaturated ketones (enone) proceeds with more modest
selectivity.[8a,b] As expected from previous work,the reaction
with 5 was only moderately enantioselective (entry 1). Never-
theless,we were pleased to observe clean formation of the
monoaddition product. Next we examined the catalyst
structure to improve the enantioselectivity. Previous confor-
mational analysis of 6a[8c] suggested that the acetal moiety
regulates the chiral environment around the two ammonium
cations. We designed a new catalyst 6b that has a 2,6-
disubstituted cyclohexane structure at the acetal moiety to
affect the chiral environment more strongly. Among the three
diastereomers that originate from the relative stereochemis-
try of the acetal moiety,C2-symmetric 6b was found to be most
effective in the preceding investigations (see the Supporting
Information). When 6b was applied to the reaction of 4 with
5,enantioselectivity was improved to 63% ee (entry 2). At
lower temperature (À308C) both reactivity and selectivity
The first total synthesis of optically active cylindricine C
was reported by Molander and Ronn,[7a] and several groups
also succeeded in its total synthesis.[7b–e] Because they used
stepwise strategies to construct the tricyclic ring system,their
synthesis required several steps (9–14 steps). We planned to
[*] T. Shibuguchi, H. Mihara, A. Kuramochi, S. Sakuraba, Dr. T. Ohshima,
Prof. Dr. M. Shibasaki
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax: (+81)3-5684-5206
E-mail: mshibasa@mol.f.u-tokyo.ac.jp
[**] This work was supported by RFTF, a Grant-in-Aid for the Encour-
agement of Young Scientists (A), and a Grant-in-Aid for Specially
Promoted Research from the Japan Society for the Promotion of
Science (JSPS) and the Ministry of Education, Culture, Sports,
Science and Technology (MEXT).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2006, 45, 4635 –4637
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4635

Communications
Table 1: Catalytic asymmetric Michael reaction with (S,S)-6.
affording the desired 2a (entry 2, 2a/2b/2c = 87:13:trace).
Several other additives were examined under the optimized
conditions (entries 3–6). The reaction with [La(OTf)3] (OTf =
triflate) afforded 2b as the major product (entry 3),whereas
MgCl2,MgBr 2·
(Et2O)2,and LiCl gave better reactivity and 2a as the major
product (entries 4–6). The mechanism of the additive effects
is unclear,but we assume that additives operate as Lewis acids
and organize the reacting centers through chelation.[11]
The obtained tricyclic compounds 2a–c were transformed
into (+)-cylindricine C (Scheme 3). The product mixture
from entry 4 in Table 2 (2a/2b/2c = 84:9:7) was converted
into 7a–c in three steps. Cylindricine C (1) and 5-epi-
cylindricine C (epi-1)[7c,11] were obtained in 80 and 8%
yield,respectively,after treatment of 7a–c with tetrabutyl-
ammonium fluoride (TBAF). The trans-fused AB ring of 7b
was isomerized at the C7a position to the desired cis fused AB
ring under basic conditions.[7d,e] Computational studies also
supported this result.[11] Optically pure 1 was obtained in 59%
yield after three recrystallizations of the picric acid salt of 1
from EtOH.
Entry
Catalyst
Base
T [8C]
t [h]
Yield [%][a]
ee [%][b]
1
2
3
6a
6b
6b
6b
6b
K2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
4
4
À30
À30
À40
14
14
36
24
66
96
96
86
72
84
48
63
61
74
82
4
5[c,d]
[a] Yield of the isolated product. [b] Determined by chiral stationary
phase HPLC. [c] 3-Fluorotoluene was used as the solvent. [d] Cs2CO3:
1.5 equivalents.
were lowered (entry 3). Enantioselectivity was
improved to 74% ee by using Cs2CO3 as the base
(entry 4). Further investigations revealed that the use of
1.5 equivalents of Cs2CO3 and 3-fluorotoluene as the
solvent at À408C 3 could be obtained in 84% yield of
isolated product and 82% ee (entry 5).
We next examined tandem cyclization (Table 2).
Tricyclic compound 2 was obtained when 3 was treated
with 3 equivalents of camphorsulfonic acid (CSA) in
1,2-dichloroethane. The reaction provided three diaste-
reomers (2a–c),as determined by NMR spectroscopic
analysis,whose configurations were identified as shown
in Table 2 (2a: desired cis fused AB ring; 2b: trans-
fused AB ring; 2c: cis fused AB ring and epi C5 position).
Under these conditions,the chemical yield was moderate
(47%) and 2b was obtained as the major product (entry 1, 2a/
2b/2c = 33:63:4). Several different solvents and acids were
examined,but the reactivity and diastereoselectivity were
insignificantly affected. When AlCl3 was used as an additive,
the diastereoselectivity was greatly improved,thus selectively
Scheme 3. Synthesis of (+)-cylindricine C. Reagents and conditions:
a) LiAlH4, THF, reflux; b) tert-butyldiphenylsilyl chloride (TBDPSCl), Et3N,
CH2Cl2; c) Dess–Martin periodinane, CH2Cl2 (71%; 3 steps); d) TBAF, THF,
RT (1: 80%; epi-1: 8%).
Thus,we succeeded in the synthesis of enantiomerically
pure 1 from pimelic acid in nine steps,including the
recrystallization process. The number of synthetic steps
required to obtain 1 could be further decreased by using a
mixed anhydride reduction process.[12] Thereby,
1 was
obtained in two steps from 2a (Scheme 4; total 6 steps).
Table 2: Tandem cyclization and additive effects.
Scheme 4. Shorter approach to (+)-cylindricine Cfrom 2a.
Entry
Additive
t [h]
d.r.
Yield [%][b]
[2a/2b/2c][a]
In conclusion,we have achieved a short synthesis of ( +)-
cylindricine C (6 steps) using a catalytic asymmetric Michael
reaction of a glycine Schiff base and subsequent tandem
cyclization. Further improvement of each step and the
expansion of current strategies are in progress.
1
2
3
4
5
6
–
AlCl3
[La(OTf)3]
MgCl2
MgBr2·(Et2O)2
LiCl
18
24
12
12
18
18
33:63:4
87:13:trace
27:65:8
84:9:7
82:13:5
89:6:5
47
47
57
65
61
57
[a] Determined by 1H NMR spectroscopic analysis. [b] Yield of the
isolated product.
Received: May 2,2006
Published online: June 21,2006
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Angew. Chem. Int. Ed. 2006, 45, 4635 –4637

Angewandte
Chemie
Keywords: cyclization · Michael addition · phase-transfer
.
catalysis · spiro compounds · total synthesis
[1] For representative reviews of tandem reactions in organic
synthesis,see: a) J. D. Winkler, Chem. Rev. 1996, 96,167;
b) P. J. Parsons,C. S. Penkett,A. J. Shell, Chem. Rev. 1996, 96,
195; c) K. C. Nicolaou,T. Montagnon,S. A. Snyder,
Chem.
Commun. 2003,551; d) J. C. Wasilke,S. J. Obrey,R. T. Baker,
G. C. Bazan, Chem. Rev. 2005, 105,1001.
[2] For general reviews,see: a) R. Noyori, Asymmetric Catalysis in
Organic Synthesis,Wiley,New York, 1994; b) Comprehensive
Asymmetric Catalysis (Eds.: E. N. Jacobsen,A. Pflatz,H.
Yamamoto),Springer,New York, 1999; c) I. Ojima,Catalytic
Asymmetric Synthesis,2nd ed.,Wiley,New York, 2000.
[3] a) A. J. Blackman,C. Li,D. C. R. Hockless,B. H. Skelton,
Tetrahedron 1993, 49,8645; b) A. J. Blackman,C. Li, Aust. J.
Chem. 1994, 47,1355; c) A. J. Blackman,C. Li, Aust. J. Chem.
1995, 48,955.
[4] a) A. D. Patil,A. J. Freyer,R. Reichwein,B. Carte,L. B. Killmer,
L. Faucette,R. K. Johnson,D. J. Faulkner,
Tetrahedron Lett.
1997, 38,363; b) S. Dutta,H. Abe,S. Aoyagi,C. Kibayashi,K. S.
Gates, J. Am. Chem. Soc. 2005, 127,15004.
[5] M. F. Raub,J. H. Cardellina,M. I. Choudhary,C.-Z. Ni,J.
Clardy,M. C. Alley, J. Am. Chem. Soc. 1991, 113,3178.
[6] For a review of the synthesis of cylindricines,see: J. Liu,R. P.
Hsung, ChemTracts 2005, 18,321.
[7] a) G. A. Molander,M. Ronn, J. Org. Chem. 1999, 64,5183;
b) B. M. Trost,M. T. Rudd, Org. Lett. 2003, 5,4599; c) S. Canesi,
D. Bouchu,M. A. Ciufolini, Angew. Chem. 2004, 116,4436;
Angew. Chem. Int. Ed. 2004, 43,4336; d) T. Arai,H. Abe,S.
Aoyagi,C. Kibayashi, Tetrahedron Lett. 2004, 45,5921; e) J. Liu,
R. P. Hsung,S. D. Peter, Org. Lett. 2004, 6,3989.
[8] a) T. Shibuguchi,Y. Fukuta,Y. Akachi,A. Sekine,T. Ohshima,
M. Shibasaki, Tetrahedron Lett. 2002, 43,9539; b) T. Ohshima,T.
Shibuguchi,Y. Fukuta,M. Shibasaki, Tetrahedron 2004, 60,7743;
c) A. Okada,T. Shibuguchi,T. Ohshima,H. Masu,K. Yama-
guchi,M. Shibasaki, Angew. Chem. 2005, 117,4640; Angew.
Chem. Int. Ed. 2005, 44,4564.
[9] For recent reviews of asymmetric phase-transfer catalysis (PTC)
reactions,see: a) K. Maruoka,T. Ooi, Chem. Rev. 2003, 103,
3013; b) M. J. OꢀDonnell, Acc. Chem. Res. 2004, 37,506; c) B.
Lygo,B. I. Andrews, Acc. Chem. Res. 2004, 37,518.
[10] For the catalytic asymmetric phase-transfer Michael reaction of
the glycine Schiff base,see: a) E. J. Corey,M. C. Noe,F. Xu,
Tetrahedron Lett. 1998, 39,5347; b) M. J. OꢀDonnell,F. Delgado,
E. Dominguez,J. de Blas,W. L. Scott, Tetrahedron: Asymmetry
2001, 12,821; c) S. Arai,R. Tsuji,A. Nishida, Tetrahedron Lett.
2002, 43,9535; d) T. Akiyama,M. Hara,K. Fuchibe,S.
Sakamoto,K. Yamaguchi, Chem. Commun. 2003,1734; e) B.
Lygo,B. Albutt,E. H. M. Kirton, Tetrahedron Lett. 2005, 46,
4461; f) P. V. Ramachandran,S. Madhi,L. Bland-Berry,M. V. R.
Reddy,M. J. OꢀDonnell, J. Am. Chem. Soc. 2005, 127,13450.
[11] a) K. M. Werner,J. M. de los Santos,S. M. Weinreb,M. Shang, J.
Org. Chem. 1999, 64,8263; b) J. J. Swidorski,J. Wang,R. P.
Hsung, Org. Lett. 2006, 8,777.
[12] a) K. Ishizumi,K. Koga,S. Yamada, Chem. Pharm. Bull. 1968,
16,492; b) G. Kokotos, Synthesis 1990,299.
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www.angewandte.org
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