Entry to heterocycles based on indium-catalyzed Conia-ene reactions: Asymmetric synthesis of (-)-salinosporamide A

Article abstract of DOI:10.1002/anie.200801967

Conica can: The In(OTf)₃-catalyzed cyclization of nitrogen- and oxygen-tethered acetylenic malonic esters gives five- to seven-membered heterocycles in moderate to excellent yields (see scheme; Tf = trifluoromethanesulfonyl). The asymmetric synthesis of (-)-salinosporamide A illustrates the synthetic utility of the method. (Chemical Equation Presented).

Full text of DOI:10.1002/anie.200801967

Communications
DOI: 10.1002/anie.200801967
Heterocycle Synthesis
Entry to Heterocycles Based on Indium-Catalyzed Conia-Ene
Reactions: Asymmetric Synthesis of (À)-Salinosporamide A**
Keisuske Takahashi, Michiko Midori, Kei Kawano, Jun Ishihara, and Susumi Hatakeyama*
The importance of nitrogen-containing heterocycles as drugs
and other chemical entities continue to inspire the develop-
ment of tactical methods for their synthesis. In connection
with a project directed towards the synthesis of intriguing
natural products[1] having a highly functionalized pyrrolidi-
none core, such as salinosporamide A, lactacyctin,[2] and
oxazolomycins,[3] we became interested in developing a novel
approach which relied upon the Conia-ene reaction of
amidomalonate 1 to give pyrrolidinone 3 via 2 (Scheme 1).
effectively catalyze the cyclization reaction to give 3a in
97% yield (Table 1, entries 1–3). The In(OTf)3-catalyzed
reaction was also applicable to nonterminal alkynes
(Table 1, entries 5–8). It should be highlighted that the
cyclization proceeded with complete E selectivity and with-
out racemization, even at higher temperatures. Addition of an
equimolecular amount of DBU relative to In(OTf)3 markedly
accelerated the reaction, (Table 1, entries 3–8) and in partic-
ular resulted in better yields for the reactions of nonterminal
alkynes 1b and 1c. Importantly, no endo cyclization and no
isomerization of the olefinic double bond (from the b,g- to the
a,b-position) were observed. Treatment of 1d with In(OTf)3
or In(OTf)3/DBU did not promote the cyclization at all
(Table 1, entries 9 and 10), thus suggesting that a malonyl
functionality is vital for this cyclization to occur. This
structural requirement and the E selectivity observed for 1b
and 1c lead us to propose a catalytic cycle involving
carbometalation of indium enolate 4 and proton exchange
between alkenylindium 5 and 1 to produce (E)-3 and
regenerate 4 (Scheme 2).[13]
Scheme 1. An approach to preparation of pyrrolidinones by the Conia-
ene reaction.
Recently, in place of the original thermal Conia-ene reac-
tion,[4] a number of metal-catalyzed reactions that are carried
out under mild conditions have been devised for the
preparation of carbocycles[5,6] and heterocycles,[7,8] although
the latter are largely limited to 3-methylene pyrrolidines and
tetrahydrofurans. However, it was unknown whether metal-
catalyzed versions of the Conia-ene reaction would be
applicable to our envisaged transformation (Scheme 1).
Herein, we report a new route to pyrrolidinones and other
heterocycles based on the indium-catalyzed Conia-ene-type
cyclization of nitrogen- and oxygen-tethered acetylenic
malonic esters. We also demonstrate the utility of this reaction
by its application to the synthesis of (À)-salinosporamide A, a
highly potent 20S proteasome inhibitor produced by the
marine actinomycete Salinispora tropica.[9–12]
Table 2shows the substrate scope for the In(OTf) /DBU
method. Gratifyingly, this method was found to be applicable
3
Table 1: Cyclization of amidomalonates 1 to give pyrrolidinones 3.
Entry Substrate
Method[a] t [h] Product[b,c]
Yield [%][d]
1
2
3
4
A
B
C
D
24
0.8
1
0
19
97
90
0.5
5
6
C
D
2.5
1
70
80
7
8
C
D
4
1
48
69
We examined AuI-,[5a] NiII-,[5c] and InIII-catalyzed[5f,6]
reactions of 1a (Table 1). In(OTf)3 was found to most
9
10
C
D
5
4
0[e]
0[f]
[*] K. Takahashi, M. Midori, K. Kawano, Dr. J. Ishihara,
Prof. Dr. S. Hatakeyama
Graduate School of Biomedical Sciences
Nagasaki University
1-14 Bnkyo-machi, Nagasaki 852-8521 (Japan)
Fax: (+81)95-819-2426
[a] Method A: [AuCl(PPh3)] (5 mol%), AgOTf (5 mol%), CH2Cl2, RT.
Method B: [Ni(acac)2] (10 mol%), Yb(OTf)3 (7 mol%), 1,4-dioxane,
508C. Method C: In(OTf)3 (5 mol%), toluene, reflux. Method D: In-
(OTf)3 (5 mol%), DBU (5 mol%), toluene, reflux. acac=acetylaceto-
nate, DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, PMB=para-methoxy-
benzyl, Tf=trifluoromethanesulfonyl. [b] The configurations of 3b and
3c were determined by NOESY spectroscopy. [c] The enantiomeric
purities of 1c and 3c were determined by HPLC on a chiral stationary
phase. [d] Yield of isolated products. [e] The corresponding allene was
obtained in 15% yield. [f] Decomposed.
E-mail: susumi@nagasaki-u.ac.jp
[**] This work was partly supported by a Grant-in-Aid for Scientific
Research of 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://dx.doi.org/10.1002/anie.200801967.
6244
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 6244 –6246

Angewandte
Chemie
Scheme 3 illustrates the synthesis of salinosporamide A
and shows the synthetic utility of the above-mentioned
methodology. Our synthesis began with the preparation of
amide 11, a precursor of the key In(OTf)3-catalyzed cycliza-
tion, from the chiral propargyl alcohol 8.[14] According to the
procedure developed by Marshall,[15] 8 was converted into the
mesylate, which was then treated with (tert-butyldimethylsi-
lyloxy)acetaldehyde via the allenylzinc species to give 9 as a
Scheme 2. A plausible reaction mechanism.
to the synthesis of other five- to seven-membered hetero-
cycles such as piperidinone 7a, azepanone 7b, pyrrolidines 7c
and 7d, piperidine 7e, tetrahydroisoquinoline 7 f, tetrahydro-
furan 7g, and tetrahydropyran 7h in moderate to excellent
yields. In the case of carbamate 6c (Table 2, entry 3), the
reaction was rather sluggish possibly because of the tight
coordination of indium(III) to the benzyloxycarbonyl and the
ester groups. It should be stressed that even basic amines
cleanly underwent the cyclization (Table 2, entries 4–6).
Table 2: In(OTf)3-catalyzed cyclization of 6 to give 7.
Entry
Substrate
Reaction
Product
Yield [%][b]
conditions[a]
5 mol% cat.,
1 h
1
2
84
41
15 mol% cat.,
4 h
10 mol% cat.,
3 h
3
55 (74)[c]
5 mol% cat.,
5 h
Scheme 3. Synthesis of (À)-salinosporamide A: a) MsCl, Et3N, DMAP,
CH2Cl2, 08C, 95%; b) Pd(OAc)2, PPh3, Et2Zn; then TBSOCH2CHO,
THF, À78 to À208C, 63%; c) DDQ, CH2Cl2/H2O (10:1), 08C, 87%;
d) AcCl, 2,4,6-collidine, CH2Cl2, À788C, quant.; e) TBAF, THF, 08C,
92%; f) CrO3, HIO4, acetone, H2O, 08C; g) (COCl)2, DMF, CH2Cl2,
08C; then PMBNHCH(CO2Me)2, toluene, 75%; h) In(OTf)3 (5 mol%),
toluene, 1108C, 96%; i) Lipase PS, phosphate buffer, acetone, 358C,
89%; j) Dess–Martin periodinane, CH2Cl2, 88%; k) PhSeBr, AgBF4,
PhCH2OH, CH2Cl2, À20 to 08C, 85%; l) AIBN, (nBu)3SnH, toluene,
1008C, 83%; m) NaBH4, THF/EtOH, 88%; n) Dess–Martin period-
inane, CH2Cl2, 94%; o) cyclohex-2-enylzinc chloride, THF, À788C,
88%; p) CAN, aq MeCN, 08C, 83%; q) Na, liq. NH3, THF, À788C;
r) NaBH4, aq THF, 71% (over 2 steps); s) (Me2AlTeMe)2, toluene;
t) BOP-Cl, pyridine, CH2Cl2, 54% (over 2 steps); u) Ph3PCl2, pyridine,
77%. AIBN=2,2’-azobisisobutyronitrile, Bn=benzyl, BOP-Cl=bis(2-
oxo-3-oxazolidinyl)phosphinic chloride, CAN=ceric ammonium ni-
trate, DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone, DMAP=4-
dimethylaminopyridine, Ms=methanesulfonyl, TBAF=tetra-n-butylam-
monium fluoride, TBS=tert-butyldimethylsilyl.
4
5
93
93
5 mol% cat.,
3 h
10 mol% cat.,
14 h
6
7
8
71
74
75
5 mol% cat.,
2.5 h
5 mol% cat.,
6 h
[a] The reactions were carried out in toluene at reflux using In(OTf)3/
DBU (1:1) as the catalyst. [b] Yield of isolated products. [c] Yield was
calculated based on the consumed starting material.
Angew. Chem. Int. Ed. 2008, 47, 6244 –6246
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
6245

Communications
Pd0-catalyzed cyclization of an amidomalonate with an alkenyl
iodide.
[4] For a review, see: J. M. Conia, P. L. Percheg, Synthesis 1975, 1 –
19.
90:10 mixture of epimers.[16] Upon removal of the PMB group,
selective acetylation,[17] and desilylation, 9 afforded 10.
[18]
Exposure of 10 to CrO3 and HIO4
in aqueous acetone
gave the corresponding carboxylic acid, which was then
condensed with dimethyl 2-(4-methoxybenzylamino)malo-
nate[19] via the acid chloride. Surprisingly during purification
by column chromatography on silica gel amide 11 partially
underwent cyclization to give an inseparable 72:28 mixture of
11 and 12.[20] Treatment of this mixture with a catalytic
amount of In(OTf)3 in toluene at reflux led to complete
conversion of 11 into 12 to give an almost quantitative yield.
Notably in this particular case, significant loss of enantiomeric
purity of the substrate was not observed. As 12 was very labile
under basic conditions, the acetoxy group was hydrolyzed
under mild lipase-catalyzed reaction conditions to give
alcohol 13, which was then oxidized to aldehyde 14. For the
assembly of the C3 quaternary center, 14 was subjected to
acetal-mediated cationic cyclization as reported by Danishef-
sky and Endo.[10c] Thus, 14 was treated with phenylselenenyl
bromide and AgBF4 in the presence of benzyl alcohol to give
15 (d.r. 93:7 at C13) which, upon radical deselenenylation,
afforded 16. Reduction of 16 with NaBH4 resulted in excellent
discrimination of the geminal esters, and aldehyde 17 was
obtained as the sole product after oxidation with Dess–Martin
periodinane. Reaction of 17 with cyclohex-2-enylzinc chloride
under the protocol developed by Corey et al.[10a] yielded 18 as
a single stereoisomer. Removal of the PMB group of 18
afforded 19, which was subjected to reductive ring-opening of
the cyclic acetal to give known intermediate 20.[10a] Finally,
upon dealkylative cleavage of the methyl ester promoted by
(Me2AlTeMe)2,[11a,21] b-lactonization, and chlorination, 20
furnished (À)-salinosporamide A. The specific rotation, melt-
ing point, and spectroscopic properties of the synthesized
natural product were in full accordance with the reported
data.[9]
[5] a) J. J. Kennedy-Smith, S. T. Staben, F. D. Toste, J. Am. Chem.
Soc. 2004, 126, 4526 – 4527; b) S. T. Staben, J. J. Kennedy-Smith,
F. D. Toste, Angew. Chem. 2004, 116, 5464 – 5466; Angew. Chem.
Int. Ed. 2004, 43, 5350 – 5352; c) Q. Gao, B.-F. Zheng, J. H. Li, D.
Yang, Org. Lett. 2005, 7, 2185 – 2188; d) A. Ochida, H. Ito, M.
Sawamura, J. Am. Chem. Soc. 2006, 128, 16486 – 16487; e) B. K.
Corkey, F. D. Toste, J. Am. Chem. Soc. 2007, 129, 2764 – 2765;
f) H. Tsuji, K. Yamagata, Y. Itoh, K. Endo, M. Nakamura, E.
Nakamura, Angew. Chem. 2007, 119, 8206 – 8208; Angew. Chem.
Int. Ed. 2007, 46, 8060 – 8062, and references therein.
[6] For an intermolecular version of the Conia-ene reaction, see: K.
Endo, T. Hatakeyama, M. Nakamura, E. Nakamura, J. Am.
Chem. Soc. 2007, 129, 5264 – 5271, and references therein.
[7] For related metal-catalyzed cyclization reactions that produce 3-
methylene pyrrolidines and tetrahydrofurans, see: a) X. Marat,
N. Monteiro, G. Balme, Synlett 1997, 845 – 847; b) B. Clique, N.
Monteiro, G. Balme, Tetrahedron Lett. 1999, 40, 1301 – 1304;
c) M. Cavicchioli, X. Marat, N. Monteiro, B. Hartmann, G.
Balme, Tetrahedron Lett. 2002, 43, 2609 – 2611; d) M. Nakamura,
C. Liang, E. Nakamura, Org. Lett. 2004, 6, 2015 – 2017; e) S.
Morikawa, S. Yamazaki, Y. Furusaki, N. Amano, K. Zenke, K.
Kakiuchi, J. Org. Chem. 2006, 71, 3540 – 3544.
[8] For related metal-catalyzed cyclization reactions that produce
lactams, see: a) E. C. Minnihan, S. L. Colletti, F. D. Toste, H. C.
Shen, J. Org. Chem. 2007, 72, 6287 – 6289; b) C.-Y. Zhou, C.-M.
Che, J. Am. Chem. Soc. 2007, 129, 5828 – 5829.
[9] Isolation: R. H. Feling, G. O. Buchanan, T. J. Mincer, C. A.
Kauffman, P. R. Jensen, W. Fenical, Angew. Chem. 2003, 115,
369 – 371; Angew. Chem. Int. Ed. 2003, 42, 355 – 357.
[10] Total synthesis: a) E. J. Corey, P. Saravanan, L. R. Reddy, J. Am.
Chem. Soc. 2004, 126, 6230 – 6231; b) L. R. Reddy, J.-F. Fournier,
B. V. S. Reddy, E. J. Corey, Org. Lett. 2005, 7, 2699 – 2701; c) S. J.
Danishefsky, A. Endo, J. Am. Chem. Soc. 2005, 127, 8298 – 8299;
d) T. Ling, V. R. Macherla, R. R. Manam, K. A. McArthur,
B. C. M. Potts, Org. Lett. 2007, 9, 2289 – 2292.
[11] Racemic synthesis: a) N. P. Mulholland, G. Pattenden, I. A. S.
Walters, Org. Biomol. Chem. 2006, 4, 2845 – 2846; b) G. Ma, H.
Nguyen, D. Romo, Org. Lett. 2007, 9, 2143 – 2146.
[12] Formal synthesis: V. Caubert, J. Masse, P. Retailleau, N.
Langlois, Tetrahedron Lett. 2007, 48, 381 – 384.
[13] This follows the reaction mechanism for the related intermo-
lecular In(OTf)3-catalyzed reaction proposed by Nakamura
et al., see Ref. [6].
[14] Y. Kiyotsuka, J. Igarashi, Y. Kobayashi, Tetrahedron Lett. 2002,
43, 2725 – 2729.
In conclusion, the work presented here provides a new
entry to pyrrolidinones and other heterocycles. The key
In(OTf)3-catalyzed reaction features broad applicability,
atom-economical efficiency, and operational simplicity. The
synthesis of (À)-salinosporamide A illustrates the power of
this newly developed methodology for natural product syn-
thesis.
[15] J. A. Marshall, J. Org. Chem. 2007, 72, 8153 – 8166, and
references therein.
[16] The enantiomeric purities for each epimer of this mixture were
determined by HPLC on a chiral stationary phase and were both
93% ee.
[17] K. Ishihara, H. Kurihara, H. Yamamoto, J. Org. Chem. 1993, 58,
3791 – 3793.
[18] M. A. Kinsella, V. J. Kalish, S. M. Weinreb, J. Org. Chem. 1990,
55, 105 – 110.
[19] S. Husinec, I. Juranic, A. Llobera, A. E. A. Porter, Synthesis
1988, 721 – 723.
[20] The enantiomeric purity (90% ee) of 12 suggested production by
a silica gel promoted Conia-ene reaction rather than cyclization
through the corresponding achiral allenylamide.
Received: April 26, 2008
Published online: July 4, 2008
Keywords: Conia-ene reaction · cyclization · heterocycles ·
.
indium · synthetic methods
[1] For a review, see: M. Shibasaki, M. Kanai, N. Fukuda, Chem.
Asian J. 2007, 2, 20 – 38.
[2] H. Ooi, N. Ishibashi, Y. Iwabuchi, J. Ishihara, S. Hatakeyama, J.
Org. Chem. 2004, 69, 7765 – 7768.
[3] E. O. Onyango, J. Tsurumoto, N. Imai, K. Takahashi, J. Ishihara,
S. Hatakeyama, Angew. Chem. 2007, 119, 6823 – 6825; Angew.
Chem. Int. Ed. 2007, 46, 6703 – 6705; in this synthesis, we
prepared the compound of general structure 3 by intramolecular
[21] B. V. S. Reddy, L. R. Reddy, E. J. Corey, Tetrahedron Lett. 2005,
46, 4589 – 4593.
6246 www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 6244 –6246