Niobium-catalyzed highly enantioselective aza-diels-alder reactions

Article abstract of DOI:10.1002/adsc.200700615

Niobium-based chiral Lewis acid was found to be highly effective catalyst for aza-Diels-Alder reactions of imines with Danishefsky's dienes. The reactions proceed in high yield with high enantioselectivity for both aromatic and aliphatic imines. The developed methodology was applied to total synthesis of (+)-anabasine.

Full text of DOI:10.1002/adsc.200700615

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DOI: 10.1002/adsc.200700615
Niobium-Catalyzed Highly Enantioselective Aza-Diels–Alder
Reactions
a
a
a
a
ˇ
Vµclav Jurcík, Kenzo Arai, Matthew M. Salter, Yasuhiro Yamashita,
and Shu¯ Kobayashia,*
Department of Chemistry, School of Science and Graduate School of Pharmaceutical Sciences, The University of Tokyo,
The HFRE Division, ERATO, Japan Science Technology Agency (JST), Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax : (+81)-3-5684-0634; e-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
a
Received: December 27, 2007; Revised: January 19, 2008; Published online: March 17, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Niobium-based chiral Lewis acid was
found to be highly effective catalyst for aza-Diels–
Alder reactions of imines with Danishefskyꢀs
dienes. The reactions proceed in high yield with
high enantioselectivity for both aromatic and ali-
phatic imines. The developed methodology was ap-
plied to total synthesis of (+)-anabasine.
Keywords: anabasine; aza-Diels–Alder reaction;
Lewis acid; niobium
Figure 1. Tridentate ligand and proposed catalyst structure.
We have recently developed a highly functionalized
chiral Nb(V) catalyst system 1 (Figure 1) generated
from tridentate ligand 2 and related systems as cata-
The enantioselective aza-Diels–Alder reactions of lysts for Mannich reactions[10] and the desymmetriza-
Danishefskyꢁs diene with imines[1] represent a useful tion of meso-epoxides and meso-aziridines with ani-
route to chiral piperidine-enones, which themselves line nucleophiles.[11] These catalysts are characterized
are important intermediates in the synthesis of highly not only by their ability to activate both oxygen-cen-
functionalized piperidines.[2] Although remarkable tered and nitrogen-centered electrophiles, but also by
progress has been made in the field of Lewis acid-cat- their ability to distinguish between small steric differ-
alyzed Diels–Alder reactions in recent years,[3] in the ences in substrates arising from their well defined
case of the aza-Diels–Alder reaction, an additional asymmetric environments, which are believed to be
hurdle that must be overcome is the tendency of the due to a highly organized dinuclear bridged structure.
Lewis acid to bind to the nucleophilic nitrogen atom We sought to investigate the chemical scope of this
of the reactants or product, leading to catalyst deacti- catalyst, and herein we report the first enantioselec-
vation and low catalyst turnover, which makes the tive aza-Diels–Alder reaction catalyzed by a niobium
catalytic reaction difficult. Indeed, early attempts to Lewis acid.
catalyze aza-Diels–Alder reactions were plagued by
this problem, which led to the requirement for stoi- Nb
We initially prepared the catalyst from ligand 2 and
ACHTREUNG
chiometric use of catalyst/activator in some instan- N-methylimidazole (NMI) for 3 h at room tempera-
ces.[4] We have previously reported the first truly cata- ture in dichloromethane (DCM). Gratifyingly we dis-
lytic enantioselective aza-Diels–Alder reaction of covered that the catalyst prepared under these condi-
imines with Danishefskyꢁs diene using catalyst sys- tions efficiently promoted the reaction of Danishef-
tems based on complexes of substituted 2,2’-binaph- skyꢁs diene 3a[12] with imine 4a, where at À208C for
thol (BINOL) and Zr(IV).[5] Some other catalyst sys- 36 h, and following protic work-up the corresponding
tems for the aza-Diels–Alder reactions of Danishef- piperidine-enone 5a was isolated in 76% yield with
skyꢁs diene based on Cu,[6] Ag[7] and Zn[8] as well as 81% ee (Table 1, entry 1). The tert-butyl-substituted
organocatalytic versions[9] of these reactions have diene 3b, also reacted smoothly giving 5a in 80%
been reported.
yield and 72% ee (entry 2). The absolute configura-
Adv. Synth. Catal. 2008, 350, 647 – 651
ꢂ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
647

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Vµclav Jurcík et al.
COMMUNICATIONS
Table 1. Effect of solvents.
Entry
Diene
Conc. [M]
Solvent
Nbsource
t (h)
Product 5a
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
3a
3b
3a
3a
3b
3b
3b
0.2
0.2
0.2
0.1
0.1
0.1
0.1
DCM
DCM
Nb
Nb
Nb
Nb
Nb
Nb
Nb
U
36
36
48
48
48
48
48
76
80
84
81
79
84
63
81
72
94
96
96
70
64
PhMe/DCM[c]
PhMe/DCM[c]
PhMe/DCM[c]
PhMe/DCM[c]
PhMe/DCM[c]
[a]
Isolated yield.
[b]
[c]
Determined by chiral HPLC. The absolute configuration assigned by X-ray analysis of the camphanic ester.
PhMe/DCM=1/1.
tion was established as R by reference to the single dilute conditions, we were able to obtain 5a in 81%
crystal X-ray diffraction analysis of the corresponding yield and slightly improved ee (96%) (entry 4). Simi-
camphanic ester.[13]
lar results were obtained with 3b (entry 5). We next
Encouraged by these results we next set about opti- probed the effect of niobium sources from which cata-
mizing the conditions for catalyst generation. After lyst may be generated, but soon discovered that the
careful examination, we found catalyst generation in use of Nb
N
N
toluene at 608C for 3 h, followed by addition of the tion product with significantly lower enantioselectivity
substrates 3a and 4a in DCM at À208C gave the cor- (entries 6 and 7).
responding product in 84% yield with 94% ee
We next turned our attention to the effect of desic-
(entry 3). By performing the reaction under more cants and catalyst loadings. A range of experiments
Table 2. Effect of loadings and desiccants on the Nbcatalyzed aza-Diels–Alder reaction.
Entry
4a [mmol]
Cat. x [mol%][a]
MS [mg]
Product 5a
Yield [%][b]
ee [%][c]
1
0.3
0.3
0.3
0.6
0.6
0.3
0.3
10[d]
5
5
2.5
2.5
5
3Š (50)
3Š (50)
3Š (25)
3Š (25)
3Š (12.5)
4Š (25)
5Š (25)
81
70
82
67
59
77
83
96
84
96
93
92
96
86
2[e]
3
4
5
6
7
5
[a]
0.015 mmol catalyst used unless otherwise stated.
Isolated yield.
Determined by chiral HPLC.
0.03 mmol catalyst used.
[b]
[c]
[d]
[e]
Reaction carried out at 0.2 M.
648
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ꢂ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 647 – 651

Niobium-Catalyzed Highly Enantioselective Aza-Diels–Alder Reactions
COMMUNICATIONS
revealed that the ratio of the substrate to molecular of the reaction with respect to the imine fragment.
sieves (MS) exerted a profound influence on the effi- Reactions proceed smoothly with aromatic imines
ciency of the reaction. For example, in the reaction (Table 3, entries 1 and 2), and those bearing electron-
using 10 mol% catalyst (0.03 mmol) with 50 mg 3Š donating (Table 3, entry 3) and electron withdrawing
MS the yield and ee were 81% and 96% respectively groups (Table 3 , entries 4 and 5), as well as heteroar-
(Table 2, entry 1). However, reducing the catalyst omatic imines (entry 6). To our delight, the reactions
loading to 5 mol% (0.015 mmol) whilst maintaining of aliphatic imines generated in situ also proceeded in
the amount of 3Š MS at 50 mg led to a noticeable good yields with high enantioselectivities (entries 7–
decrease in both yield and selectivity (70%, 84%, 9).
entry 2). Pleasingly, we discovered that by reducing
The phenolic OH group ortho to the nitrogen atom
the amount of molecular sieves to 25 mg and using is necessary for high yields and selectivities. When the
0.015 mmol catalyst (5 mol%), (i.e., the same ratio of OH group was substituted by a methoxy group, the
MS to the catalyst to that of entry 1), both yield and reaction barely turned over and the piperidine-enone
selectivity were restored to the levels observed with was formed in very low yield and enantiomeric excess
10 mol% catalyst loading (82% and 96%, respectively, (9%, 34% ee). The ortho-hydroxyphenyl group can
entry 3). Reducing the catalyst loading still further to be converted to the o-methoxyphenyl (OMP) group,
2.5 mol% (0.015 mmol on an overall scale of a common nitrogen protecting.
0.6 mmol) with 25 mg 3Š MS resulted in a drop in
To demonstrate the applicability of the developed
yield to 67% although the product was still obtained methodology, we have synthesized the minor nicotine
in very high enantioselectivity (entry 4). Cutting the alkaloid (+)-anabasine (Scheme 1). First, the aza-
amount of molecular sieves further to 12.5 mg versus Diels–Alder product (5f) was transformed to the cor-
0.015 mmol of catalyst had no positive effect, as the responding methyl ether using methyl iodide/NaH in
yield dropped still further although the ee was main- THF at 08C. After reduction using L-Selectride and
tained (92%). Interestingly, use of other types of MS free radical deoxygenation, the OMP protecting
in the reaction (4Š, 5Š) in the ratio 25 mg/ group was removed using CAN, giving the (+)-anaba-
0.015 mmol also permitted the generation of the de- sine as a single enantiomer.
sired product with excellent enantioselectivity al-
though with no advantage in yield compared with the tal X-ray diffraction data,[10] we tentatively assume a
procedure employing 3Š MS. transition state for the reaction in which the imine is
Based on several observations as well as single crys-
Having established optimum conditions for the re- coordinated to niobium in a bidentate fashion displac-
action we turned our attention to probing the scope ing the NMI and one alkoxy group from the catalyst.
Table 3. Scope of the Nb(V)-catalyzed asymmetric aza-Diels–Alder reaction.
Entry
Imine
Solvent
R1
R2
Product
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
4g
4h
4i[f,g]
PhMe/DCM (1:1)
PhMe/DCM (1:1)
PhMe/DCM (1:1)
PhMe/DCM (1:1)
PhMe/DCM (1:1)
PhMe/DCM (1:1)
DCM
2-OH-C6H4
2-OH-C6H4
2-OH-C6H4
2-OH-C6H4
2-OH-C6H4
2-OH-C6H4
2-OH-5-Me-C6H3
2-OH-5-Me-C6H3
2-OH-5-Me-C6H3
Ph
5a
5b
5c
5d
5e
5f
5g
5h
5i
81
89
90
94
89
74
67
63
47
96
92
94
99
91
92
90
92
90
1-Naphthyl
4-Me-C6H4
2-CF3-C6H4
2-Cl-C6H4
3-Pyridyl
c-Hex
7[c,d]
8[c,e]
9[c,e]
PhMe
PhMe
i-Pr
CH2CH(CH3)2
A
[a]
Isolated yield.
Determined by chiral HPLC.
[b]
[c]
[d]
[e]
[f]
Imine generated in situ by condensation of the corresponding aldehyde and o-amino-p-cresol in the presence of MgSO4.
4Š MS used instead of MgSO4.
Reaction carried out at 0 8C.
Imine added over 25 h.
[g]
Reaction time 96 h.
Adv. Synth. Catal. 2008, 350, 647 – 651
ꢂ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
649

ˇ
Vµclav Jurcík et al.
COMMUNICATIONS
Scheme 1. Synthesis of (+)-anabasine.
ture was purified by preparative TLC (hexane/EtOAc, 1/1)
to give the product as a solid.
The rigid stereochemical environment generated by
the ligand field then forces attack by the Danishef-
skyꢁs diene approaching from the re face to give the
piperidine-enone product with the observed R enan-
tiomer with very high stereofidelity.
In conclusion, we have developed highly enantiose-
lective aza-Diels–Alder reactions of imines with Dani-
shefskyꢁs diene, catalyzed by a chiral Nb(V) Lewis
acid. It should be noted that high yields and enantio-
selectivities were obtained using both aliphatic and ar-
omatic imines and that the reaction was applied to
the synthesis of (+)-anabasine. Further studies aimed
at broadening the scope of the reaction and elucidat-
ing the precise mechanism of the reaction are current-
ly underway in our laboratories.
Three-Component Aza-Diels–Alder Reaction
The reaction was conducted in the same manner as de-
scribed in the typical procedure. An imine was generated in
DCM or PhMe (1.0 mL) from 2-amino-p-cresol (0.30 mmol)
and an aldehyde (0.30 mmol) using MgSO4 or 4Š MS as a
drying agent. After 2 h at room temperature, MgSO4 was fil-
tered off by inverse filtration using cotton wool on the top
of a syringe needle, and the solution of the imine was added
to the cooled solution of the catalyst. Another portion of
the solvent (0.5 mL) was used to wash the MgSO4 and then
was added to the reaction mixture. The reaction was
quenched and worked up in the same manner as in the typi-
cal procedure.
Experimental Section
Acknowledgements
Typical Procedure for the Aza-Diels–Alder Reaction
Catalyzed by Niobium
This work was partially supported by a Grant-in-Aid for Sci-
ence Research from the Japan Society for the Promotion of
Science (JSPS). V. J. thanks the JSPS for postdoctoral fellow-
ship.
To a solution of ligand 2 (7.8 mg, 0.018 mmol) in PhMe
(1.0 mL), NMI (1.5 mL, 0.018 mmol) was added. After 5 mi-
nutes stirring, Nb
a solid with gentle stream of argon. A trace of Nb
which remained on the wall was washed with additional por-
ACHTREUNG
AHCTREUNG
tion of PhMe (0.5 mL). The reaction mixture was heated to References
608C for 3 h. After cooling to room temperature, molecular
sieves 3Š (25 mg) were added. The catalyst solution was
cooled to appropriate temperature and a solution of imine
(0.3 mmol) in DCM (1.5 mL) was added, followed by diene
(0.4 mmol, 100 mL). After 48 h, the reaction mixture was
quenched by addition of saturated NaHCO3 solution (3 mL)
and the resulting mixture was extracted with EtOAc (4”
5 mL). The combined organic fractions were dried over
Na2SO4 and the solvent was removed under reduced pres-
sure. The crude product was cooled to 08C and treated with
0.1M HCl in THF (10 mL). After 15 min., the mixture was
basified by addition of satutated NaHCO3 solution and the
product was extracted with EtOAc (4”5 mL). The com-
bined organic fractions were dried over Na2SO4 and the sol-
vent was removed under reduced pressure. The crude mix-
[1] a) K. A. Jørgensen, Angew. Chem. Int. Ed. 2000, 39,
3558; b) S. Kobayashi, K. A. Jørgensen, Cycloaddition
Reactions in Organic Synthesis, Wiley-VCH, Weinheim,
2002, Chap. 5.
[2] D. L. Comins, D. H. LaMunyon, X. Chen, J. Org.
Chem. 1997, 62, 8182.
[3] E. J. Corey, Angew. Chem. Int. Ed. 2002, 41, 1650.
[4] a) H. Yamamoto, K. Hattori, J. Org. Chem. 1992, 57,
3264; b) K. Hattori, H. Yamamoto, Tetrahedron 1993,
49, 1749; c) K. Ishihara, M. Miyata, K. Hattori, T.
Tada, H. Yamamoto, J. Am. Chem. Soc. 1994, 116,
10520.
[5] a) S. Kobayashi, S. Komiyama, H. Ishitani, Angew.
Chem. Int. Ed. 1998, 37, 979; b) S. Kobayashi, K. Kusa-
650
asc.wiley-vch.de
ꢂ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 647 – 651

Niobium-Catalyzed Highly Enantioselective Aza-Diels–Alder Reactions
COMMUNICATIONS
kabe, S. Komiyama, H. Ishitani, J. Org. Chem. 1999, 64,
4220.
H. Morita, K. Fuchibe, Synlett 2006, 141; c) T. Akiya-
ma, H. Morita, K. Fuchibe, J. Am. Chem. Soc. 2006,
128, 13070; d) C. A. Newman, J. C. Antilla, P. Chen,
A. V. Predeus, L. Fielding, W. D. Wulff , J. Am. Chem.
Soc. 2007, 129, 7216.
[6] a) S. Yao, M. Johannsen, R. G. Hazell, K. A. Jørgensen.
Angew. Chem. Int. Ed. 1998, 37, 3121; b) S. Yao, M. Jo-
hannsen, S. Saaby, R. G. Hazell, K. A. Jørgensen,
Chem. Eur. J. 2000, 6, 2435; c) O. G. Mancheno, R. G.
Arrayas, J. C. Carretero, J. Am. Chem. Soc. 2004, 126,
456.
[7] J. S. Josephsohn, M. L. Snapper, A. H. Hoveyda, J. Am.
Chem. Soc. 2003, 125, 4018.
[8] a) S. Guillarme, A. Whiting, Synlett 2004, 711; b) L. Di
Bari, S. Guillarme. J. Hanan, A. P. Henderson, J. A. K.
Howard, G. Pescitelli, M. R. Probert, P. Salvadori, A.
Whiting, Eur. J. Org. Chem. 2007, 5771.
[10] S. Kobayashi, K. Arai, H. Shimizu, Y. Ihori, H. Ishitani,
Y. Yamashita, Angew. Chem. Int. Ed. 2005, 44, 761.
[11] a) K. Arai, M. M. Salter, Y. Yamashita, S. Kobayashi,
Angew. Chem. Int. Ed. 2007, 46, 955; b) K. Arai, S. Lu-
carini, M. M. Salter, K. Ohta, Y. Yamashita, S. Kobaya-
shi, J. Am. Chem. Soc. 2007, 129, 8103.
[12] a) S. Danishefsky, K. Kitahara, J. Am. Chem. Soc. 1974,
96, 7807; b) M. Bednarski, C. Maring, S. Danishefsky,
Tetrahedron Lett. 1983, 24, 3451.
[9] a) J. Itoh, K. Fuchibe, T. Akiyama, Angew. Chem. Int.
[13] See Supporting Information.
Ed. 2006, 45, 4796; b) T. Akiyama, Y. Tamura, J. Itoh,
Adv. Synth. Catal. 2008, 350, 647 – 651
ꢂ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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