Synthesis of heterocycles using zirconinm-catalyzed asymmetric diene cyclization

Full text of DOI:10.1021/ja964462h

J. Am. Chem. Soc. 1997, 119, 7615-7616
7615
Synthesis of Heterocycles Using
Zirconium-Catalyzed Asymmetric Diene Cyclization
Yousuke Yamaura, Masaru Hyakutake, and Miwako Mori*
Faculty of Pharmaceutical Sciences
Hokkaido UniVersity, Sapporo 060, Japan
ReceiVed December 31, 1996
Zirconium-promoted cyclizations of enynes, dienes, and
diynes are useful in synthetic organic chemistry,1 and various
natural products have been synthesized using this procedure.2
Zirconium-catalyzed carbomagnesation and cyclization in the
presence of Grignard reagent have recently been reported.3 On
the basis of these results, asymmetric carbomagnesation,4a,b
carboalumination,4c and kinetic resolution4d have been reported
using a chiral zirconium complex.5 These studies prompted us
to develop a zirconium-catalyzed asymmetric diene cyclization
using chiral zirconium complex 1, as shown in Figure 1. For
this purpose, the stereochemistry of the ring junction of the
zirconacycle generated from the diene must be controlled. In
general, when a stoichiometric amount of zirconium complex
is used for cyclization, a thermodynamic zirconacycle is formed,
and in a zirconium-catalyzed cyclization using Grignard reagent,
a kinetic zirconacycle is formed.6 Here we report an asymmetric
synthesis of heterocycles using zirconium-catalyzed diene
cyclization.
Figure 1.
Scheme 1
Scheme 2
When a THF solution of 2 was refluxed with (R)-(EBTHI)-
ZrBINOL (1) (10 mol %) in the presence of Bu2Mg (8 equiv)
for 64 h, we obtained 3a and 3b in yields of 13 and 6%,
respectively,7 and the enantiomeric excess (ee) of the trans
isomer 3b8,9 was only 13% (Scheme 1).10 Surprisingly, when
diallylamine 4, which has a methyl group on the alkene, was
treated in a similar manner, it gave the cyclized product 58 in
(1) (a) Negishi, E.; Holms, S. J.; Tour, J. M.; Miller, J. A. J. Am. Chem.
Soc. 1985, 107, 2568. Negishi, E.; Holmes, S. J.; Tour, J. M.; Miller, J.
A.; Cederbaum, F. E.; Swanson, D. R.; Takahashi, T. J. Am. Chem. Soc.
1989, 111, 3336. (b) Nugent, W. A.; Calabrese, J. C. J. Am. Chem. Soc.
1984, 106, 6422.
(2) (a) Mori, M. ReViews on Hetero Atom Chemistry; Oae, S., Ed.;
MYU: Tokyo, 1993; Vol. 8, p 256. (b) RajanBabu, T. V.; Nugent, W. A.;
Taber, D. F.; Fagan. P. J. J. Am. Chem. Soc. 1988, 110, 7128. (c) Wender,
P. A.; McDonald, F. E. J. Am. Chem. Soc. 1990, 112, 4956. (d) Wender,
P. A.; McDonald, F. E. Tetrahedron Lett. 1990, 31, 3691. (e) Agnel, G.;
Negishi, E. J. Am. Chem. Soc. 1991, 113, 7424. (f) Agnel, G.; Owczarczyk,
Z.; Negishi, E. Tetrahedron Lett. 1992, 33, 1543. (g) Mori, M.; Uesaka,
N.; Shibasaki, M. J. Org. Chem. 1992, 57, 3519. Mori, M.; Uesaka, N.;
Saitoh, F.; Shibasaki, M. J. Org. Chem. 1994, 59, 5643. (h) Ito, H.; Ikeuchi,
Y.; Taguchi, T.; Hanzawa, Y. J. Am. Chem. Soc. 1994, 116, 5469.
(3) (a) Dzhemilev, U. M.; Vostrikova, O. S. J. Organomet. Chem. 1985,
285, 43. (b) Takahashi, T.; Seki, T.; Nitto, Y.; Saburi, M.; Rousset, C. J.;
Negishi, E. J. Am. Chem. Soc. 1991, 113, 6266. (c) Knight, K. S.;
Waymouth, R. M. J. Am. Chem. Soc. 1991, 113, 6268. (d) Hoveyda, A.
H.; Xu, Z. J. Am. Chem. Soc. 1991, 113, 5079.
(4) (a) Morken, J. P.; Didiuk, M. T.; Hoveyda, A. H. J. Am. Chem. Soc.
1993, 115, 6997. (b) Bell, L.; Whitby, R. J.; Jones, R. V. H.; Standen, M.
C. H. Tetrahedron Lett. 1996, 37, 7139. (c) Kondakov, D. Y.; Negishi, E.
J. Am. Chem. Soc. 1995, 117, 10771. Kondakov, D. Y.; Negishi, E. J.
Am. Chem. Soc. 1996, 118, 1577. (d) Morken, J. P.; Didiuk, M. T.; Visser,
M. S.; Hoveyda, A. H. J. Am. Chem. Soc. 1994, 116, 3123. Didiuk, M. T.;
Johannes, C. W.; Morken, J. P.; Hoveyda, A. H. J. Am. Chem. Soc. 1995,
117, 7097. Hoveyda, A. H.; Morken, J. P. Angew. Chem., Int. Ed. Engl.
1996, 35, 1262.
(5) (a) Wild, F. R. W. P.; Wasiucionek, M.; Huttner, G.; Brintzinger, H.
H. J. Organomet. Chem. 1985, 288, 63. (b) Collins, S.; Kuntz, B. A.;
Taylor, N. J.; Ward, D. G. J. Organomet. Chem. 1988, 342, 21. (c)
Grossman, R. B.; Davis, W. M.; Buchwald, S. L. J. Am. Chem. Soc. 1991,
113, 2321.
(6) (a) Mori, M.; Uesaka, N.; Saitoh, F.; Shibasaki, M. J. Org. Chem.
1994, 59, 5643. (b) Saitoh, F.; Mori, M.; Okamura, K.; Date, T. Tetrahedron
1995, 51, 4439.
(7) Negishi et al. reported that the cyclization of 2 using a stoichiometric
amount of Cp2ZrCl2 gave the trans isomer 3b. (a) Rousset, C. J.; Swanson,
D. R.; Lamaty, F.; Negishi, E. Tetrahedron Lett. 1989, 30, 5105. (b) Nugent,
W. A.; Taber, D. F. J. Am. Chem. Soc. 1989, 111, 6435.
84% yield with 61% ee after only 4.5 h of reflux in THF
(Scheme 2). As Grignard reagents, EtMgBr, iPrMgCl, iBuMgCl,
and BuMgCl did not give good results in this case. The
t
hydrolysis product 5 was obtained from both of the cis and trans
magnesium complexes, 6a and 6b, generated in this reaction.
Thus, the reaction mixture was treated with O2 and then with
10% HCl to give two products, 7a8,11 and 8a,8 in 36% yield
with 62% ee and 12% yield with 70% ee, respectively.
Interestingly, NOESY experiments with 7b and 8b indicated
that only zirconacycle 10 with a cis ring junction was formed
in this reaction, which means that the magnesium complexes
6a and 9 were formed from cis-zirconacycle 10 and Bu2Mg.
To establish a catalytic asymmetric cyclization using RMgX in
the presence of 1 (10 mol %), the reaction was carried out under
various conditions. The results are shown in Table 1. It was
quite interesting that only magnesium complex 9 was formed
from zirconacycle 10 and BuMgCl (runs 4-8). At higher
(10) Typical Procedure for the Zirconium-Catalyzed Asymmetric Diene
Cyclization: To a solution of (S)-(EBTHI)ZrBINOL (1) (127 mg, 0.199
mmol) and 4 (400 mg, 1.99 mmol) in THF (3.9 ml) was added BuMgCl
(1.89 M solution in THF, 2.1 ml, 3.97 mmol) at -78 °C. The solution
was stirred at the same temperature for 1 h and was refluxed for 14 h.
Then, an atmosphere of argon in the reaction vessel was changed to oxygen,
and the solution was stirred at room temperature for 2 h. To the solution
was added 10% HCl at 0 °C, and the resultant mixture was basified with
saturated aqueous NaHCO3. After the usual workup, the residue was
purified by column chromatography (AcOEt/MeOH ) 1:0, 10:1) to afford
316 mg (72%, 71% ee) of 7a as a pale yellow oil.
(8) The determinations of ees in the zirconium-catalyzed asymmetric
cyclizations were carried out by GC and HPLC analyses, and the detailed
procedures are described in the Supporting Information.
(11) Compound 7a was converted into methyl (S)-[(3S,4R)-3,4-dimethyl-
1-tosylpyrrolidine-3-carboxamide]phenylacetate, and its absolute configu-
ration was determined by a X-ray diffraction method.
(9) The absolute configuration of 3b was not determined.
S0002-7863(96)04462-9 CCC: $14.00 © 1997 American Chemical Society

7616 J. Am. Chem. Soc., Vol. 119, No. 32, 1997
Communications to the Editor
Table 2. Zirconium-Catalyzed Asymmetric Cyclizationa
Table 1. Reaction of 4 with RMgX in the Presence of (S)-1
Followed by Treatment with O2
7a
8a
RMgX
(equiv)
time
run
solvent temp
(h) yield ee yield ee
1
2
3
4
5
6
7
8
Bu2Mg (8)
Bu2Mg (8)
Bu2Mg (8)
BuMgCl (8)
BuMgCl (4)
BuMgCl (2)
THF
THF
Et2O
THF
THF
THF
reflux
rt
rt
4.5
71.5
88
36
24
18
79
54
21
72
16
62
54
44
61
71
78
71
86
12
2
27
70
46
46
reflux
9.5
reflux 24
reflux 24
reflux 14
BuMgCl (2)a THF
BuMgCl (4)
THPb 80 °C 36
a In all other cases, a 0.082 M solution of the substrate was used;
however, in this case, a 0.33 M solution was used. b THP tetrahydro-
pyran.
Scheme 3
Scheme 4. Possible Reaction Course
a A THF solution of diene, 1 (10 mol %), and BuMgCl (4 equiv)
was refluxed, and then the reaction mixture was treated with electro-
philes. The determinations of the relative configurations are described
in the Supporting Information. The absolute configurations were
assigned by analogy to 7a.
stage at which enantioselection occurs is not yet clear.15
Subsequently, we attempted to synthesize various heterocycles
using the zirconium-catalyzed asymmetric cyclization. The
results are shown in Table 2. Magnesium complexes generated
from dienes were treated with H3O+ or O2, and we could obtain
the pyrrolidine and piperidine derivatives 17, 19,8 and 228 and
spiro-compounds 248,16 and 268 with high ees. The diphenyl-
methyl group on nitrogen improved the yield of the cyclized
product.
These results indicate that a catalytic asymmetric diene
cyclization using a chiral zirconium complex was realized. In
this reaction, the substituent on the alkene carbon affects the
reaction course and five- and six-membered cyclized products
were obtained with high ees. Further studies are in progress.
temperature, the reaction gave good yields with higher ees (runs
1, 2, and 8), and with an excess of Grignard reagent, the reaction
gave decreased ees of the product (runs 4-6). As a result, when
a THF solution of 4 and BuMgCl (2 equiv) was refluxed in the
presence of 1 (10 mol %) for 14 h, the cyclized product 7a
with 71% ee was obtained in 72% yield (run 7).
If the enantioselection occurs at the stage of the formation
of zirconacycle, the same ee should be obtained when the
stoichiometric amount of (S)-(EBTHI)ZrBu2 is used for this
reaction. Thus, when a THF solution of compound 4 was
refluxed in the presence of a stoichiometric amount of (S)-
(EBTHI)ZrBu2 generated from 1 (1.15 equiv) and BuLi (2.3
equiv)12 for 4 h, the cyclized product 5 was obtained in 59%
yield, but 5 is almost racemic (9% ee) (Scheme 3).13 This result
indicates that enantioselection did not occur when zirconacycle
10 was formed from 4 and chiral zirconium complex 1.
On the basis of these results, the predicted reaction course
of 4 and BuMgCl in the presence of 1 is shown in Scheme 4.
The zirconacycles 10 and ent-10 are formed from 4 and (S)-
(EBTHI)ZrBu2 generated from 1 and BuMgCl, and the ring
junctions of zirconacycles 10 and ent-10 show cis stereochem-
istry.14 Notably, the ratio of the zirconacycles 10 and ent-10 is
almost 1:1 because the ee of the hydrolysis product 5 is only
9%. However, we obtained alcohol 7a with 86% ee (Table 1,
run 8). Thus, enantioselection should occur at the subsequent
steps, ate-complexation (step b) or transmetalation (step c).
Presumably, the formation of ate-complex 13 from zirconacycle
10 (and/or the formation of 14 from ate-complex 13) is faster
than that of ate-complex from diastereomer ent-10 (and/or that
of the magnesium complex of the diastereomer). However, the
Acknowledgment. We thank the Japan Society for the Promotion
of Science (JSPS) Research Fellowships for Young Scientists (to Y.Y.).
Supporting Information Available: Experimental and X-ray
crystallographic details (44 pages). See any current masthead page
for ordering and Internet access instructions.
JA964462H
(14) Compound 4 was treated with a stoichiometric amount of Cp2ZrBu2
generated from Cp2ZrCl2 and BuLi, followed by successive treatment with
carbon monoxide and iodine. After acid hydrolysis, bicyclic compound
11 was obtained in 54% yield as a single isomer. To determine the
stereochemistry of the ring junction, 11 was reduced with NaBH4 to give
alcohol 12 in 66% yield. The NOE experiment with 12 indicated that the
ring junction of 12 is cis.
(15) One explanation for why magnesium complex 14 was formed from
the ate complex 13 may involve steric release between the methyl group
and the Cp* group or the butyl group on ate-complex 13. Presumably, the
reaction rate for the cyclization of 4 is faster than that of 2 for the same
reason; the zirconacycle or ate-complex formed from 2 is more stable than
that formed from 4.
(12) Negishi, E.; Cederbaum, F. E.; Takahashi, T. Tetrahedron Lett. 1986,
27, 2829.
(13) The enantioselection of 5 obtained by a zirconium-promoted
asymmetric cyclization (a stoichiometric reaction) is same as that of 5
obtained by a zirconium-catalyzed asymmetric cyclization.
(16) Aza-spiro compound (24, R ) CH2Ph) was synthesized by
zirconium-promoted cyclization. Negishi, E.; Maye, J. P.; Choueiry, D.
Tetrahedron 1995, 51, 4447.