C O M M U N I C A T I O N S
Scheme 4. Elucidation of the Absolute Configuration
Scheme 3
crystallography (Scheme 4). Accordingly, ent-18e is (R)-configured
and 18e is (S)-configured. We assume that the absolute configura-
tions of compounds 18a-d,f-k corresponds to 18e.
Table 1. Highly Enantioselective Nazarov Cyclizations
In summary, we have described the first truly catalytic asym-
metric Nazarov reactions that proceed with high levels of enantio-
selectivity and in good yields. Although we cannot claim to have
achieved highly enantioselective electrocyclizations, we have
developed catalytic asymmetric proton-transfer reactions, a concept
that will be further explored in our laboratories. The application of
other chiral Lewis acids8 as well as substrates with different olefin
geometries and heteroatom substituents to asymmetric Nazarov
cyclizations is also being actively investigated in our laboratories.
entry
X
R
yielda (%)
ee (%)
a
b
c
d
eb
f
g
h
jb
k
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
O
Me
Et
65
75
70
70
88
94
76
65
65
80
85
92
93
94
95
97
76
87
72
91
n-Pr
n-Bu
i-Pr
t-Bu
Cy
Ph
i-Pr
t-Bu
Acknowledgment. We thank Dr. Frederick J. Hollander as well
as Dr. Allen G. Oliver for the crystal structure determination of
compound 19. Financial support by Glaxo Smith Kline, Eli Lilly,
and Merck & Co. is also gratefully acknowledged.
Supporting Information Available: Synthetic procedures and
spectroscopic data for compounds 17a-k, 18a-k, and 19 including
X-ray crystallographic data in CIF format. This material is available
of 19 has been deposited at the Cambridge Crystallographic Data Centre
(CCDC 238395).
O
a Isolated yield after silica gel column chromatography. b Reaction
performed at 0 °C (3 h).
temperature or below, alkoxy dienones 17a-k cleanly afforded
products 18a-k within 0.5-3 h (Table 1). Under these conditions,
racemization was not found to be a problem.
References
(1) (a) Habermas, K. L.; Denmark, S. E.; Jones, T. K. Org. React. (N.Y.)
1994, 45, 1-158. (b) Krohn, K. Org. Synth. Highlights 1991, 137-144.
(c) Santellirouvier, C.; Santelli, M. Synthesis 1983, 429-442. (d) Giese,
S.; Kastrup, L.; Stiens, D.; West F. G. Angew. Chem., Int. Ed. 2000, 39,
1970. (e) Tius, M. A. Acc. Chem. Res. 2003, 36, 284-290.
(2) For examples of Nazarov cyclizations with low catalyst loadings, see:
(a) Jones, T. K.; Denmark, S. E. HelV. Chim. Acta 1983, 66, 2377-2396.
(b) Giese, S., West. F. G. Tetrahedron 2000, 56, 10221-10228. (c)
References 3a and 3b. (d) References 5a and 5b.
(3) (a) Liang, G.; Gradl. S. N.; Trauner, D. Org. Lett. 2003, 5, 4931-4934.
Similar substrates have been investigated by Tius as well as Occhiato
and Prandi: (b) Bee, C.; Leclerc, E.; Tius, M. A. Org. Lett. 2003, 5,
4927-4930. (c) Occhiato, E. G.; Prandi, C.; Ferrali, A.; Guarna, A.;
Venturello, P. J. Org. Chem. 2003, 68, 9728-9241.
(4) Aggarwal, V. K.; Beffield, A. J. Org. Lett. 2003, 5, 5075-5078.
(5) (a) He, W.; Sun, X. F.; Frontier, A. J. J. Am. Chem. Soc. 2003, 125,
14278-14279. (b) Janka, M.; He, W.; Frontier, A. J.; Eisenberg, R. J.
Am. Chem. Soc. 2004, 126, 6846-6865.
(6) For the use of scandium-pybox complexes in asymmetric synthesis, see:
(a) Evans, D. A.; Scheidt, K. A.; Fandrick, K. R.; Lam, H. W.; Wu, J. J.
Am. Chem. Soc. 2003, 125, 10780-10781. (b) Evans, D. A.; Wu, J.;
Masse, C. E.; MacMillan, D. W. C. Org. Lett. 2002, 4, 3379-3382. (c)
Evans, D. A.; Masse, C. E.; Wu, J. Org. Lett. 2002 4, 3375-3378. (d)
Evans, D. A.; Sweeney, Z. K.; Rovis, T.; Tedrow, J. S. J. Am. Chem.
Soc. 2001, 123, 12095-12096. (e) Yang, D.; Yang, M.; Zhu, N.-Y. Org.
Lett. 2003, 5, 3749-3752. (f) Desimoni, G.; Faita, G.; Guala, M.; Pratelli,
C. J. Org. Chem 2003, 68, 7862-7866. (g) Suga, H.; Inoue, K.; Inoue,
S.; Kakehi A. J. Am. Chem. Soc. 2002, 124, 14836-14837.
With the exception of cyclohexyl derivative 17g, substrates
carrying bulky substituents in position 4, e.g. 17e,f and 17k, proved
to be most reactive and provided the highest levels of enantiose-
lectivity. For instance, tert-butyl-substituted dienone 17f gave the
corresponding cyclopentenone 18f in 94% yield and 97% ee. Even
phenyl-substituted cyclopentenone 18h was formed with relatively
high ee. By contrast, dioxenes 17j and 17k were found to cyclize
with slightly reduced enantioselectivities.
Notably, in the case of substrates 17, the only stereocenter formed
in the course of the 4π-electrocyclization is destroyed upon
deprotonation of the allylic cation (cf. 3 in Scheme 1). The absolute
configuration of the products is therefore established in the course
of the reprotonation of the dienolate intermediate (cf. 4) in position
4. The influence of the chiral ligand sphere surrounding the Lewis
acid, which is presumably bound to the substrates in a bidendate
fashion, should be greater in this position than at the termini of the
alkoxy dienone system. This may explain the higher levels of
enantioselectivity observed with substrates of type 17.
Several catalytic asymmetric proton-transfer reactions have been
described in the literature,7 including one that involves 1,4-addition
and diastereoselective protonation of a rhodium enolate.7e None of
these, however, proceeds with concomitant cyclization and all
require an external proton source.
The absolute configuration of the products 18 was investigated
using compound ent-18e as a representative. Diastereoselective
reduction of ent-18e, followed by esterification, gave camphanoyl
ester 19, whose relative configuration was established by X-ray
(7) (a) Yanagisawa, A., Yamamoto, H. In ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds; Springer:
Berlin, 1999; pp 1295-1306. (b) Hamashima, Y.; Somei, H.; Shimura,
Y.; Tamura, T.; Sodeoka, M. Org. Lett. 2004, 11, 1861-1864. (c) Emori,
E.; Arai, T.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1998, 120, 4043-
4044. (d) Nishimura, K.; Ono, M.; Nagaoka, Y.; Tomioka, K. Angew.
Chem., Int. Ed. 2001, 40, 440-442. (e) Navarre, L.; Darses, S.; Genet,
J.-P. Angew. Chem., Int. Ed. 2004, 43, 719-723.
(8) Kanemasa, S.; Oderaotoshi, Y.; Yamamoto, H.; Tanaka, J.; Wada, E.;
Curran, D. P. J. Am. Chem. Soc. 1998, 120, 3074-3088.
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