Cyclic 1,2-diketones as building blocks for asymmetric synthesis of cycloalkenones [8]

Full text of DOI:10.1021/ja000274m

J. Am. Chem. Soc. 2000, 122, 3785-3786
3785
Table 1. Selected Optimization Experimentsa
entry base catalyst mol % ligand % yieldb
Cyclic 1,2-Diketones as Building Blocks for
Asymmetric Synthesis of Cycloalkenones
% ee (er)c
1
2
3
4
NaH
NaH
None
None
5
5
5
1
4
5
5
5
77
55
76
99
-34d (33:67)
84 (92:8)
92 (96:4)
Barry M. Trost* and Gretchen M. Schroeder
95 (97.5:2.5)
Department of Chemistry, Stanford UniVersity
Stanford, California 94305-5080
a All reactions were performed in methylene chloride (0.2 M in
nucleophile) at room temperature using 1.1 equiv of 2a. b Isolated yield.
c Determined by chiral HPLC. d The negative sign indicates the opposite
chirality of product from the other entries.
ReceiVed January 25, 2000
Cyclic 1,2-diketones1 have found little use in organic synthesis.
However, their functionality offers much flexibility for further
structural variations. The fact that 3-substituted cyclic 1,2-
diketones exist as single tautomeric species raised the prospect
of an asymmetric synthesis of cycloalkenones as shown in eq 1.
pentenyl methyl carbonate (2a) to give the allylated product 3
using our standard ligand 46a (eq 2 and Table 1). While the yield
For such a scheme, nucleophiles must be shown to be capable of
participating in palladium-catalyzed allylic alkylations.2 Further-
more, the anticipated O-alkylated products must be capable of
good transfer of chirality to the C-alkylated products. We report
the realization of such a scheme based upon an asymmetric allylic
alkylation (AAA)-Claisen rearrangement3,4 protocol and the
development of a new lanthanide catalyst for the rearrangement.5
The first stage of the sequence requires the development of an
asymmetric O-alkylation. For this purpose, commercially available
3-methylcyclopentane-1,2-dione 1a was alkylated with 3-cyclo-
was fine, the ee was only 34% (entry 1). Tightening the pocket
by switching to the naphtho linker as in ligand 56b dramatically
increased the enantioselectivity to 84% ee (entry 2). Two
additional optimization experiments proved quite interesting. In
the first, removal of any exogeneous base further increased the
selectivity to 92% ee. In the second, lowering the catalyst loading
to 1% (no attempt to reduce this loading further was made) also
increased the selectivity to 95%.6 In this way, a nearly quantitative
yield of the O-alkylated product 3 of 95% ee was isolated.
Switching to the six-membered ring nucleophile 1b led to a more
sluggish reaction and required 40 °C but still gave an excellent
ee (96%). The six-membered ring electrophile 2b showed a
parallel trend (see eq 2).7
(1) For the synthesis of cyclic 1,2-diketones, see: (a) Hach, C. C.; Banks,
C. V.; Diehl, H. Organic Syntheses; John Wiley & Sons: New York, 1963;
Collect. Vol. IV, p 229. (b) Bauer, D. P.; Macomber, R. S. J. Org. Chem.
1970, 40, 1990. (c) Sato, K.; Inoue, S.; Ohashi, M. Bull. Chem. Soc. Jpn.
1974, 47, 2519. (d) Rao, D. V.; Stuber, F. A.; Ulrich, H. J. Org. Chem. 1979,
44, 456. (e) Utaka, M.; Matsushita, S.; Takeda, A. Chem. Lett. 1980, 779. (f)
Vankar, Y. D.; Chaudhuri, N. C.; Rao, C. T. Tetrahedron Lett. 1987, 28,
551. (g) Trost, B. M.; Mikhail, G. K. J. Am. Chem. Soc. 1987, 109, 4124. (h)
Kawada, K.; Gross, R. S.; Watt, D. S. Synth. Comm. 1989, 19, 777. (i)
Horiuchi, C. A.; Kiyomiya, H.; Takahashi, M.; Suzuki, Y. Synthesis 1989,
10, 785. (j) Kanu, B. C.; Jana, U. J. Org. Chem. 1999, 64, 6380.
(2) For reviews of the palladium-catalyzed allylic alkylation reaction, see:
(a) Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996, 96, 395. (b) Heumann,
A.; Reglier, M. Tetrahedron 1995, 51, 975. (c) Hayashi, T. In Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; VCH Publishers Inc.; New York, 1993.
(d) Sawamura, M.; Ito, Y. Chem. ReV. 1992, 92, 857. (e) Fiaud, J. C. In Metal-
Promoted SelectiVity in Organic Synthesis; Graziani, M., Hubert, A. J., Noels,
A. F., Eds.; Kluwer Academic Publishers: Dordrecht, 1991. (f) Consiglio,
G.; Waymouth, R. M. Chem. ReV. 1989, 89, 257.
Symmetrical acyclic substrates also behaved well as shown in
eq 3.8 In these cases, the more standard ligand 4 proved to be
(3) For reviews of the Claisen rearrangement, see: (a) Ito, H.; Taguchi, T.
Chem. Soc. ReV. 1999, 28, 43. (b) Gaweski, J. J. Acc. Chem. Res. 1997, 30,
219. (c) Ganem, B. Angew. Chem., Int. Ed. Engl. 1996, 35, 936. (d) P. Wipf
in, ComprehensiVe Organic Synthesis ed. B. M. Trost and I. Fleming,
Pergamon Press: Oxford, 1991, vol 5, 827. (e) Ziegler, F. E. Chem. ReV.
1988, 88, 1423. (f) Rhoads, S. J.; Rawlins, N. R. Org. React. 1975, 22, 1.
(4) For examples of Claisen rearrangements of cyclic 1,2-diketones, see:
(a) Ponaras, A. A. J. Org. Chem. 1983, 48, 3866. (b) Ponaras, A. A.
Tetrahedron Lett. 1983, 24, 3. (c) Dauben, W. G.; Ponaras, A. A.; Chollet,
A. J. Org. Chem. 1980, 45, 4413. (d) Ponaras, A. A. Tetrahedron Lett. 1980,
21, 4803.
satisfactory. The simple 1,3-dimethylallyl system, which fails to
give useful enantioselectivity with most chiral ligands, gives
excellent (92-97% ee) results. Increasing the steric size of the
substituents to phenethyl decreased the enantioselectivity some-
(6) (a) Trost, B. M.; Van Vranken, D. L.; Bingel, C. J. Am. Chem. Soc.
1992, 114, 9327. (b) Trost, B. M.; Bunt, R. C. Angew. Chem., Int. Ed. Engl.
1996, 35, 99.
(7) The absolute configuration shown in eq 2 was assigned by applying
the mnemonic developed in the group for the palladium-catalyzed asymmetric
allylic alkylation reaction using ligands 4 and 5 (see ref 2a and 6a).
(8) The absolute configuration shown in eqs 3 and 4 was assigned by
comparison of the optical rotation of a derivative to that reported in the
literature.
(5) The palladium-catalyzed asymmetric O-alkylation of phenols and
Claisen rearrangement of the resulting allyl aryl ethers was recently reported.
(a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1998, 120, 815. (b) Trost, B.
M.; Toste, F. D. J. Am. Chem. Soc. 1998, 120, 9074.
10.1021/ja000274m CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/31/2000

3786 J. Am. Chem. Soc., Vol. 122, No. 15, 2000
Communications to the Editor
what. The unsymmetrical tiglyl system raises the question of both
regio- and enantioselectivity (eq 4).9 The intrinsic propensity of
the ligand to favor nucleophilic attack at the more substituted
allyl terminus with sterically nondemanding nucleophiles is
observed.10 The regioselectivity favoring 9a and 9b over attack
at the less substituted allyl terminus was 14:1 and 7:1, respectively.
Finally, butadiene monoepoxide gave excellent regio- (only one)
and enantioselectivity (92% ee) using the naphtho ligand 5 as
appears to be required in all the reactions of this electrophile (eq
5).11,12 No boron cocatalysts were required for good regioselec-
NMR spectroscopy and hplc, was observed. The excellent chirality
transfer from the side chain to the ring in forming 16 and 17
represents the equivalent of an asymmetric C-alkylation. The latter
product is particularly interesting since an allyl acetate, which
can be used for further metal catalyzed, as well as noncatalyzed
(such as Ireland-Claisen rearrangement) transformations are
readily available. The holmium catalyst appears to be a quite
useful catalyst generally for aromatic as well as aliphatic Claisen
rearrangements. The utility of the R-diketone products for
asymmetric synthesis of cycloalkenones is illustrated in eq 7.
tivity in contrast to simple alcohol nucleophiles. On the other
hand, best ee’s required chloride ion, low palladium loading (0.2
mol %), and slightly elevated temperatures (50 °C).
With the viability of a broad diversity of enantioselective
O-alkylations established, the chirality transfer in a Claisen
rearrangement was examined in the case of the cyclic substrate
3a. The classical thermal process required temperatures >110°
and gave a great deal of ionization competing with rearrangement.
Classical Lewis acids such as mercuric acetate and dimethylalu-
minum chloride as well as bis(acetonitrile)dichloropalladium(II)
resulted in no reaction or cleavage of the allylic ether bond.
Lanthanide triflates such as lanthanum and europium triflate
proved too reactive.13 On the other hand, the FOD complexes of
the lanthanides did prove to be effective. Among Pr, Eu, Ho, Er,
and Yb, the most effective in maintaining kinetic reactivity but
minimizing dissociation recombination that leads to racemization
were Eu and Ho, with the latter being slightly more effective.
Thus, use of 10 mol % Ho(fod)3 in a minimal amount of
chloroform at 50-80 °C was adopted as our standard protocol.
The rearrangement of 3a and 3b proved to be the worst cases.
The former required 75° which resulted in 87% chirality transfer
in forming 12a (eq 6).14 Reducing the steric hindrance as in 3c
and 3e allowed the rearrangement to proceed to give 13a and b
respectively at 50-60° with 98% chirality transfer.
Thus, subjecting the triflate15 18 to palladium-catalyzed cross-
coupling allows access to the unsubstituted (i.e., 19) or substituted
(i.e., 20) cyclohexenones.
Acknowledgment. We thank the National Science Foundation and
the National Institutes of Health, General Medical Sciences, for their
generous support of our programs and NSF for a predoctoral fellowship
to G.M.S.. Mass spectra were provided by the Mass Spectrometry
Regional Center of the University of California-San Francisco supported
by the NIH Division of Research Resources. We thank Chirotech and
NSC Technologies for their generous gifts of ligands.
The acyclic substrates 7a-c, 9a,b, and 11b rearranged more
smoothly to give 14-17 with excellent chirality transfer (95-
100%). In each case, the alkene geometry is only E. The facility
of the rearrangement in these cases is indicated by the fact that
only 1 mol % of Ho(fod)3 was required to form 14b.6
In cases where there is the prospect of forming diastereomers
(12a, 14a, and 14b), only one diastereomer, as determined by
Supporting Information Available: Experimental details (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
(9) For recent papers on controlling the regiochemistry of Pd-catalyzed
allylic alkylations, see: (a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999,
121, 4545. (b) Pretot, R.; Pfaltz, A. Angew. Chem., Int. Ed. 1998, 37, 323. (c)
Hayashi, T.; Kawatsura, H.; Uozumi, Y. J. Am. Chem. Soc. 1998, 120, 1681.
(10) Trost, B. M.; Verhoeven, T. R. J. Am. Chem. Soc. 1980, 102, 4730.
(11) Trost, B. M.; McEachern, E. J.; Toste, F. D. J. Am. Chem. Soc. 1998,
120, 12702.
JA000274M
(14) Chirality transfer is defined as (% ee product/% ee starting material)
× 100%. In reporting ee’s, the first number in parentheses is the observed ee
of the product and the second represents this number corrected for the ee of
the starting material.
(15) For a recent review of triflate chemistry, see: Ritter, K. Synthesis
1993, 735.
(16) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1984, 25, 4821.
(17) Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett. 1992, 33, 4815.
(12) The absolute stereochemistry was assigned in analogy to previous
work, see: ref 6b.
(13) Imamoto, T. In Lanthanides in Organic Synthesis; Academic Press:
London, U. K., 1994; Chapter 5, pp 67-118.