Palladium-catalyzed asymmetric alkylation of ketone enolates [7]

Full text of DOI:10.1021/ja991135b

J. Am. Chem. Soc. 1999, 121, 6759-6760
Table 1. Selected Optimization Studiesa
6759
Palladium-Catalyzed Asymmetric Alkylation of
additiveb
time (h) % yieldc % eed
Ketone Enolates
entry base (eq no.)
Barry M. Trost* and Gretchen M. Schroeder
1
2
3
4
5
6
7
8
9
LDA (1)
LDA (1)
LDA (1)
(C4H9)3SnOSO2CF3
(C4H9)3SnCl
3
21
53
65
78
99
99
61
94
99
96
32
65
69
78
80
88
84
71
86
85
2
Department of Chemistry, Stanford UniVersity
(CH3)3SnCl
3
Stanford, California 94305-5080
LDA (1.25) (CH3)3SnCl
2.5
2.5
0.5
1.75
2
LDA (1.5)
LDA (2)
LDA (3)
LiHMDS (2) (CH3)3SnCl
LiTMP (2)
(CH3)3SnCl
(CH3)3SnCl
(CH3)3SnCl
ReceiVed April 12, 1999
The asymmetric alkylation of ketone enolates to generate
quaternary centers has been the subject of investigation in recent
years.1 Initial attempts took advantage of stoichiometric chiral
auxiliaries or self-replicating chirality to induce asymmetry.2 The
alkylation of enolates using catalytic amounts of a chirality
inducing agent has proven more difficult; however, recent
advances have been made in this area.3,4 We5 and others6 have
been interested in developing the palladium-catalyzed asymmetric
allylic alkylation (AAA reaction) of prochiral nucleophiles.7 In
order for chiral ligands to effect stereochemical control in this
reaction, they must influence bond making and bond breaking
events occurring outside the coordination sphere of the metal;
thus, they must transmit their stereochemical information through
space. Discrimination of enantiotopic faces of the nucleophile is
especially difficult as the nucleophile is segregated from the chiral
environment by the π-allyl moiety. The success with stabilized
nucleophiles such as â-ketoesters5 emboldened us to inquire
whether simple ketone enolates, perhaps the most important class
of nucleophiles, would function, let alone give good enantiose-
lectivity. Nonstabilized enolates have generally proven to be
unsatisfactory in palladium-catalyzed allylic alkylations although
some success has been achieved with their tin8 and boron9
derivatives. With the family of chiral ligands being developed in
these laboratories, the presence of the secondary amides would
seem to limit the operable pH range. Due to increased basicity
of simple enolates, will the nucleophile deprotonate the amide
hydrogens on the ligand? If so, will the reaction still proceed
and with what ee? Herein we wish to report the successful
application of the palladium-catalyzed AAA reaction to nonsta-
bilized ketone enolates.
(CH3)3SnCl
none
0.5
1
10 LDA (2)
a All reactions were performed in DME (0.15 M in nucleophile) at
room temperature using 1.1 equiv of allyl acetate using the catalyst
system of eq 1. b Use of 1.0 equiv of the additive. c Isolated yields.
d The ee was determined by chiral HPLC using a Chiracel OD column
with 99.9:0.1 heptane/2-propanol, tR ) 17.95 (R), 19.14 (S) min.
The reaction was optimized by varying the solvent, base, and the
addition of various Lewis acids. The choice of solvent had a
moderate effect on the yield and enantioselectivity of the reaction.
DME, THF, methylene chloride, toluene, dioxane, and 10%
HMPA/THF were all examined with DME giving the best results.
The effect of solvent on the state of aggregation of the enolate
may be the source of this selectivity.
The presence of additives and choice of base conditions had a
much more significant effect. A variety of Lewis acids were
screened and, in general, stannanes gave far superior results than
did boranes and borates. The yield and enantioselectivity of the
reaction was found to correlate with the leaving group ability on
the tin (Table 1, entry 1 vs 2). Lewis acids with poor leaving
groups gave better results than those with good leaving groups.
This suggests that an ate complex rather than a simple trialkyl-
stannyl ether may be the nucleophile. Also, the size of the Lewis
acid and the enantioselectivity correlated as smaller Lewis acids
gave higher yields and slightly higher ee’s than did more sterically
demanding Lewis acids (entry 2 vs 3). Given these observations,
trimethyltin chloride became the Lewis acid of choice.
The choice of base had a dramatic effect on the reaction. Only
lithium bases gave the desired reaction whereas sodium and
potassium bases gave recovery of the starting material. The
reaction was found to be dependent on the amount of base used
in the reaction with 2 equiv of base giving the best results (entries
3-7). Changing the amide to hexamethyldisilazide (entry 8)
decreased the ee but changing to the piperidide (entry 9) had little
effect. To summarize, the optimum reaction conditions were found
to consist of using DME as the solvent, 2 equiv of LDA as the
base, and trimethyltin chloride as the Lewis acid. With these
conditions, the allylated product 5a could be isolated in 99% yield
and 88% ee. It should be noted that the use of tin is not absolutely
necessary as the reaction could be performed in the absence of
any Lewis acid (entry 10). Thus, upon generation of the lithium
enolate of 1 with 2 equiv of LDA, 5a could be obtained in 96%
yield and in slightly lower ee (85%). A similar observation
occurred in the alkylations of 2-ethyltetralone in the presence (vide
infra) or absence of tin. While the lowering of the ee, in the
absence of tin, was small in both cases, it was very reproducible.
As a result, we chose to include the tin in our general protocol.
These results emphasize the robust nature of the catalyst as the
Initial studies examined the reaction of 2-methyl-1-tetralone
(1) with allyl acetate (2) using chiral ligand 3 and palladium
complex 4 (eq 1). Gratifyingly, formation of the tin derivative
by in situ treatment of the lithium enolate with tri-n-butyltin
chloride led to alkylated product 5a in 53% yield and 63% ee.
(1) Corey, E. J. Angew. Chem., Int. Ed. Engl. 1998, 388. Noyori, R.
Asymmetric Catalysis in Organic Synthesis; Wiley: New York, 1994. Fuji,
K. Chem. ReV. 1993, 93, 2037.
(2) J. Seyden-Penne Chiral Auxiliaries and Ligands in Asymmetric
Synthesis; Wiley: New York, 1995.
(3) Ahman, J.; Wolfe, J. P.; Troutman, M. V.; Palucki, M.; Buchwald, S.
L. J. Am. Chem. Soc. 1998, 120, 1918. Palucki, M.; Buchwald, S. L. J. Am.
Chem. Soc. 1997, 119, 11108.
(4) Bhattacharya, A.; Dolling, U.-H.; Grabowski, E. J. J.; Karady, S.; Ryan,
K. M.; Weinstock, L. M. Angew. Chem., Int. Ed. Engl. 1986, 25, 476. Conn,
R. S. E.; Lowell, A. V.; Karady, S.; Weinstock, L. M. J. Org. Chem. 1986,
51, 4710. Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc.
1984, 104, 446. Hughes, D. L.; Dolling, U.-H.; Ryan, K. M.; Schoenewaldt,
E. F.; Grabowski, E. J. J. J. Org. Chem. 1987, 52, 4745.
(5) Trost, B. M.; Radinov, R.; Grenzer, E. M. J. Am. Chem. Soc. 1997,
119, 7879.
(6) Hayashi, T.; Kanehira, K.; Hagihara, T.; Kumada, M. J. Org. Chem.
1988, 53, 113.
(7) For reviews of the palladium-catalyzed allylic alkylation reaction, see:
Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996, 96, 395. Heumann, A.;
Reglier, M. Tetrahedron 1995, 51, 975. Hayashi, T. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; VCH Publishers: New York, 1993. Sawamura, M.;
Ito, Y. Chem. ReV. 1992, 92, 857. Fiaud, J. C. In Metal-Promoted SelectiVity
in Organic Synthesis; Graziani, M., Hubert, A. J., Noels, A. F., Eds.; Kluwer
Academic Publishers: Dordrecht, 1991. Consiglio, G.; Waymouth, R. M.
Chem. ReV. 1989, 89, 257.
(8) Trost, B. M.; Self, C. R. J. Org. Chem. 1984, 49, 468. Trost, B. M.;
Keinan, E. Tetrahedron Lett. 1980, 21, 2591.
(9) Negishi, E.-I.; Matsushita, H.; Chatterjee, S.; John, R. A. J. Org. Chem.
1982, 47, 3188.
10.1021/ja991135b CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/02/1999

6760 J. Am. Chem. Soc., Vol. 121, No. 28, 1999
Table 2. AAA Reaction of 1-Tetralonesa
Communications to the Editor
entry
R1
R2
R3
R4
R5
X
time (h)
product, yield
% eed
1
2
3
4
5
6
7
8
CH3
CH3
CH2CH3
CH2Ph
CH3
CH3
CH3
CH2CHdCH2
CH3
H
H
H
H
H
H
H
H
0.5
1
5, 99%
88%
85%
80%
85%
90%
82%
47%
85%
CH3
H
H
OCH3
H
6a, 83%
6b, 96%
6c, 71%
6d,d 84%
6e,d 72%
6f, 82%
6g,d 71%
CH3
CH3
OCH3
OCH3
OCH3
OCH3
H
H
H
CH3
H
H
CH3
0.5
1
H
H
H
H
3
H
TBDMSO(CH2)2
H
5
CH3
H
H
H
H
4
H
4
a All reactions were performed in DME (0.15 M in nucleophile) at room temperature using 1.1 equivalents of electrophile, 2 equivalent of LDA,
and 1 equivalent of (CH3)3SnCl. b Isolated yields. c The ee was determined by chiral hplc. d The alkene geometry in the product was E.
reaction proceeds even in the presence of a second equivalent of
LDA. The absolute configuration of 5, generated with the S,S
ligand, has been established as R using the O-methylmandelate
esters of an alcohol derivative.10 No asymmetric alkylation occurs
in the absence of palladium.
Using the optimized conditions, we explored a range of tetra-
lones and allylating agents as summarized in eq 2 and Table 2.
Figure 1. Rational for chiral recognition.
transposition16 of keto ketene dithioacetal 10 gives R,â-unsaturated
thiol ester 12, a useful substrate for annulation protocols (eq 5).17
The reaction shows little sensitivity to the substituent in the 2-
position since methyl (entries 1, 2, 5-7), ethyl (entry 3), allyl
(entry 8), and benzyl (entry 4) all gave comparable results.
Linearly substituted allyl systems starting from either E (entries
5 and 8) or Z (entry 6) isomers gave products of only E geometry
with good ee. On the other hand, a branched allyl system (entry
7) gave good yields but lower ee’s. Changing ring sizes to either
indanone or benzosuberone also led to alkylations with rather low
ee’s.
Other cyclohexanones participate equally well in these alky-
lations. The benzylidene11 7a gave the allylated product 8a12
These results indicate that allylations of simple ketone enolates
of six-membered rings can now be achieved asymmetrically in a
catalytic fashion. The importance of the cations associated with
the enolate is illustrated by their effect (on both reactivity and
ee). This strongly suggests that the actual structure of the
nucleophile is not simple and likely an aggregate. Quaternary
centers are being formed with a high degree of absolute
stereochemical control. The mnemonic that we developed depicted
in Figure 1 provides a rationale for the observed stereochemistry.
The success of less stabilized nucleophiles such as simple enolates
provides impetus for exploring a much broader range of nucleo-
philes. The compatibility of the types of ligands employed herein,
which contain secondary amides, to such strong bases raises
questions about whether these amides are deprotonated under the
reaction conditions. The allylated products available by this
method are quite versatile for further elaboration including
annulation protocols.18
nearly quantitatively (98% yield of 82% ee (eq 3). In the case of
the furanylidene derivative 7b,13 we explored a temperature effect.
At room temperature (normal optimized conditions) the product
was produced in 79% ee (89% yield), whereas at 0 °C the
enantioselectivity increased to 92% (95% yield). A similar effect
was observed with the ketene thioacetal derivative 914 (eq 4). In
Acknowledgment. We thank the National Science Foundation and
the National Institutes of Health, General Medical Sciences for the
generous support of our programs. G.M.S. is supported by a NSF Pre-
doctoral Fellowship. Mass spectra were provided by the Mass Spectrom-
etry Regional Center of the University of California-San Francisco
supported by the NIH Division of Research Resources.
this case, the reaction at room temperature gave 10 of 70% ee
(64% yield) which increased to 82% ee (67% yield) at -10 °C.15
The allylated products generated in this reaction are versatile
substrates for further transformations. For example, 1,3-carbonyl
Supporting Information Available: Experimental details (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
JA991135B
(15) Two equivalents of allyl acetate were used in the experiment performed
at -10 °C.
(10) This assignment required hydroboration-oxidation of the alkene and
ketone reduction to produce diastereomeric diols whose relative and absolute
stereochemistry were established by NMR methods. Details appear in the
Supporting Information.
(11) Johnson, W. S. J. Am. Chem. Soc. 1943, 65, 1317.
(12) Cornubert, C. Ann. Chim. (Paris) 1921, 16, 172.
(13) Islam, A. M.; Zemaity, M. T. J. Am. Chem. Soc. 1957, 79, 6023.
(14) Dieter, R. K. J. Org. Chem. 1981, 46, 5031.
(16) Dieter, R. K.; Lin, Y. J.; Dieter, J. W. J. Org. Chem. 1984, 49, 3183.
Trost, B. M.; Stanton, J. L. J. Am. Chem. Soc. 1975, 97, 4018.
(17) Aggarwal, V. K.; Thomas, A.; Schade, S. Tetrahedron 1997, 53, 16213.
(18) After submission of this manuscript, the report of the alkylation of
the lithium enolate of 2-substituted tetralones generated from enol silyl ethers
using chiral amine inducers appeared, see: Yamashita, Y.; Odashima, K.;
Koga, K. Tetrahedron Lett. 1999, 40, 2803.