Asymmetric alkylation of β-ketones

Full text of DOI:10.1021/ja971523i

J. Am. Chem. Soc. 1997, 119, 7879-7880
Asymmetric Alkylation of â-Ketoesters
7879
Barry M. Trost,* Rumen Radinov, and Ellen M. Grenzer
Department of Chemistry, Stanford UniVersity
Stanford, California 94305-5080
ReceiVed May 12, 1997
Creating quaternary carbon centers in which the absolute
stereochemistry can be controlled by alkylation represents a
major challenge. â-Ketoesters become interesting substrates
because the structural diversity of the substituents permits ready
and selective manipulation. Conceptually, catalytic asymmetric
alkylations of such substrates are not straightforward.1 Ex-
trapolation of the concept of asymmetric allylic alkylations2 to
induce absolute stereochemistry in a prochiral nucleophile is
tenuous, at best, given the known stereochemistry of the
process.3 As depicted in Figure 1, the pronucleophile resides
very distal to the chiral ligands in the transition state for
alkylation. Not surprisingly, the best ee’s for alkylation of
2-carboethoxycyclohexanone have been less than 30%4 although
with a â-diketone significantly higher ee’s have been obtained.4-7
An imaginative solution to this problem arises in the case of
R-cyanoesters wherein a chiral rhodium complex activates the
pronucleophilesthereby bringing the asymmetric inducing
ligands more proximal to the nucleophilic center.8 An alterna-
tive strategy examines whether the geometric requirements of
a chiral pocket would permit its chirality to be transmitted to
the pronucleophile as depicted in Figure 1. We wish to report
the feasibility of this strategy for the alkylation of â-ketoesters
and the application of this methodology to a simple synthesis
of the spiro-alkaloid nitramine.9
of ester, ethyl vs methyl vs benzyl, had no effect with sodium
carbonate in methylene chloride (entry 4 vs 7 vs 9) and a small
but notable effect with TMG in toluene (entry 6 vs 8 vs 10).
Preparatively, performing the reaction at 1 M concentration of
1 (R ) C2H5) for 24 h at room temperature with 2 as ligand
gave a quantitative yield of S-3 of 86% ee. Expectedly, using
the S,S ligand corresponding to 2 gave R-3 quantitatively also
of 86% ee. Thus, both enantiomers of 3 are equally available.
The absolute configuration was assigned by comparison to the
literature.4,10
The tetralone system showed somewhat higher selectivities
as shown in eqs 2-4 and Table 2. An initial experiment with
the methyl ester corresponding to 4a with allyl acetate gave
the allylated product in 97% yield of 77% ee, whereas the benzyl
ester gave the product 6a11 of 89% ee (eq 2 and Table 2, entry
1). As a result, the benzyl ester was employed for the
The reaction of 2-carboalkoxycyclohexanone (1) with allyl
acetate using the chiral ligand (2) in a Pd catalyzed reaction
was examined as summarized in eq 1 and Table 1. The results
of Table 1 reveal the sensitivity of the reaction to conditions.
Choice of base and solvent have dramatic effects. Both
parameters would be expected to influence the exact structure
of the nucleophile both in terms of the nature of the ion pair
and the state of aggregation. The use of a highly delocalized
cation, N,N,N′,N′-tetramethylguanidinium (TMG), in a nonpolar
solvent, toluene (entry 6), proved most expeditious. The choice
subsequent studies. In general, the reactions appeared to
proceed more rapidly (cf. Table 1, entry 10 and Table 2, entry
1) than the simple cyclohexanone derivative. 6-Methoxytetra-
lone gave a slight enhancement (Table 2, entry 2). Substituting
the allylating agent showed the biggest effect (Table 2, entries
3-7). Using 2-substituted allylating agents gave excellent ee’s,
Table 2, entries 3 and 4.
With 1,3-disubstituted allylating agents, the issue of diastereo-
as well as enantioselectivity arises. 3-(Methoxycarboxy)-2-
pentene (7) gave excellent diastereoselectivity and enantiose-
lectivity (Table 2, entry 5). Typically, this substrate does not
participate well with almost all chiral ligands for asymmetric
induction.2 This observation demonstrates that with our ligands,
excellent selectivity can be observed not only with respect to
the allyl system12 but also with respect to the nucleophile.
(1) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley-
Interscience: New York, 1994; pp 207-212 and 333-342.
(2) For reviews, 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,
Inc.: 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: Dor-
drecht, 1991. Consiglio, G.; Waymouth, R. M. Chem. ReV. 1989, 89, 257.
(3) Trost, B. M.; Verhoeven, T. R. J. Am. Chem. Soc. 1980, 102, 4730.
Hayashi, T.; Hagihara, T.; Konishi, M.; Kumada, M. J. Am. Chem. Soc.
1983, 105, 7767. Hayashi, T.; Konishi, M.; Kumada, M. Chem. Commun.
1984, 107.
(4) Hayashi, T.; Kanehira, K.; Hagihara, T.; Kumada, M. J. Org. Chem.
1988, 53, 113. Fiaud, J. C.; De Gournay, A. H.; Lacheve´que, M.; Kagan,
H. B. J. Organomet. Chem. 1978, 154, 175.
(5) Sawamura, M.; Nagata, H.; Sakamoto, H.; Ito, Y. J. Am. Chem. Soc.
1992, 114, 2586.
(6) For other examples of asymmetric induction in pronucleophiles,
see: Sawamura, M.; Nakayama, Y.; Tang, W.-M.; Ito, Y. J. Org. Chem.
1996, 61, 9090. Genet, J.-P.; Juge, S.; Achi, S.; Mallart, S.; Montes, J. R.;
Levif, G. Tetrahedron 1988, 44, 5263. Genet, J-P.; Juge, S.; Montes, J. R.;
Gaudin, J. M. Chem. Commun. 1988, 718. Ito, Y.; Sawamura, M.; Matsuoka,
M.; Matsumoto, Y.; Hayashi, T. Tetrahedron Lett. 1987, 28, 4849. Genet,
J.-P.; Ferroud, D.; Juge, S.; Montes, J. R. Tetrahedron Lett. 1986, 27, 4573.
Hayashi, T.; Kanehira, K.; Tsuchiya, H.; Kumada, M. Chem. Commun. 1982,
1162.
The effect of the geometry of the π-allylpalladium intermedi-
ate was explored. The acyclic example above involves a syn,-
syn-π-allylpalladium intermediate. Utilizing a cyclic substrate
invokes the intermediacy of an anti,anti complex. Such
(7) Also, see: Baldwin, I. C.; Williams, J. M. J. Tetrahedron: Asymmetry
1995, 6, 679.
(10) Chitkul, B.; Pinyopronpanich, Y.; Thebtaranonth, C.; Thebtaranonth,
Y.; Taylor, W. C. Tetrahedron Lett. 1994, 35, 1099.
(8) Sawamura, M.; Sudoh, M.; Ito, Y. J. Am. Chem. Soc. 1996, 118,
3309.
(9) Novgorodova, N. Y.; Maekh, S. K.; Yunusov, S. Y. Chem. Nat. Prod.
1973, 9, 191. Osmanov, Z.; Ibragimov, A. A.; Yunusov, S. Y. Chem. Nat.
Prod. 1977, 13, 607. Osmanov, Z.; Ibragimov, A. A., Yunusov, S. Y. Chem.
Nat. Prod. 1982, 18, 121.
(11) New compounds have been satisfactorily characterized spectroscopi-
cally, and elemental composition was established by combustion analysis
or high resolution mass spectrometry.
(12) Trost, B. M.; Krueger, A. C.; Bunt, R. C.; Zambrano, J. J. Am.
Chem. Soc. 1996, 118, 6520.
S0002-7863(97)01523-0 CCC: $14.00 © 1997 American Chemical Society

7880 J. Am. Chem. Soc., Vol. 119, No. 33, 1997
Communications to the Editor
Scheme 1. An Asymmetric Synthesis of (-)-Nitramine (14)a
Table 1. Asymmetric Alkylation of 2-Carboalkoxycyclohexanone
temp
time
%
% ee
entry
R
solvent
C2H5 THF
C2H5 PhCH3 NaH
base
(°C)
(h) yielda
(er S:R)b,c
1
2
3
4
5
6
7
8
9
NaH
-78 to 20 16
88 -16 (42:58)
0 to 20 16 (60) -21 (39.5:60.5)
C2H5 PhCH3 n-C4H9Li -78 to 20 16 (90) -22 (39:61)
C2H5 CH2Cl2 Na2CO3
C2H5 CH2Cl2 TMGd
C2H5 PhCH3 TMGd
CH3
CH3
40
20
20
40
0
24
16
16
16
2
74
85
86
61
85
24
81
70 (85:15)
75 (87.5:12.5)
86 (93:7)
71 (85.5:14.5)
79 (89.5:10.5)
72 (86:14)
CH2Cl2 Na2CO3
a (a) THF, -15 °C to room temperature then NaBO3.4H2O, H2O.
(b) i. (C2H5)3N, CH3SO2Cl, -60 °C f 0 °C, CH2Cl2; ii. NaN3, DMF,
40 °C. (c) H2 (1 atm), Pd(OH)2/C, K2CO3, C2H5OH, room temperature
to reflux. (d) LAH, THF; room temperature.
PhCH3 TMGd
CH2Ph CH2Cl2 Na2CO3
40
0
12
3
10 CH2Ph PhCH3 TMGd
86 (93:7)
a Isolated yields except those listed in parenthesis represent GC
yields. b The ee was determined by HPLC using Chiralpak AD column.
c Negative ee’s reflect the fact that the major enantiomer obtained was
opposite to that depicted in eq 1. d TMG ) N,N,N′,N′-tetramethylguani-
dine.
undertook a simple synthesis of the spiro-alkaloid nitramine
(14),14 representative of a class of such alkaloids that have shown
interesting biological activities.15 Scheme 1 outlines the
synthesis from 3. Hydroboration of the alkene with disiamyl-
borane followed by oxidative workup with sodium perborate16
gave a single diol 11. Thus, a novel diastereoselective ketone
reduction accompanied alkene hydration presumably by a
mechanism depicted in Scheme 1.17 Activation of the primary
alcohol as the mesylate allowed chemoselective substitution with
azide to give hydroxyazide 12. Catalytic reduction at room
temperature produced the amino group which required heating
at reflux to effect complete cyclization to lactam 1314b,g,h whose
recrystallization from ethyl acetate enhanced the ee to 95%.
Reduction of the latter gave (-)-nitramine, identical in properties
to those previously reported.9,14 From 2-carboethoxycyclohex-
anone, this alkaloid is synthesized asymmetrically in six steps
and 43% overall yield.
This report represents the first examples of catalytic asym-
metric alkylation of â-ketoesters with high ee’s. The presence
of three different functional groups (ketone, ester, and allyl) on
the stereogenic center provide great flexibility for further
structural elaboration. It appears that this family of ligands may
be tailored for the asymmetric alkylation of pronucleophiles.
However, since so many variables exist for each different
nucleophile, fine tuning for each would appear likely to be
needed. For example, alkylation of 2-benzyloxycarbonylin-
danone, under the general conditions for the cyclohexanone
derivatives, gave the desired product in 99% yield with 65%
ee. These promising results suggest that such asymmetric
alkylation of prochiral â-ketoesters may become reasonably
general.
Figure 1. Geometrical issues for asymmetric induction at a pronu-
cleophile in Pd catalyzed allylic alkylation.
Table 2. Enantioselectivity of Allylic Alkylation of Tetralonesa
entry tetralone allylic ester time product % yield dr
ee (er)b
1
2
3
4
5
6
7
4a
4b
4a
4a
4a
4a
4a
5a
5a
5b
5c
7
0.25
1
3
1.5
3
2
6a, 94%
6b, 98%
6c, 81%
6d, 80%
8, 71%
89 (94.5: 5.5)
91 (95.5:4.5)
95 (97.5:2.5)
94 (97:3)
94:6 97c (98:2)
9a
9b
10a, 87%
10b, 91%
99:1 96c (98:2)
3
98:2 99c (99.5:0.5)
Acknowledgment. We thank the National Science Foundation and
the National Institutes of Health, General Medical Sciences, for their
generous support of our programs. E.M.G. thanks the NIHGMS for a
postdoctoral fellowship. Mass spectra were kindly provided by the Mass
Spectrometry Facility, University of San Francisco, supported by the
NIH Division of Research Resources.
a All reactions were run with 0.4 mol % [η3-C3H5PdCl]2, 0.9 mol %
2, 1.2-1.4 equiv of TMG, 1.2-1.7 equiv of allyl ester, in toluene (0.2-
0.4 M in tetralone) at 0 °C. b Enantioselectivities determined by HPLC
using a Chiracel OD column eluting with heptane-isopropyl alcohol
mixtures. c Enantioselectivity of major diastereomer.
substrates have given excellent enantioselectivities with achiral
nucleophiles.13 As illustrated in eq 4 and Table 2, entries 6
and 7, these cyclic allylic esters gave even higher diastereose-
lectivities and excellent enantioselectivities. The stereochem-
Supporting Information Available: Characterization data for 3,
6a-d, 8m, 10a,b, and 11-14 illustrative experimental procedure, and
table of enantioselectivity assay data (5 pages). See any current
masthead page for ordering and Internet access instructions.
JA971523I
(14) For some earlier asymmetric syntheses: (a) Yamane, T.; Ogasawara,
K. Synlett 1996, 925. (b) Keppens, M.; DeKimpe, N. J. Org. Chem. 1995,
60, 3916. (c) Westermann, B.; Scharmann, H. G.; Kortmann, I. Tetrahe-
dron: Asymmetry 1993, 4, 2119. (d) Wanner, M. J.; Koomen, G.
Tetrahedron 1992, 48, 3935. (e) Tanner, D.; He, H. M.; Tetrahedron 1989,
45, 4309. (f) Carruthers, W.; Moses, R. C. J. Chem. Soc., Perkin Trans. I
1988, 1625. (g) McCloskey, P. J.; Schultz, A. G. Heterocycles 1987, 25,
437. (h) Hellberg, L. H.; Beeson, C. Tetrahedron Lett. 1986, 27, 3955. (i)
Mieczkowski, J. B. Bull. Pol. Acad. Sci., Chem. 1985, 33, 13. (j) Snider,
B. B.; Cartaya-Marin, C. P. J. Org. Chem. 1984, 49, 1688.
(15) Daly, J. W. In Progress in the Chemistry of Organic Natural
Products; Herz, W., Grisebach, H., Kirby, G. W., Eds.; Springer Verlag:
New York, 1982; Vol. 41, p 205.
(16) Kabalka, G. W.; Shoup, T. M.; Goudgaon, N. M. J. Org. Chem.
1989, 54, 5930.
istry is assigned only by analogy to our previous observations.
In the cases of 6a-d,11 the assignments are by analogy to the
absolute configuration established for 3. In the cases of 8,11
10a,11 and 10b,11 the assignments are by analogy to the
established sense of asymmetric induction with respect to the
allyl systems as well as for 3.12,13
The ability to effect asymmetric induction in the alkylations
of â-ketoesters can be quite useful. As an example, we
(17) For a recent example of a similar phenomenon with borane, see:
Sha, C.-K.; Chiu, R.-T.; Yang, C.-F.; Yao, N.-T.; Tseng, W.-H.; Liao, F.-
L.; Wang, S.-L. J. Am. Chem. Soc. 1997, 119, 4130.
(13) Trost, B. M.; Bunt, R. C. J. Am. Chem. Soc. 1994, 116, 4089.