Cu-catalyzed asymmetric conjugate additions of alkylzinc reagents to acyclic aliphatic enones

Article abstract of DOI:10.1021/ja0122849

Cu-catalyzed enantioselective conjugate additions to acyclic aliphatic enones are reported. The resulting enolates may be functionalized intra- and intermolecularly, leading to the formation of an additional C-C bond. The utility of the present method is not limited to reactions involving Et₂Zn; a variety of alkylzincs may be used. Moreover, many of the requisite substrates can be easily accessed through catalytic olefin cross metathesis. Copyright

Full text of DOI:10.1021/ja0122849

Published on Web 01/12/2002
Cu-Catalyzed Asymmetric Conjugate Additions of Alkylzinc Reagents to
Acyclic Aliphatic Enones
Hirotake Mizutani, Sylvia J. Degrado, and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467
Received October 3, 2001
Scheme 1
We recently reported Cu-catalyzed asymmetric conjugate addi-
tions of alkylzincs to cyclic enones, where peptidic phosphines serve
as chiral ligands to deliver the desired products in high yields and
enantioselectivities.1 A noteworthy aspect of the latter study is that
it offers a solution to the problem of asymmetric conjugate additions
to unfunctionalized cyclopentenones (up to >98% ee),2 a class of
substrates that typically undergoes reactions with lower efficiency
and asymmetric induction than their larger ring analogues.3 Despite
significant progress made in the area of Cu-catalyzed conjugate
additions to cyclic enones, extension of such protocols to include
Table 1. Cu-Catalyzed Enantioselective Conjugate Addition of
highly enantioselective reactions of aliphatic acyclic enones has
proved to be far from routine.4-6 Promising data have been reported
in certain cases; however, Et2Zn is nearly always the alkylating
agent probed, the majority of studies has involved aromatic enones,
and selectivities are rarely >90% ee when aliphatic substrates are
used.4g,k Herein we report the results of our investigations regarding
the development of highly efficient and enantioselective catalytic
conjugate additions of acyclic aliphatic R,â-unsaturated ketones.
These processes are readily extended to a variety of alkylzinc
reagents and are promoted by Cu complexes of chiral dipeptide
phosphine 1 (Scheme 1).
Et2Zn to Aliphatic Acyclic Enonesa
Brief preliminary catalyst screening, involving methyl ketone 2
and Et2Zn (entry 1, Table 1), indicated that phosphine 1 consistently
provides high reactivity and enantioselectivity. Thus, as shown in
entry 1 of Table 1, treatment of unsaturated methyl ketone 2 with
1 mol % (CuOTf)2‚C6H6, 2.4 mol % 1, and 3 equiv of Et2Zn at
-20 °C (toluene, 3 h) leads to formation of chiral ketone 37 in
93% ee and 90% yield after silica gel chromatography.8 As the
data in entries 2-4 of Table 1 illustrate, altering the electronic
character of the â-aryl substituent does not affect reaction efficiency
or asymmetric induction; ketones 5, 7, and 9 are isolated in >70%
yields and in 94%, 92%, and 90% ee, respectively. Catalytic
asymmetric conjugate addition to the fully aliphatic enone 10 (entry
5) affords 11 in 95% ee and 85% yield within 1 h at 22 °C.7 High
enantioselectivity is observed in the formation of 13 (entry 6),
despite the small â-Me substituent in 12. The reaction of the
sterically hindered i-Pr ketone 14 (entry 7) occurs smoothly within
an hour at 22 °C, yielding 15 in 90% ee (75% yield). When the
derived t-Bu ketone 16 is employed (entry 8), the rate of reaction
suffers significantly (69% conversion after 36 h), and 17 is obtained
with diminished enantiopurity (58% ee).9 The process depicted in
entry 9 of Table 1 illustrates that efficient and highly enantio-
selective catalytic additions can be carried out in the presence of a
bulky substituent at the â carbon of the enone. The functional group
tolerance of the catalytic method is illustrated in the reaction of
acylated enone 20, yielding chiral 21 in 88% yield and 89% ee
(entry 10).
a Conditions: 1 mol % (CuOTf)2‚C6H6, 2.4 mol % 1, 3 equiv of Et2Zn,
toluene; 5 mol % 1 for entries 6 and 10. b Isolated yields after chromatog-
raphy; all conversion >98% except for entry 8 (GLC). c Selectivities
determined by chiral GLC (γ-DEX entry 1; CDGTA entries 3-6, 9; â-DEX
entries 7-8, 10) or HPLC (chiralcel OJ, entry 2). d Sign of optical rotation.
intermediate can be employed for additional functionalization. As
illustrated in Scheme 2, reaction of tosylate 22 with methylvinyl
ketone (CH2Cl2, 22 °C) in the presence of 2.5 mol % recyclable
Ru catalyst 2310 affords the corresponding unsaturated tosyl-enone
(>96% trans) which is then treated with 5 mol % 1 and 1 mol %
(CuOTf)2‚C6H6 to give cyclopentyl ketone 24 in 85% ee, >98%
diastereoselectivity, and 78% overall isolated yield (1 h, 22 °C).11
Many of the requisite substrates can be readily accessed through
Ru-catalyzed olefin cross metathesis, and the purported Zn-enolate
9
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C O M M U N I C A T I O N S
Scheme 2. Sequential Catalytic Cross Metathesis/Asymmetric
Table 2. Cu-Catalyzed Enantioselective Conjugate Addition of
Conjugate Additiona
Various Alkylzinc Reagents to Aliphatic Acyclic Enonesa
a Conditions: see Scheme 2. b Isolated yields after chromatography; all
conversion >98% (by GLC and TLC). c Enantioselectivities determined by
chiral GLC (γ-DEX for entry 1, CDGTA for entries 2-4). d Sign of optical
rotation. e See Supporting Information for proof of absolute stereochemistry.
f >98% trans diastereoselectivity (by GLC).
a Conditions: (1) 2.5 mol % 23, CH2Cl2; (2) 5 mol % 1, 1 mol %
(CuOTf)2‚C6H6, 3 equiv of Et2Zn, toluene, 22 °C, 1 h; >98% conversion;
isolated overall yields; ee’s by chiral GLC or HPLC (Supporting Informa-
tion).
serves as a bifunctional catalyst.14 It may be suggested that the
resident acetate or sulfonate sites can disrupt the delivery of the
alkylmetal by the peptide moiety of the chiral ligand; the importance
of the AA2 unit to enantioselectivity is consistent with this proposal.
Detailed studies to clarify these and other issues are in progress.
The Cu-catalyzed alkylations presented here are not limited to
additions of Et2Zn; representative data are shown in Table 2. The
relatively less reactive Me2Zn and (i-Pr)2Zn can be employed in
these asymmetric conjugate additions efficiently and with ap-
preciable asymmetric induction. As illustrated in entries 3 and 4
(Table 2), in situ intramolecular alkylations deliver optically
enriched functionalized carbocycles (>98% trans diastereoselec-
tivity). Similar to transformations with Et2Zn, reactions of Me2Zn
typically provide higher levels of enantioselectivity than the
sterically bulky (i-Pr)2Zn.
To the best of our knowledge, this study outlines the most
general, efficient, and enantioselective catalytic protocol for ef-
fecting catalytic asymmetric conjugate additions of alkylmetals to
acyclic aliphatic enones. The ease of preparation of the chiral
catalysts and substrates, the functional group compatibility of the
requisite alkylmetals, the possibility of using alkylzincs other than
Et2Zn, together with the efficiency and high levels of asymmetric
induction, should render the present approach of notable utility in
asymmetric organic synthesis. Design and development of additional
catalytic asymmetric conjugate additions promoted by various
peptide-based ligands are in progress and will be reported shortly.15
A similar protocol leads to the formation of cyclohexyl ketone 26
(95% ee, >98% anti, 81% yield). Repeated attempts to prepare
the corresponding seven-membered ring product from reaction of
tosylate 27 resulted in the formation of conjugate addition product
28 in 95% ee and 91% overall yield after chromatography. As the
example in eq 1 demonstrates, (2 f 29), enolate alkylation may
be effected intermolecularly as well.12
Several points regarding the data in Table 1 and Scheme 2 are
noteworthy: (1) The identity of the peptide moiety of the chiral
ligand is critical to enantioselectivity. For example, when the chiral
ligand related to 1, but with AA1 ) L-Val and AA2 ) L-Phe, is
used in catalytic alkylations of 2 and 20 (entries 1 and 10, Table
1), ketones 3 and 21 are obtained in 89% ee and 5% ee (70% and
88% yields, respectively). (2) The AA2 moiety must be present to
ensure high asymmetric induction. Catalytic addition of Et2Zn to
10 in the presence of 2.4 mol % 30 proceeds to completion within
Supporting Information Available: Experimental procedures and
spectral and analytical data for all products (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
1 h, but affords 11 in only 59% ee (vs 95% ee with 1). (3) In most
reactions examined, optimal selectivities are conveniently attained
at ambient temperature.13 Only reactions in entries 1-4 of Table 1
proceed with lower levels of enantioselectivity at 22 °C (e.g., 3 is
obtained in 78% ee) and produce notable amounts of unidentified
byproducts. (4) A comparison of the levels of enantioselectivity in
reactions of enones 20 (entry 10, Table 1) and those described in
Scheme 2 suggests the presence of Lewis basic functionalities within
a certain distance of the reactive enone group can lead to lowering
of asymmetric induction. It is plausible that, as suggested by
extensive mechanistic data related to other processes promoted by
this class of chiral ligands, the peptidic Schiff base-metal complex
References
(1) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc. 2001,
123, 755-756.
(2) For a subsequent report on catalytic asymmetric conjugate additions of
activated cyclopentenones (up to 97% ee), see: Arnold, L. A.; Naasz, R.;
Minaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2001, 123, 5841-5842.
(3) For a review on asymmetric conjugate additions, see: Krause, N.;
Hoffmann-Ro¨der, A. Synthesis 2001, 171-196.
(4) (a) Soai, K.; Okudo, M.; Okamoto, M. Tetrahedron Lett. 1991, 32, 95-
96. (b) van Klaveren, M.; Lambert, F.; Eijkelkamp, J. F. M.; Grove, D.
M.; Van Koten, G. Tetrahedron Lett. 1994, 35, 6135-6138. (c) Strange-
land, E. L.; Sammakia, T. Tetrahedron 1997, 53, 16503-16510. (d)
Alexakis, A.; Burton, J.; Vastra, J.; Mangeney, P. Tetrahedron: Asymmetry
1997, 8, 3987-3990. (e) Bennet, S. M. W.; Brown, S. M.; Muxworthy,
9
780 J. AM. CHEM. SOC. VOL. 124, NO. 5, 2002

C O M M U N I C A T I O N S
J. P.; Woodward, S. Tetrahedron Lett. 1999, 40, 1767-1770. (f) Yan,
M.; Yang, L.-W.; Wong, K.-Y.; Chan, A. S. C. Chem. Commun. 1999,
11-12. (g) Hu, X.; Chen, H.; Zhang, X. Angew. Chem., Int. Ed. 1999,
38, 3518-3521. (h) Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A.
H. M.; Naasz, R.; Feringa, B. L. Tetrahedron 2000, 56, 2865-2878. (i)
Yamanoi, Y.; Imamoto, T. J. Org. Chem. 1999, 64, 2988-2989. (j) Escher,
I. H.; Pfaltz, A. Tetrahedron 2000, 56, 2879-2888. (k) Bo¨rner, C.; Dennis,
M. R.; Sinn, E.; Woodward, S. Eur. J. Org. Chem. 2001, 2435-2446. (l)
Alexakis, A.; Rosset, S.; Allamand, J.; March, S.; Guillen, F.; Benhaim,
C. Synlett 2001, 1375-1378. (m) Chataigner, I.; Gennari, C.; Ongeri, S.;
Piarulli, U.; Ceccarelli, S. Chem.-Eur. J. 2001, 7, 2628-2634.
(7) For proof of the identity of major product enantiomer, see the Supporting
Information.
(8) The order of addition can be critical to obtaining optimal levels of
enantioselectivity (treatment of a solution of Cu salt and ligand with
dialkylzinc before addition of substrate leads to slightly higher yields and
enantioselectivities).
(9) When the peptidic Schiff base corresponding to 1 but with L-Val and
L-Phe as AA1 and AA2 is used (2 mol % Cu salt and 4.8 mol % ligand),
17 is obtained in 70% ee and 42% isolated yield.
(10) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem.
Soc. 2000, 122, 8168-8179.
(5) For Ni-catalyzed conjugate additions of Et2Zn to acyclic enones (mostly
chalcone), see: (a) Bolm, C.; Ewald, M.; Felder, M. Chem. Ber. 1992,
125, 1205-1215. (b) Corma, A.; Iglesias, M.; Martin, M. V.; Rubio, J.;
Sanchez, F. Tetrahedron: Asymmetry 1992, 3, 845-848. (c) de Vries,
A. H. M.; Imbos, R.; Feringa, B. L. Tetrahedron: Asymmetry 1997, 8,
1467-1473. (d) Yin, Y.; Li, X.; Lee, D.-S.; Yang, T.-K. Tetrahedron:
Asymmetry 2000, 11, 3329-3333. (e) Spieler, J.; Huttenloch, O.;
Waldmann, H. Eur. J. Org. Chem. 2000, 391-399. For related Co-
catalyzed additions to chalcone, see: (f) de Vries, A. H. M.; Feringa, B.
L. Tetrahedron: Asymmetry 1997, 8, 1377-1378.
(6) For catalytic asymmetric conjugate additions of nonalkylmetal carbon
nucleophiles to acyclic unsaturated carbonyls, see: (a) Takaya, Y.;
Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura, N. J. Am. Chem. Soc.
1998, 120, 5579-5580. (b) Appella, D. H.; Moritani, Y.; Shintani, R.;
Ferreira, E. M.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9473-
9474. (c) Corey, E. J.; Zhang, F.-Y. Org. Lett. 2000, 2, 4257-4259. (d)
Jensen, K. B.; Thorhauge, J.; Hazell, R. G.; Jrgensen, K. A. Angew. Chem.,
Int. Ed. 2001, 40, 160-163.
(11) For a previous example of sequential catalytic olefin metathesis/catalytic
asymmetric olefin alkylation, see: Visser, M. S.; Heron, N. M.; Didiuk,
M. T.; Sagal, J. F.; Hoveyda, A. H. J. Am. Chem. Soc. 1996, 118, 4291-
4298.
(12) In the absence of HMPA, the yield of alkylation products is <20%.
(13) With the majority of reactions studied (other than entries 1-4, Table 1),
higher enantioselectivities and yields are obtained at 22 °C (vs 0 or 40
°C). For example, in reaction of 12 with Et2Zn, 82% ee and 81% yield
are observed at 0 °C and 85% ee and 65% yield at +40 °C (see entry 6,
Table 1 for comparison).
(14) Josephsohn, N. S.; Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2001, 123, 11594-11599.
(15) This research was supported by grants from the NIH (GM-47480 and
GM-57212).
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