Enantioselective synthesis of α-alkyl-β,γ-unsaturated esters through efficient Cu-catalyzed allylic alkylations

Article abstract of DOI:10.1021/ja0300618

Treatment of an (allyl)organosilane with silica gel in refluxing toluene brought about deallylation forming an Si-O-Si bond with the silicon on the silica gel. This Si-O-Si bond formation provides us with a new reliable method for the functionalization of a silica gel surface. Copyright

Full text of DOI:10.1021/ja0300618

Published on Web 03/29/2003
Enantioselective Synthesis of r-Alkyl-â,γ-unsaturated Esters through Efficient
Cu-Catalyzed Allylic Alkylations
Kerry E. Murphy and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467
Received January 29, 2003; E-mail: amir.hoveyda@bc.edu
Chart 1
Catalytic methods for enantioselective synthesis of R-alkyl
carbonyls, where C-C bond formation proceeds by alkylation of
the derived enolate, have been the subject of several recent
disclosures.1 An alternative strategy would involve allylic alkylation
of an R,â-unsaturated carbonyl that bears a leaving group at its γ
site with a nucleophile (eq 1).2 A catalytic enantioselective allylic
substitution3 may therefore be effected to access synthetically
versatile R-alkyl-â,γ-unsaturated carbonyls in the optically enriched
form.
Herein we report an efficient Cu-catalyzed enantioselective
method for allylic alkylations of unsaturated esters bearing a primary
was isolated in >98% yield after the reaction in entry 7 and reused
γ-phosphate with alkylzincs. Reactions deliver products in 87-
to deliver equally high reactivity and selectivity. (4) Whereas
97% ee and are effected by a peptidic Schiff base that can be
reactions with 1e uniformly afford a single regioisomer, with smaller
carboxylic esters, selectivity suffers when sterically demanding
alkylzincs 9 and 10 are employed. (5) Commercially available
recovered and reused. The utility of the method is illustrated in a
total synthesis of topoisomerse II inhibitor (R)-elenic acid.4
Catalytic additions of Et2Zn to 1a (Table 1) were chosen as the
representative reaction for our screening studies.5 Selection of a
phosphate was based on past findings regarding allylic substitutions
involving such electrophiles with alkylzincs.3b We initially focused
on reactions promoted by different Cu salts with phosphine and
(CuOTf)2‚PhMe (Aldrich) can be used; as an example, (R)-2f is
formed with the same regioselectivity but in 84% ee and 70% yield
(under otherwise identical conditions as in Table 1).8
pyridyl ligands represented by 3 and 4 (Chart 1), because such
systems have proven optimal in other Cu-catalyzed processes.2d,3b,6
These investigations indicated that with CuCN and 3 or 4 (10 mol
%, THF, -30 °C), (S)-2a is formed with >98% regioselectivity in
∼25% ee; enantioselectivity slightly improved to ∼35% ee with
(CuOTf)2‚C6H6 and 4, but the regioselectivity was lower (4:1;
>98% conv in all cases). Whereas solvent screening led to little
improvement in alkylations with CuCN, in toluene the (CuOTf)2‚
C6H6/4 combination delivered (S)-2a in 90% ee but without
regioselectivity. To identify more desirable conditions, the activities
of various other Schiff base ligands (such as 5) and their derived
amines and amides were also screened (∼20 ligands examined).
These studies indicated that (R)-2a is formed in 68% ee and 5:1
regioselection with 10 mol % 5 and 5 mol % (CuOTf)2‚C6H6
(toluene, -30 °C). We then determined that in THF the desired
regioisomer is generated with >20:1 selectivity. Subsequent screen-
ing (∼100 ligands) indicated that Schiff bases 6-8 provide the
highest efficiency, regio-, and enantioselectivity. As shown in entry
1 of Table 1, reaction of 1a with Et2Zn is promoted by 6 to proceed
in 95% ee, 17:1 regioselectivity, and in 93% yield.
Table 1. Enantioselective Cu-Catalyzed Allylic Substitutionsa
ligand
(mol %) product
yieldb
(%)
eed
(%)
c
entry
R′
alkylzinc
SN2′:SN2
1
2
3
4
5
6
7
8
9
Me
Me
Me
1a Et2Zn
6, 10
6, 10
6, 10
7, 1
8, 10
6, 10
6, 10
6, 1
6, 10
6, 10
6, 10
6, 10
2a
2b
2c
2d
2e
2f
2g
2g
2h
2i
93
72
64
83
47
86
79
72
80
68
85
75
17:1
8:1
7:1
20:1
13:1
8:1
17:1
>20:1
>20:1
>20:1
>20:1
>20:1
95
92
87
94
93
94
94
97
90
97
95
90
1a
9
1a 10
n-Bu 1b Et2Zn
allyl
allyl
i-Pr
1c Et2Zn
1c
9
1d Et2Zn
1d Et2Zn
1e Me2Zne
1e Et2Zn
i-Pr
t-Bu
t-Bu
t-Bu
t-Bu
10
11
12
1e
9
2j
2k
1e 10
As illustrated in Table 1, various alkylzincs react with unsaturated
esters to afford the desired products with high enantioselectivity.7
The following points merit mention: (1) Lower catalyst loadings
(1 mol %) deliver similarly high levels of selectivity (entries 4 and
8). (2) Although results with ligands 7 and 8 are shown in entries
4 and 5, selectivities observed with 6 are not substantially lower
(within 5% ee). (3) Chiral ligands are recyclable; for example, 6
a Conditions: (CuOTf)2‚C6H6 equivalent to one-half the indicated ligand
amount, 3 equiv of alkylzinc, THF, -50 °C (entries 3, 9, and 12 were carried
out at -30 °C), 12 h, N2 atm. b Isolated yields. c Determined by GLC
(entries 1, 4-5, 7-8) or 400 MHz 1H NMR. d Determined by GLC
(CDGTA column for entry 1, â-DEX column for others); except for entries
1 and 9, analyses were performed on derived alcohols. e Six equivalents of
Me2Zn was used with a reaction time of 48 h.
9
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J. AM. CHEM. SOC. 2003, 125, 4690-4691
10.1021/ja0300618 CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Enantioselective Total Synthesis of Elenic Acida
a (a) 5 mol % 12, Cl(CH2)2Cl, 2 h, then H2 (200 psi); 92%. (b) (1) K2CO3, MeOH, CH2Cl2; 80%. (2) I2, PPh3, imid., Et2O, MeCN; 98%. (c) (1)
p-OMeC6H4MgBr, 10 mol % CuI, THF, 4 °C; 49%. (2) LiCCH‚EDA, DMSO, THF; 79%. (d) Cp2ZrCl2, Me3Al, CH2Cl2, 66%. (e) 1 equiv of 2h (90% ee),
2 equiv of 16, 35 mol % 12, THF, 40 °C, 24 h, 3:1 E:Z; 40%. (f) BBr3, CH2Cl2, -78 to 22 °C; 85%.
4, 1051-1054. For a related enantioselective process, see: (d) Luchaco-
Cullis, C. A.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 8192-8193.
(3) For catalytic asymmetric allylic substitutions with alkylzincs, see: (a)
Dubner, F.; Knochel, P. Tetrahedron Lett. 2000, 41, 9233-9237. (b)
Luchaco-Cullis, C. A.; Mizutani, H.; Murphy, K. E.; Hoveyda, A. H.
Angew. Chem., Int. Ed. 2001, 40, 1456-1460. (c) Malda, H.; van Zijl, A.
W.; Arnold, L. A.; Feringa, B. L. Org. Lett. 2001, 3, 1169-1171. (d)
Ongeri, S.; Piarulli, U.; Roux, M.; Monti, C.; Gennari, C. HelV. Chim.
Acta 2002, 85, 3388-3399. (e) Piarulli, U.; Daubos, P.; Claverie, C.; Roux,
M.; Gennari, C. Angew. Chem., Int. Ed. 2003, 42, 234-236.
(4) Isolation: (a) Juagdan, E. G.; Kalidindi, R. S.; Scheuer, P. J.; Kelly-Borges,
M. Tetrahedron Lett. 1995, 36, 2905-2908. Total syntheses: (b)
Takanashi, S.; Takagi, M.; Takakawa, H.; Mori, K. J. Chem. Soc., Perkin
Trans. 1 1998, 1603-1606. (c) Hoye, R. C.; Baigorria, A. S.; Danielson,
M. E.; Pragman, A. A.; Rajapakse, H. A. J. Org. Chem. 1999, 64, 2450-
2453.
(5) Cole, B. M.; Shimizu, K. D.; Krueger, C. A.; Harrity, J. P. A.; Snapper,
M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. Engl. 1996, 35, 1668-
1671. See the Supporting Information for details of screening studies.
(6) (a) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc. 2001,
123, 755-756. (b) Mizutani, H.; Degrado, S. J.; Hoveyda, A. H. J. Am.
Chem. Soc. 2002, 124, 779-781. (c) Degrado, S. J.; Mizutani, H.;
Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 13362-13363. (d) Hird,
A. W.; Hoveyda, A. H. Angew. Chem., Int. Ed. Engl. 2003, 42, 1276-
1279.
The Cu-catalyzed asymmetric alkylation has been used in a
convergent total synthesis of (R)-(-)-elenic acid (Scheme 1). One-
pot catalytic homodimerization/hydrogenation9 of 11 with 5 mol
% 12 (Aldrich)10 delivers 13 in 92% yield. Conversion to diiodide
14 and subsequent alkylations afford alkyne 15, which is converted
to 16 by Zr-mediated alkylalumination.11 Cross-metathesis between
16 and optically enriched 2h, obtained from enantioselective
alkylation of 1e with Me2Zn (entry 9, Table 1), proceeds in the
presence of 35 mol % 12 to afford 17 in 40% yield (80% based on
recovered 16) and 3-4:1 E:Z selectivity.12 Model studies involving
cross-metathesis of 2h and 2-methyl-1-hexene indicate that <5%
erosion of enantiopurity occurs when 12 is used; reactions with
Grubbs’ catalyst13 under identical conditions lead to 10% diminution
in ee. Treatment of 17 with BBr3 delivers (R)-elenic acid.14
Studies toward the development of other catalytic asymmetric
allylic alkylations are in progress.
Acknowledgment. This work was supported by the NIH (GM-
(7) Isolated yields are at times moderate due to product volatility.
(8) Initial studies with secondary alkylzincs (e.g., (i-Pr)2Zn) result in efficient
alkylations that proceed with low enantioselectivity (<20% ee).
(9) Louie, J.; Bielawski, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123,
11312-11313.
(10) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem.
Soc. 2000, 122, 8168-8179.
47480) and the NSF (CHE-0213009).
Supporting Information Available: Experimental procedures and
spectral and analytical data for reaction products (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
(11) Van Horn, D. E.; Negishi, E. J. Am. Chem. Soc. 1978, 100, 2252-2254.
(12) Higher catalyst loading is required probably due to internal chelation of
the terminal Ru carbene with the neighboring carbonyl oxygen, which
diminishes its reactivity. Metathesis yields suffer from formation of
homodimers of 2h. For utility of 12 in cross-metathesis, see: (a) Cossy,
J.; BouzBouz, S.; Hoveyda, A. H. J. Organomet. Chem. 2001, 624, 327-
332. (b) Randl, S.; Gessler, S.; Wakamatsu, H.; Blechert, S. Synlett 2001,
430-432.
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