Cu-catalyzed asymmetric allylic alkylations of aromatic and aliphatic phosphates with alkylzinc reagents. An effective method for enantioselective synthesis of tertiary and quaternary carbons

Article abstract of DOI:10.1021/ja0478779

Efficient enantioselective Cu-catalyzed allylic alkylations of aromatic and aliphatic allylic phosphates bearing di- and trisubstituted olefins are disclosed. Enantioselective C-C bond forming reactions are promoted in the presence of 10 mol % readily available chiral amino acid-based ligand (5 steps, 40% overall yield synthesis) and 5 mol % (CuOTf)₂·C ₆H₆. Reactions deliver tertiary and quaternary stereogenic carbon centers regioselectively and in 78-96% ee. Data regarding the effect of variations in ligand structure on the efficiency and enantioselectivity of the alkylation process, as well as a mechanistic working model, are presented. The suggested model involves a dual role for the chiral Cu complex: association of the Cu(I) center to the olefin is facilitated by a two-point binding between the carbonyl of the ligand's amide terminus and the P=O of the substrate.

Full text of DOI:10.1021/ja0478779

Published on Web 08/07/2004
Cu-Catalyzed Asymmetric Allylic Alkylations of Aromatic and
Aliphatic Phosphates with Alkylzinc Reagents. An Effective
Method for Enantioselective Synthesis of Tertiary and
Quaternary Carbons
Monica A. Kacprzynski and Amir H. Hoveyda*
Contribution from the Department of Chemistry, Merkert Chemistry Center,
Boston College, Chestnut Hill, Massachusetts 02467
Received April 13, 2004; E-mail: amir.hoveyda@bc.edu
Abstract: Efficient enantioselective Cu-catalyzed allylic alkylations of aromatic and aliphatic allylic
phosphates bearing di- and trisubstituted olefins are disclosed. Enantioselective C-C bond forming reactions
are promoted in the presence of 10 mol % readily available chiral amino acid-based ligand (5 steps, 40%
overall yield synthesis) and 5 mol % (CuOTf)2‚C6H6. Reactions deliver tertiary and quaternary stereogenic
carbon centers regioselectively and in 78-96% ee. Data regarding the effect of variations in ligand structure
on the efficiency and enantioselectivity of the alkylation process, as well as a mechanistic working model,
are presented. The suggested model involves a dual role for the chiral Cu complex: association of the
Cu(I) center to the olefin is facilitated by a two-point binding between the carbonyl of the ligand’s amide
terminus and the PdO of the substrate.
presence of chiral aryl5a and ferrocenyl5b thiols as well as
P-based ligands5c-e have led to several regioselective and
Introduction
Allylic alkylations are important C-C bond forming reactions
that deliver synthetically versatile organic molecules. Although
many related catalytic asymmetric protocols have been outlined
involving stabilized carbon nucleophiles,1 additions of alkyl
nucleophiles are significantly less developed.2 One recent
example is in regards to Cu-catalyzed additions of alkylzincs
to disubstituted olefins of allylic chlorides, where >90% ee can
be obtained with the sterically bulky bis(neopentyl)zinc; reac-
tions of less hindered alkylzinc reagents proceed with signifi-
cantly lower enantioselectivity (e72% ee).3 Chiral phosphor-
amidites and phosphites have also been shown to promote
additions of smaller alkylzinc reagents (predominantly Et2Zn)
to disubstituted alkenes of allylic chlorides in up to 77% ee.4
Efforts concerning reactions of alkylmagnesium halides with
allylic acetates and chlorides (also disubstituted olefins)5 in the
efficient catalytic asymmetric alkylations. High enantioselec-
tivities (up to 96% ee) have been observed in the latter studies;5e
however, substrate range is somewhat limited (a single aliphatic
and two nearly identical aromatic allylic halides) and does not
include trisubstituted olefins.
We recently disclosed Cu-catalyzed additions of alkylzinc
reagents to allylic phosphates promoted by pyridyl Schiff bases
1a-c (Scheme 1).6,7 Selectivities of 78-90% ee were observed
for reactions of trisubstituted olefins, leading to asymmetric
formation of quaternary carbon centers; synthetic utility was
demonstrated through a concise total synthesis of (-)-sporochnol
in 82% overall yield (82% ee). However, several shortcomings
detracted from the utility of our method. As with the previously
mentioned protocols,3-7 transformations involving disubstituted
olefins often proceed with low enantioselectivity (66-87% ee).
Moreover, highly enantioselective reactions of aliphatic sub-
strates (di- or trisubstituted olefins), a synthetically important
and challenging category of alkylations, continued to prove
elusive. It should be noted that, except for two cases involving
a single substrate,3b,5e catalytic alkylation of aliphatic substrates
typically yield products with inferior levels of optical purity
(<75% ee).5
(1) For recent reviews, see: (a) Trost, B. M.; van Vranken, D. L. Chem. ReV.
1996, 96, 395-422. (b) Trost, B. M.; Crawley, M. L. Chem. ReV. 2003,
103, 2921-2943.
(2) For a review, see: Hoveyda, A. H.; Heron, N. M. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, Germany, 1999; pp 431-454.
(3) (a) Dubner, F.; Knochel, P. Angew. Chem., Int. Ed. 1999, 38, 379-381.
(b) Dubner, F.; Knochel, P. Tetrahedron Lett. 2000, 41, 9233-9237.
(4) (a) Malda, H.; van Zijl, A. W.; Arnold, L. A.; Feringa, B. L. Org. Lett.
2001, 3, 1169-1171. (b) Shi, W.-J.; Wang, L.-X.; Fu, Y.; Zhu, S.-F.; Zhou,
Q.-L. Tetrahedron: Asymmetry 2003, 14, 3867-3872. For related studies,
see (products obtained in <65% ee): (c) Borner, C.; Gimeno, J.; Gladiali,
S.; Goldsmith, P. J.; Ramazzotti, D.; Woodward, S. Chem. Commun. 2000,
2433-2444.
(5) (a) Meuzelaar, G. J.; Karsltrom, A. S. E.; van Klaveren, M.; Persson, E. S.
M.; del Villar, A.; van Koten, G.; Backvall, J.-E. Tetrahedron 2000, 56,
2895-2903. (b) Karlstrom, A. S. E.; Huerta, F. F.; Meuzelaar, G. J.;
Backvall, J.-E. Synlett 2001, 923-926. (c) Alexakis, A.; Malan, C.; Lea,
L.; Benhaim, C.; Fournioux, X. Synlett 2001, 927-930. (d) Alexakis, A.;
Croset, K. Org. Lett. 2002, 4, 4147-4149. (e) Tissot-Croset, K.; Polet, D.;
Alexakis, A. Angew. Chem., Int. Ed. 2004, 43, 2426-2428.
After the above studies, we discovered that chiral dipeptide
2, derived from a salicyl aldehyde, in the presence of (CuOTf)2‚
(6) Luchaco-Cullis, C. A.; Mizutani, H.; Murphy, K. E.; Hoveyda, A. H. Angew.
Chem., Int. Ed. 2001, 40, 1456-1460.
(7) For related studies, see: (a) Piarulli, U.; Daubos, P.; Claveric, C.; Roux,
M.; Gennari, C. Angew. Chem., Int. Ed. 2003, 42, 234-236. (b) Ongeri,
S.; Piarulli, U.; Roux, M.; Monti, C.; Gennari, C. HelV. Chim. Acta 2002,
85, 3388-3399. (c) Piarulli, U.; Claverie, C.; Daubos, P.; Gennari, C.;
Minnaard, A. J.; Feringa, B. L. Org. Lett. 2003, 5, 4493-4496.
9
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J. AM. CHEM. SOC. 2004, 126, 10676-10681
10.1021/ja0478779 CCC: $27.50 © 2004 American Chemical Society

Enantioselective Synthesis of Tertiary/Quaternary Carbons
A R T I C L E S
Scheme 1. Chiral Ligands Used in Cu-Catalyzed Asymmetric Alkylations of Allylic Phosphates
Table 1. Enantioselective Cu-Catalyzed Allylic Alkylations of Disubstituted Unsaturated Aryl Phosphatesa
c
entry
Ar
C6H5
alkylzinc
product
yieldb (%)
SN2′:SN2
eed (%)
ee with 1e (%)
1
2
3
4
5
6
7
8
9
4a
4a
4b
4b
4c
4c
4d
4e
4f
Et2Zn
5a
5b
5c
5d
5e
5f
5g
5h
5i
61
90
73
62
95
82
67
66
64
90:10
87:13
90:10
81:19
85:15
87:13
86:14
50:50
40:60
95
91
94
84
95
95
94
96
93
66
na
na
na
87
na
75
72
na
C6H5
[Me2CH(CH2)3]2Zn
Et2Zn
[AcO(CH2)4]2Zn
Et2Zn
[Me2CH(CH2)3]2Zn
Et2Zn
p-CF3C6H4
p-CF3C6H4
o-NO2C6H4
o-NO2C6H4
p-NO2C6H4
o-MeC6H4
2-naphth
Et2Zn
Et2Zn
1
a Conditions: 3 equiv of alkylzinc, THF, -15 °C, 24 h, N2 atm. b Isolated yields. c Determined by 400 MHz H NMR. d Determined by chiral GLC or
HPLC (see Supporting Information for details). e See ref 6; >98% SN2′ in all cases. na ) not available.
C6H6 effectively promotes catalytic alkylations of unsaturated
esters bearing γ-phosphates to deliver R-alkyl-â,γ-unsaturated
carbonyls with excellent levels of optical purity (Scheme 1).8
The synthetic utility of this latter catalytic asymmetric protocol
was demonstrated through application to a concise enantio-
selective total synthesis of topoisomerase II inhibitor (-)-elenic
acid. These observations prompted us to examine the ability of
the salicyl-based peptidic chiral ligands in effecting Cu-catalyzed
asymmetric alkylations of the previously mentioned class of
allylic phosphates (first equation in Scheme 1). Our aim was to
enhance the enantioselectivity levels of the C-C bond forming
reactions as well as expand the scope of the catalytic asymmetric
method to include additions to the more difficult aliphatic
substrates.
In this article, we report a new method for Cu-catalyzed
enantioselective alkylations of allylic phosphates with alkylzinc
reagents that is significantly more general and effective than
the approaches mentioned above. Transformations are promoted
by dipeptide Schiff base 3 and (CuOTf)2‚C6H6 and afford
products in up to 96% ee. A wide range of substrates can be
effectively alkylated: aromatic and aliphatic phosphates that
bear di- or trisubstituted olefins undergo highly enantioselectiVe
alkylations. Unlike the previously reported dipeptide 1,6 access
to which requires synthesis of a functionalized pyridyl aldehyde,
chiral ligand 3 is readily obtained in gram quantities in five
reliable steps from a commercially available salicyl aldehyde
and optically pure protected amino acids (40% overall yield;
unoptimized).
Results and Discussion
I. Cu-Catalyzed Asymmetric Allylic Alkylations of Aro-
matic Phosphates. As illustrated in Table 1, in the presence of
10 mol % chiral Schiff base 39 and 5 mol % (CuOTf)2‚C6H6
(THF, -15 °C, 24 h), aromatic disubstituted allylic phosphates
4a-f undergo highly enantioselective (84-96% ee) allylic
alkylations with various alkylzinc reagents. The regioselectivities
(9) A brief initial screening with selected di- and trisubstituted olefinic substrates
(see Tables 1 and 2, below) indicated that although chiral ligand 2 is
typically as effective in promoting catalytic alkylations, in a few instances
dipeptide 3 promotes more efficient and/or enantioselective C-C bond
forming reactions.
(8) Murphy, K. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 4690-
4691.
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A R T I C L E S
Kacprzynski and Hoveyda
Table 2. Enantioselective Cu-Catalyzed Allylic Alkylations of Trisubstituted Unsaturated Aryl Phosphatesa
c
entry
Ar
C6H5
p-CF3C6H4
p-NO2C6H4
p-NO2C6H4
p-OTsC6H4
alkylzinc
product
yieldb (%)
SN2′:SN2
eed (%)
ee with 1e (%)
1
2
3
4
5
6a
6b
6c
6c
6d
Et2Zn
Et2Zn
Et2Zn
7a
7b
7c
7d
7e
64
58
79
86
92
>30:1
>30:1
>30:1
>30:1
>30:1
92
88
87
83
88
78
81
86
na
90
[Me2CH(CH2)3]2Zn
Et2Zn
1
a Conditions: 3 equiv of alkylzinc, THF, -15 °C, 24 h, N2 atm. b Isolated yields. c Determined by 400 MHz H NMR. d Determined by chiral GLC or
HPLC (see Supporting Information for details). e See ref 6; >98% SN2′ in all cases. na ) not available.
Table 3. Enantioselective Cu-Catalyzed Allylic Alkylations of
phosphates shown in Table 1 (<10% conversion in most cases).
Catalytic alkylation of alkenyl allylic phosphate 10 proceeds
Unsaturated Alkyl, Alkenyl, and Alkynyl Allylic Phosphatesa
regioselectively (85:15 SN2′:SN2′) to afford 1,4-diene 11 in 89%
ee. Cu-catalyzed addition of Et2Zn to alkynyl substrate 14 (entry
6) is less regioselective but delivers enyne 15 in 96% ee.
Efficient catalytic enantioselectiVe alkylations of the trisubsti-
tuted allylic phosphates 16 and 18, leading with high regio-
control to the formation of a quaternary carbon stereogenic
centers in diene 17 and enyne 19 in 82% and 91% ee,
respectiVely, underline the significant potential of the present
protocol in organic synthesis.
III. Effect of the Chiral Ligand Structure on Efficiency
and Enantioselectivity of Alkylations. The data illustrated in
Table 4 shed light on the inner workings of the Cu-catalyzed
transformations. As suggested by the alkylation in entry 1 (20,
Table 4), the AA2 moiety (amino acid forming Schiff base is
AA1) is necessary for high enantioselectivity but not for efficient
alkylation. It is important to note that there is <2% conversion
in the absence of a chiral ligand. The inability of ligand 21
a Conditions: 10 mol % 3, 5 mol % (CuOTf)2‚C6H6, 3 equiv of Et2Zn
(entry 2) to promote addition together with effectiveness of its
or 6 equiv of Me2Zn, THF, -15 °C, 24 h for Et2Zn and 48 h for Me2Zn,
THF, N2 atm. b Isolated yields. c Determined by 400 MHz 1H NMR.
d Determined by chiral GLC (see Supporting Information for details).
diastereomer 3 indicates that the presence of an AA2 is not
sufficient for high selectivity; the AA2 unit must also carry the
proper stereochemical identity. The data in entries 3 and 4 show
that, whereas chirality at AA1 raises the efficiency of a catalytic
alkylation (reaction of 22), it is not nearly as critical as the
chirality resident within AA2 (reaction of 23). Data in entries
3 and 4 demonstrate that asymmetric induction mainly originates
at the AA2 site.
shown in Table 1, although synthetically useful, are lower than
some of the previously reported cases.3-7 However, the enan-
tioselectivites are by far the highest reported for allylic alky-
lations with small alkylmetal reagents. In all cases, the increase
in asymmetric induction is significant compared to reactions
promoted by 1 (entries 1, 5, 7, and 8, Table 1).
The inability of tertiary amide 24 to promote reaction points
to the significance of peptide conformation preferences that
accompany secondary amide structures.11 The lack of reactivity
with unsaturated ligand 25 and the inability of methyl ester 26
and dialkyl amide 27 to promote efficient or enantioselective
reactions imply that the requirement for the terminal secondary
amide moiety is conformational as well as steric: the presence
of a sufficiently Lewis basic and sterically accessible amide is
critical to a high yielding and enantioselective alkylation.
IV. Mechanistic Working Model. A working model (Scheme
2) is proposed based on the above data and recent mechanistic
studies regarding other C-C bond forming reactions promoted
by this class of chiral ligands.12 Complex I, bearing a pseudo-
tetrahedral Cu(I), represents the resting state of the chiral
complex. Upon association of an unsaturated phosphate, com-
plex II is generated. Catalytic alkylations likely proceed through
The findings summarized in Table 2 illustrate that chiral
ligand 3 also catalyzes alkylations of trisubstituted allylic
phosphates with high regioselectivity (>30:1 SN2′:SN2) to afford
products bearing quaternary carbon centers in 83-92% ee.
Optical purities obtained through the use of 3 are either nearly
identical or higher than observed with pyridyl ligand 1 (92%
vs 78% ee in entry 1, Table 2).10
II. Cu-Catalyzed Asymmetric Allylic Alkylations of Ali-
phatic Phosphates. One of the more important and unique
attributes of the present method is that it can be used for
alkylations of di- and trisubstituted aliphatic phosphates ef-
ficiently and with unprecedented enantioselectivity and excellent
regioselectivity (Table 3). Facile alkylations of aliphatic sub-
strates 8 and 12 with the less reactive Me2Zn (vs Et2Zn) stands
in stark contrast to the significantly lower reactivity of aromatic
(10) Allylic phosphates with aryl units that bear o- or p-electron donating
substituents are typically unstable. However, such substrates do undergo
highly enantioselective catalytic alkylations. As an example, reaction of
allylic phosphate 6 with an o-OMeC6H4 group proceeds to 50% conversion
after 30 h to afford the desired product in 80-85% ee (>30:1 SN2′).
(11) For a general discussion, see: Creighton, T. E. In Proteins. Structures and
Molecular Properties; Freeman: New York, 1984; pp 159-197.
(12) Josephsohn, N. S.; Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2001, 123, 11594-11599.
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Enantioselective Synthesis of Tertiary/Quaternary Carbons
A R T I C L E S
Table 4. Ligand Structure and Cu-Catalyzed Alkylation of 4a with
The presence of an AA1 substituent (R in Scheme 2) is not
required for a highly enantioselective process (cf. entry 3 in
Table 4; 88% ee with Gly as AA1). Nonetheless, the alternative
diastereomer (cf. entry 2 in Table 4) would position the AA1
substituent (R) at a less favorable pseudoaxial position, raising
the energy of the requisite catalyst-substrate complex. Mode
of addition II is sterically favored: the larger olefin substituent
(RL) points away from the bulk of the ligand structure. The
presence of an O-Cu bond in II is suggested by the observation
that the methyl ether derived 28 (entry 9, Table 4) promotes
<10% alkylation.
Et2Zna
As illustrated in eq 1, catalytic alkylation of 29, the cis isomer
of 4a (cf. Table 1), with Et2Zn under identical conditions as
those in Table 1, proceeds to completion but affords (R)-5a in
only 50% ee (>30:1 SN2′:SN2, 61% yield). It is plausible that
positioning of the large Ph group at the RS site leads to
destabilization of II (steric interaction with ligand’s Schiff base
moiety) and lowers enantioselectivity as a result of addition
through other energetically competitive catalyst-substrate
complexes. The increase in regioselectivity, however, is difficult
to explain at this time.
Further evidence for the substrate-catalyst complexes shown
in Scheme 2 is found in Cu-catalyzed alkylations of chiral
nonracemic phosphate 30. As illustrated in Scheme 3, catalytic
alkylation of 30, generated by Ru-catalyzed cross metathesis
of 5e,18 in the presence of 10 mol % 3 leads to the formation of
31 as a single diastereomer (>98% conversion, 48 h). In
contrast, when (D,D)-3 is used, 10-15% conversion is observed
(13) For representative relevant experimental and theoretical studies, see: (a)
Goering, H. L.; Kantner, S. S. J. Org. Chem. 1983, 48, 721-724. (b)
Backvall, J.-E.; Sellen, M.; Grant, B. J. Am. Chem. Soc. 1990, 112, 6615-
6621 and references therein. (c) Dorigo, A. E.; Wanner, J.; von Rague
Schleyer, P. Angew. Chem., Int. Ed. Engl. 1995, 34, 476-478. (d) Mori,
S.; Hirai, A.; Nakamura, M.; Nakamura, E. Tetrahedron 2000, 56, 2805-
2809. (e) Karlstrom, A. S. E.; Backvall, J. E. Chem.sEur. J. 2001, 7, 1981-
1989.
(14) Generation of the products derived through the SN2 process in reactions
shown in Table 1 may arise from collapse of the initial η1 Cu complex i to
π-allyl ii which then can afford the undesired product. The reason for the
propensity of aromatic disubstituted phosphates (Table 1) to afford achiral
alkylation byproducts is not clear at the present time. See ref 13 for related
discussions.
a Conditions: 10 mol % ligand, 5 mol % (CuOTf)2‚C6H6, 3 equiv of
Et2Zn, THF, -15 °C, 24 h, THF, N2 atm. b Determined by GLC (see
Supporting Information for details).
formation of Cu(III)-alkyl intermediates,13 followed by reductive
elimination to afford the desired products.14
Catalyst-substrate complex II reserves an activating, as well
as a directing role, for the terminal amide carbonyl (cf. entries
1 and 5-8 in Table 4).15 The substrate is delivered preferably
to one face of the ligand‚Cu complex by the carbonyl group of
the amide terminus16 if it is sterically unencumbered (cf. entry
8, Table 4) and sufficiently Lewis basic (cf. entry 7, Table 4).17
The preferred ligand face is predicated on the identity of the
minimized peptide structure (cf. entry 5),11 including the
conformational preorganization induced by the stereogenic
center at AA2 (cf. entries 2 and 4, Table 4).12 A preorganized
peptide structure is critical as it minimizes the entropic cost
associated with a macrocyclic transition structure, as shown in
I.
(15) For a related proposal involving two-point association between catalyst
and substrate in a Cu-catalyzed allylic alkylation reaction, see ref 5a.
(16) Although a Zn chelate involving the amide CdO is shown in II and III,
it is possible that the amide N participates in this chelation. It is also feasible
that H-bonding between the secondary amide and the PdO of the substrate
leads to the second point of contact between catalyst and substrate.
(17) Several observations point to the significance of the PdO bond in
establishing an organized substrate-catalyzed complex that translates to high
asymmetric induction. For example, catalytic alkylations of the derived
allylic bromides proceed to afford the desired products (77% SN2′) in <2%
ee. Moreover, alkylation of the thiophosphate derivative of substrate 4a
(PdS instead of PdO) with Et2Zn (under conditions described for Table
1) leads to only ∼20% conversion and <2% ee. The latter observation
may underscore the significance of specific Lewis base-Lewis acid
distances for effective generation of substrate-catalyst complexes.
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A R T I C L E S
Kacprzynski and Hoveyda
Scheme 2. Proposed Modes of Reaction for Cu-Catalyzed Allylic Alkylations
Scheme 3. Cu-Catalyzed Alkylations of Optically Enriched Allylic Phosphate (R)-30
Conclusions
(<5% de). As illustrated in Scheme 2 (III), it may be proposed
that association of (R)-30 with 3 occurs through a complex
where the small H points toward the catalyst structure and the
large phenyl is oriented away from the chiral complex. Alky-
lation of (S)-3019 would require the large phenyl to occupy the
“inside” position (the position Et holds in III), engendering a
higher degree of steric repulsion within the catalyst-substrate
complex.
In summary, we disclose an efficient and highly enantio-
selective method for catalytic alkylations of allylic phosphates
with various alkylzinc reagents. Special features of the present
protocol include efficient asymmetric additions to di- and
trisubstituted aliphatic substrates that deliver tertiary and
quaternary carbon centers;22 the derived optically enriched
products cannot be accessed readily by other methods. More-
over, we propose a plausible working model that explains the
origin of the observed selectivities.
The Cu-catalyzed enantioselective alkylations presented
herein are of high synthetic potential. The products obtained
can be readily functionalized in a large variety of ways. The
Ru-catalyzed cross metathesis23 shown in Scheme 3 is a case
in point; related reactions with R,â-unsaturated carbonyls can
deliver optically enriched chiral substrates for subsequent
diastereoselective conjugate addition reactions.24 Another ex-
ample is illustrated in eq 2; Wacker oxidation25 of optically
enriched 9a (cf. entry 1, Table 3) leads to formation of methyl
ketone 32 in 60% isolated yield.26
Alkylation of (R)-30 with 10 mol % CuCN (without chiral
ligand, otherwise identical conditions as in Scheme 3) affords
31 in 81% isolated yield and only 80% de (>98% conversion).
The “matched” chiral ligand thus imposes higher degrees of
transition state organization to enhance the diastereoselectivity
of the alkylation.20 It should also be noted that the significant
differences in the rates of allylic alkylations of (R)-30 (Scheme
3) suggest that related racemic substrates can be subjected to
efficient Cu-catalyzed kinetic resolutions as well.21
(18) (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168-8179. (b) Hoveyda, A. H.; Gillingham, D.
G.; Van Veldhuizen, J. J.; Garber, S. B.; Kataoka, O.; Kingsbury, J. S.;
Harrity, J. P. A. Org. Biol. Chem. 2004, 2, 8-23.
(19) The substrate/catalyst complex derived from (S)-24 and (L,L)-3 is energeti-
cally equivalent to that arising from (R)-24 and (D,D)-3 and is therefore
used here for the sake of clarity of discussion.
(20) For another example, where, in the presence of a chiral amino acid-based
ligand, diastereoselectivities are enhanced significantly, see: Cesati, R. R.;
de Armas, J.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 96-101.
(21) For recent reviews of metal-catalyzed kinetic resolutions, see: (a) Hoveyda,
A. H.; Didiuk, M. T. Curr. Org. Chem. 1998, 2, 537-574. (b) Cook, G.
R. Curr. Org. Chem. 2000, 4, 869-885. (c) Keith, J. M.; Larrow, J. F.;
Jacobsen, E. N. AdV. Synth. Catal. 2001, 1, 5-26.
The salicyl-based peptidic chiral ligands have been shown
previously to be effective for a variety of early transition metal-
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Enantioselective Synthesis of Tertiary/Quaternary Carbons
A R T I C L E S
catalyzed reactions.27 The present catalytic asymmetric protocol
further expands the utility of this emerging class of readily
available chiral ligands to include late transition metal catalysis
as well.8 Future studies will focus on the design and develop-
ment of additional chiral ligands, development of new catalytic
asymmetric C-C bond forming reactions, and applications to
the synthesis of biologically significant molecules.
(GM-47480). We are grateful to Kerry E. Murphy for many
helpful discussions.
Supporting Information Available: Experimental procedures
and spectral data for products (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
JA0478779
Acknowledgment. This paper is dedicated to our colleague
and friend, Professor Lawrence T. Scott, on the occasion of his
sixtieth birthday. Financial support was provided by the NIH
(27) (a) Nitta, H.; Yu, D.; Kudo, M.; Mori, A.; Inoue, S. J. Am. Chem. Soc.
1992, 114, 7969-7975. (b) Cole, B. M.; Shimizu, K. D.; Krueger, C. A.;
Harrity, J. P.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed.
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