Highly enantioselective Cu-catalyzed conjugate additions of dialkylzinc reagents to unsaturated furanones and pyranones: Preparation of air-stable and catalytically active Cu-peptide complexes

Article abstract of DOI:10.1002/anie.200501251

(Chemical Equation Presented) The first generally effective method for catalytic asymmetric conjugate addition (ACA) of dialkylzinc reagents to unsaturated furanones and pyranones (see scheme) with different steric and electronic properties is reported. S

Full text of DOI:10.1002/anie.200501251

Communications
Asymmetric Catalysis
DOI: 10.1002/anie.200501251
Highly Enantioselective Cu-Catalyzed Conjugate
Additions of Dialkylzinc Reagents to Unsaturated
Furanones and Pyranones: Preparation of
Air-Stable and Catalytically Active
Cu–Peptide Complexes**
M. Kevin Brown, Sylvia J. Degrado, and
Amir H. Hoveyda*
In recent years, a considerable amount of effort has been
expended on the development of catalytic methods for
asymmetric conjugate additions (ACA) of alkyl metal
reagents to unsaturated carbonyls.[1] Research in these
laboratories has led us to identify amino acid based phos-
phanes, such as 1–3 (Scheme 1), as chiral ligands for use in Cu-
[*] M. K. Brown, S. J. Degrado, Prof. A. H. Hoveyda
Department of Chemistry
Merkert Chemistry Center, Boston College
Chestnut Hill, MA 02467 (USA)
Fax: (+1)617-552-1442
E-mail: amir.hoveyda@bc.edu
[**] This research was supported by the United States National
Institutes of Health (GM-47480). S.J.D. was a Bristol-Myers Squibb
Graduate Fellow in Synthetic Organic Chemistry.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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commercially available Cu salts and utilized after storage for
at least a week.
Phosphanes 1–3 can be used to effect efficient and
enantioselective ACA of alkylzinc reagents to small and
medium ring unsaturated lactones (Table 1). A variety of
dialkylzinc reagents, including the sterically demanding
[(iPr)2Zn] (entries 2 and 5) as well as the less reactive
[Me2Zn] can be employed (entries 3 and 7). To obtain high
yield, reactions must be carried out in the presence of an
aldehyde;[10] this is presumably due to adventitious ketene
formation or intermolecular Michael addition if the enolate
intermediate is not trapped in situ. The resulting aldol adduct
can be oxidized to afford the corresponding diketone (> 98%
anti), or, as represented by the formation of 15 and 16
(Scheme 2), converted to the derived optically enriched b-
alkyl carbonyl by an efficient retro-aldol process.
This phase of our studies pointed to a chiral ligand
hierarchy: First, the simplest phosphane 3 was examined; in
cases where ACAwas sluggish, the more potent 1 was utilized
(e.g., < 10% conversion with 10 mol% 3 vs. > 98% con-
version with 1 in entry 7). Chiral phosphane 2 was employed
when ACA products from reactions with 1 were judged not to
Scheme 1. Chiral amino acid based phosphanes used for Cu-catalyzed
asymmetric conjugate additions (ACA) to various heterocyclic enones.
catalyzed ACA processes involving dialkylzinc reagents.[2]
However, the majority of investigations
have focused on transformations of unsatu-
Table 1: Cu-catalyzed ACA of alkylzinc reagents to unsaturated lactones.[a]
rated ketones;[2,3] more recently, a number
of studies have involved Cu-catalyzed ACA
of nitroalkenes.[4]
Catalytic ACA reactions of the less
reactive cyclic or acyclic unsaturated car-
boxylic esters (e.g., I, Scheme 1) have
received far less attention.[5] A number of
studies have addressed the problem of
catalytic additions of dialkylzinc reagents
to unsaturated lactones.[6–8] In spite of high
enantioselectivities (> 90% ee) in select
instances, the above disclosures address
only reactions of one or two substrates (I,
n = 1or 2) or nucleophiles (typically
[Et2Zn]; less frequently [Me2Zn]). Due to
complications that will be clarified later, in a
number of cases, isolated yields are not
Entry
Substrate
[(alkyl)2Zn]
Ligand
(mol%) Cu salt
mol%
Product
t
Yield ee
[h] [%][b] [%][c]
1
2
3[d]
4
5
6
[Et2Zn]
[(iPr)2Zn]
2 (10)
1 (10)
4
4
5b
6b
48 67
48 85
97
89
4
[Me2Zn]
[Et2Zn]
[(iPr)2Zn]
1 (10)
3 (2.4)
2 (2.4)
4
1
1
1
8b
9b
10b
11b
48 40
>98
96
6
90
7
12 91
12 78
90
96
[{Me2CH(CH2)3}2Zn] 3 (2.4)
7
8
[Me2Zn]
[Et2Zn]
1 (10)
3 (10)
4
4
13b
14b
12 66
98
94
12
6
84
[a] Reactions were carried out under N2. Oxidation step: PCC (pyridinium chlorochromate; 2.1 equiv),
NaOAc, celite, 4-Š molecular sieves, CH2Cl2; products a are obtained in 0–60% de; see the Supporting
Information for details. [b] >98% conversion in all cases, except entry 3 (65–70%); conversion
determined by analysis of 400 MHz 1HNMR spectra of unpurified products. Isolated yields for the ACA/
aldol addition step; isolated yields for oxidations are >85%. [c] Determined by chiral HPLC analysis;
see the Supporting Information for details. [d] Reaction was carried out at ꢀ158C.
indicated
(only
% conversion
dis-
closed).[6a,b,d] In addition, two reports pro-
vide examples of Cu-catalyzed ACA of
Grignard reagents to lactones (I, n =
2);[9a–b] in one disclosure,[9a] high catalyst
loading is required (32 mol%; 5–92% ee)
and the other[9b] offers only a single example (82% ee). To the
best of our knowledge, a report regarding catalytic ACA of an
alkyl metal reagent to substrate types II or III (Scheme 1) has
not appeared.
Herein, we disclose the first effective and general protocol
for catalytic ACA of dialkylzinc reagents to unsaturated
furanones and pyranones of varying steric and electronic
properties (i.e., I–III, Scheme 1). Enantioselective additions
proceed in the presence of optically pure phosphanes 1–3 to
afford the desired products in high isolated yield and in up to
> 98% ee. We report the synthesis of catalytically active CuI–
peptide complexes that are air stable, can be prepared from
Scheme 2. Unmasking of ACA products.
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Communications
be of sufficient optical purity (e.g., 5b formed in 84% ee in
enones: ACA products are formed efficiently in ꢁ 98% ee.
As was the case with transformations involving unsaturated
lactones, the presence of an aldehyde trap is required (to
circumvent b elimination or intermolecular Michael addi-
tion). A similar ligand hierarchy, as mentioned for studies
summarized in Table 1, holds here as well. Unlike reactions in
Table 1, the products a of the three-component asymmetric
process, are generated in high diastereoselectivity (80 to
> 98% de), and, as with transformations in Table 1, can be
converted to ACA products b in high yield (Table 3).
the presence of ligand 1 vs. 97% ee with phosphane 2).
As illustrated in entries 1and 4 of Table 2, under
conditions identical to those used for reactions of lactones
(see Table 1), Cu-catalyzed ACA of pyranone 17 proceed to
Table 2: Cu-catalyzed ACA of alkylzinc reagents to pyranone 17.[a]
With an effective protocol for ACA of alkylzinc reagents
to substrate classes I–III in hand, we focused our efforts on
gaining insight regarding the nature of the chiral Cu complex.
In this context, our efforts to synthesize and isolate a complex
derived from a peptide phosphane and (CuOTf)2·C6H6 was
unsuccessful (presumably due to sensitivity of the Cu–triflate
complexes). However, as depicted in Scheme 3, we have been
Entry
[(alkyl)2Zn]
Solvent
Product
Yield [%][b]
ee [%][c]
1
2
3
4
5
[Et2Zn]
[Et2Zn]
[Et2Zn]
[Me2Zn]
[Me2Zn]
toluene
Et2O
THF
toluene
THF
18
18
18
19
19
n.d.
n.d.
66
n.d.
58
64
72
98
56
>98
[a] Reactions were carried out under N2. [b] Isolated yields after silica gel
chromatography. [c] All enantioselectivities determined by chiral GLC
analysis; see the Supporting Information for details. n.d.=not deter-
mined.
> 98% conversion but with inferior enantioselectivity (64%
and 56% ee). We surmised that the diminished asymmetric
induction might be due to the neighboring Lewis basic oxygen
atom directing the enantioselective addition of an alkyl–
copper complex to the electronically activated ketone.[11]
Accordingly, we examined the effect of coordinating solvents
to disrupt the purported O!Cu chelation. As illustrated in
entries 3 and 5 of Table 2, when the catalytic ACA are
performed in THF 18 and 19 are generated in ꢁ 98% ee; as
shown in entry 2, the less Lewis basic Et2O does not have as
pronounced an effect. Remarkably, in the case of the more
electron rich unsaturated lactones (Table 1), there is < 2%
conversion when THF is used as the solvent.
Scheme 3. Preparation of air-stable chiral Cu complexes 25 and 26.
Next, we turned our attention to the least electrophilic
class of ACA substrates (III, Scheme 1). As the data
summarized in Table 3 indicate, amino acid based chiral
phosphanes are effective with this group of heterocyclic
able to prepare the complexes derived from reaction of
phosphane 1 with CuCl and CuI. Thus, treatment of
unpurified commercial samples of CuCl
and CuI with 1 at ambient temperature
Table 3: Cu-catalyzed ACA of alkylzinc reagents to 20 and 22.[a]
results in the formation of orange powders.
These air-stable Cu complexes,[5c] for which
we propose structures 25 and 26, have
been
characterized
spectroscopically
(Scheme 3).[12] As the representative data
summarized in Table 4 illustrate, not only
are 25 and 26 effective ACA catalysts
(entries 2 and 4), these chiral Cu com-
plexes deliver improved enantioselectivity
compared to when catalysts are prepared
in situ (entries 1and 3, Table 4). Higher
catalyst loading (8 vs. 2 mol% in Table 1) is
needed for reactions promoted by 25 and
26 (vs. 1–3), likely due to lower activity of
metal halide versus triflate complexes.
Complex 25 is less stable than iodide 26;
whereas a week-old sample of 26 (stored in
Entry
1
Substrate
[(alkyl)2Zn] Ligand Product Conv. Yield ee
de
Product Yield
[%][c]
[%][b] [%][c] [%][d] [%][e]
20 [Et2Zn]
1
21a
>98 68
>98 >98 21b
74
2
3
[Et2Zn]
[(iPr)2Zn]
2
2
23a
24a
80 63
71 54
>98
80 23b
80 24b
92
84
22
98
1
[a] Reactions were carried out under N2. [b] Conversion determined by analysis of 400 MHz HNMR
spectra of unpurified products. [c] Isolated yields after silica gel chromatography. [d] Enantioselectivities
determined by chiral GLC or HPLC analysis; see the Supporting Information for details. [e] See the
Supporting Information for stereochemical assignments.
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Table 4: Representative ACA catalyzed by 25 and 26.[a]
Keywords: asymmetric catalysis · conjugate addition · copper ·
enantioselectivity · zinc
.
1Þ 8 mol % catalyst, ½Et2Znꢂ, PhCHO
7
9b
ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ!
2Þ PCC, NaOAc
Entry
Catalyst
Conv. [%][b]
Yield [%][c]
ee [%][d]
[1] a) N. Krause, A. Hoffmann-Roder, Synlett 2001, 171 – 196; b) A.
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heim, 2002, pp. 224 – 258.
1
2
3
4
1 + CuCl
25
1 + Cul
26
92
92
57
92
51
87
24
74
90
94
63
89
[2] a) S. J. Degrado, H. Mizutani, A. H. Hoveyda, J. Am. Chem. Soc.
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Commun. 2004, 1779 – 1785.
[a] [Et2Zn] (3 equiv), ꢀ308C, toluene, 12 h, N2. [b] Conversion deter-
1
mined by analysis of 400 MHz HNMR spectra of unpurified mixtures.
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[3] For representative recent examples (subsequent to reviews in
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air) promotes ACA with equal efficiency and enantioselec-
tivity, a similar batch of 25 affords 9b in 87% yield and
72% ee (vs. 94% with a freshly prepared sample).
An additional example, shown in Equation (1), illustrates
that isolation of Cu-peptide chiral complexes is not limited to
[4] For representative recent examples (subse-
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the derivatives of phosphane 1. Thus, in the presence of 27
(16 mol%), derived through reaction of 2 (d = ꢀ10.7 ppm,
31P NMR) with CuCl (1equiv, CH 2Cl2, 228C; 84% yield),
heterocyclic enone 22 can be converted to 24a in 95% ee and
80% de. Similar to reactions with 25 and 26, the copper
chloride complex is less effective than when the chiral catalyst
is prepared in situ from (CuOTf)2·C6H6 and phosphane 2 (see
entry 3, Table 3).
In summary, we report the first generally effective method
for catalytic ACA of dialkylzinc reagents to unsaturated
furanones and pyranones with different steric and electronic
properties. The present method significantly enhances the
general utility of Cu-catalyzed ACA of alkylmetal reagents to
unsaturated carbonyls. Synthesis, isolation, and character-
ization of catalytically active and air-stable chiral Cu–peptide
complexes 25–27 enhance the practical utility of these
protocols and set the stage for future mechanistic investiga-
tions.
A. J. Minaard, B. L. Feringa, Chem. Commun. 2004, 792 – 793;
for a recent study involving alkyl Grignard reagents with an air-
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2812 – 2816; Angew. Chem. Int. Ed. 2005, 44, 2752 – 2756.
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2575 – 2578; for Cu-catalyzed ACA of alkylzinc and alkylalumi-
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[7] For related approaches involving catalytic asymmetric hydride
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b) B. H. Lipshutz, J. M. Servesko, B. R. Taft, J. Am. Chem. Soc.
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[8] For Rh-catalyzed enantioselective additions of arylzinc reagents
to 4-piperidones, see: a) R. Shintani, N. Tokunaga, H. Doi, T.
Hayashi, J. Am. Chem. Soc. 2004, 126, 6240 – 6241; for Rh-
Received: April 9, 2005
Published online: July 25, 2005
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catalyzed enantioselective addition of arylboroxines to 4-piper-
idones, see: b) R. B. C. Jagt, J. G. de Vries, B. L. Feringa, A. J.
Minnaard, Org. Lett. 2005, 7, 2433 – 2435; for Rh-catalyzed ACA
of arylboronic acids to unsaturated lactones, see: c) M. Reetz, D.
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Defieber, J.-F. Paquin, S. Serna, E. M. Carreira, Org. Lett. 2004,
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12784 – 12785.
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[11] For proposed examples of O-directed Cu-catalyzed or Cu-
mediated conjugate additions, see: a) R. Imbos, A. J. Minnaard,
B. L. Feringa, Tetrahedron 2001, 57, 2485 – 2489; b) G. Hareau-
Vittini, S. Hikichi, F. Sato, Angew. Chem. 1998, 110, 2221– 2223;
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[12] See the Supporting Information for details.
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