Cu-catalyzed enantioselective conjugate additions of alkyl zinc reagents to unsaturated N-acyloxazolidinones promoted by a chiral triamide phosphane

Article abstract of DOI:10.1002/anie.200390328

A chiral triamide phosphane promotes highly efficient and enantioselective Cu-catalyzed conjugate additions of alkyl zinc compounds to unsaturated oxazolidinones (see scheme). The resulting β-alkyl chiral oxazolidinones are readily converted into synthetically useful carbonyl compounds not accessible by alternative catalytic methods.

Full text of DOI:10.1002/anie.200390328

Communications
Asymmetric Conjugate Addition
Cu-Catalyzed Enantioselective Conjugate
Additions of Alkyl Zinc Reagents to Unsaturated
N-Acyloxazolidinones Promoted by a Chiral
Triamide Phosphane**
Alexander W. Hird and Amir H. Hoveyda*
An area of recent interest in organic synthesis involves the
development of protocols for efficient catalytic asymmetric
conjugate additions (ACAs) of alkyl metal compounds to
[*] Prof. A. H. Hoveyda, A. W. Hird
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).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Scheme 1. Chiral amino acid-based phosphane ligands for Cu-catalyzed asymmetric conjugate additions (ACAs) to unsaturated carbonyls.
unsaturated carbonyls.[1] In these laboratories,we have been
able to introduce methods for uniquely efficient and enantio-
selective catalytic ACAs of alkyl zinc reagents (not only
[ZnEt2]) to cyclic enones including unactivated cyclopenten-
ones,[2] acyclic enones,[3] and trisubstituted exocyclic unsatu-
rated ketones.[4] These investigations benefited from the
modularity of the amino acid based ligands and parallel
screening strategies,[5] as each of the above three sets of enone
substrates requires a different optimal ligand (Scheme 1).
From the point of synthetic utility,in spite of recent
advances outlined by various research groups,several critical
problems remain to be addressed. One is in connection to the
availability of a general approach to catalytic ACAs of alkyl
groups to unsaturated esters,[6] amides,acids,or aldehydes. It
was towards this end that we set out to develop catalytic
ACAs of alkyl zinc reagents to unsaturated N-acyloxazolidin-
ones;[7] the lure of such an approach is that enantioenriched b-
alkyl carbonyls can be converted into an assortment of
carboxylic acid and related derivatives. An efficient Cu-
catalyzed method for ACA of alkyl zinc compounds to a,b-
unsaturated oxazolidinones is disclosed herein.
tions. We then conducted a brief survey of different forms for
the phosphane attachment to the amino acid moieties (that is,
the derived amines and amides). This led us to determine that,
in contrast to the previous studies,it is a triamide ligand ( 7,
Scheme 2) that delivers product 6 with appreciable enantio-
selectivity.
We then performed screening studies to identify the
optimal amino acid moieties of amide phosphanes (5a!6
used as the representative process).[8] These investigations
indicated that subtle amino acid modifications can lead to
substantial variations in enantioselection (for example,see
entries 1–2,Table 1) and that a comprehensive screening
process should be carried out to find a more optimal ligand.
More importantly,and somewhat to our surprise,we also
established that peptidic ligands bearing a d and an l amino
acid may prove to be superior (see entries 3–4,Table 1).
Table 1: Amino acid modifications to 5a.[a]
To initiate our studies,we examined the ability of 1–3
(Scheme 1),the three chiral ligands that effect the aforemen-
tioned catalytic ACA,[2–4] in promoting additions to oxazoli-
dinone 5a (Scheme 2). As the data in Scheme 2 indicate,these
Schiff bases promote facile but relatively nonselective reac-
Entry
AA1
AA2
% ee
1
2
3
4
l-Phe
l-Cha
l-Val
l-Phe
l-Phe
l-Phe
l-Phe
ꢀ34
+45
+12
ꢀ74
d-Val
[a] All reactions have >98% conversion.
Subsequent screening of parallel libraries of ligands bearing
both l,l- and d,l-dipeptides (approximately 100 ligands) led
us to determine that treatment of 5a with 1.0 mol%
(CuOTf)2·C6H6,2.4 mol% phosphane amide 4 (Scheme 1)
and [ZnEt2] (08C,1.3 h) leads to the formation of 6 in 95% ee
[9]
and 95% yield (entry 1,Table 2).
It should be noted that
ligand 4 has two unique structural attributes compared to the
previous ligands used in reactions promoted by related
peptidic systems.[2–4,10] Phosphane 4 is a triamide (not a
diamide Schiff base or amine),and bears an l and a d amino
Scheme 2. Results of initial ligand screening.
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Table 2: Cu-catalyzed ACA of alkyl zinc reagents to unsaturated oxazolidinones.[a]
H
Me
OtBu
O
O
H
N
N
H
NHBu
O
O
O
O
alkyl O
PPh2
Me
Me
2.4–6 mol %
4
R
N
O
R
N
O
0.5–2.5 mol % (CuOTf)2•C6H6, [Zn(alkyl)2]
5
6 , 8–14
Entry
R
[Zn(alkyl)2]
[ZnEt2]
[Zn{iPr(CH2)3}2]
[Zn(iPr)2]
[ZnEt2]
[Zn{iPr(CH2)3}2]
[ZnMe2]
[ZnEt2]
Product
Mol% 4
Mol% Cusalt
t [h]
1.3
12
15
3
24
144
6
Yield [%][b]
ee [%][c]
1
2
3
4
5
6[d]
7
Me a
Me a
Me a
nPr b
nPr b
nPr b
(CH2)3OTBS c
iPr d
6
8
9
10
11
12
13
14
2.4
5.0
2.4
2.4
2.4
6.0
2.4
2.4
1.0
1.0
0.5
1.0
1.0
2.5
1.0
1.0
95
61
95
86
89
68
95
88
95
93
76
94
95
97
>98
92
8
[ZnEt2]
24
[a] Conditions: 3 equiv dialkyl zinc reagent (10 equiv in entry 6), toluene, 08C (ꢀ158C for entry 6). [b] Yields after silica gel chromatography. All
reactions proceeded to at least 95% conversion (GLC analysis). [c] All enantioselectivities determined by chiral GLC (b-DEX column for entries 1–6
and 8, CDGTA column for entry 7). [d] Phosphane 15 used as ligand.
acid (not two l or d amino acids). The highest selectivity
obtained for formation of 6 from an l,l ligand was 82% ee
(AA1 =l-Asn(Trt),AA2 =l-Phe).
As indicated by the results summarized in Table 2,a range
of unsaturated carbonyls and various alkyl zinc reagents can
be used to access b-alkyl N-acyloxazolidinones in high yield
and excellent enantioselectivity. The requisite unsaturated
carbonyl substrates are accessed through olefin cross-meta-
thesis promoted by a commercially available (Aldrich)
catalyst developed in these laboratories.[11] As an example,
5c (entry 7,Table 2) was prepared in this fashion in 94%
yield. Furthermore,Cu-catalyzed ACA reactions can be
carried out with the commercially available (CuOTf)2·PhMe
(Aldrich,used without purification). Conversion of 5a into 6
is effected in the presence of 1 mol% (CuOTf)2·PhMe and
arise from the higher solubility of 17 under the reaction
conditions and not as a result of variations in equilibrium
between s-cis and s-trans conformers.[7]
2.4 mol% 4 to give 6 in 91% ee and 88% yield (> 98%
Optically enriched b-alkyl N-acyloxazolidinones may be
converted into other carbonyl derivatives that are not yet
accessible directly through catalytic ACA reactions. Three
representative examples are given below. Ketone 19 is formed
in 93% ee through treatment of 8 (entry 2,Table 2) with
tBuLi (THF, ꢀ20 to 08C). It should be noted that Cu-
catalyzed ACAs to acyclic tert-butyl enones proceed with only
moderate levels of enantioselectivity (no greater than
[12]
conversion,4 h).
However,conjugate additions with
[ZnMe2] (for example,entry 6,Table 2) are slower than
those with longer chain alkyl zinc reagents and extended
reaction times are needed.[13] In transformations involving
[ZnMe2],superior efficiency is observed when 15 is used as
the chiral ligand instead of 4 (68% versus 43% yield under
identical conditions,shown in entry 6 of Table 2).
75% ee).[4] Weinreb amide 20,also obtained from
8
[15]
([AlMe3],MeONHMe·HCl)
and acid 21 derived from 6
As shown in Equation (1),substrate 16 is inert to Cu-
catalyzed ACA conditions. The derived dimethyloxazolidin-
one 17 can however be converted,albeit slowly,into 18 in
86% ee and 91% yield [Eq. (2)]. Control experiments[14]
indicate that this difference in reactivity is most likely to
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(LiOH,H 2O2,THF) [16] can be converted into the correspond-
ing aldehydes and a number of other carbonyl derivatives.
In conclusion,we have developed efficient Cu-catalyzed
ACA reactions that are promoted by no more than 5 mol% of
a readily accessible catalyst and deliver,in high enantiomeric
purity,compounds that cannot be easily prepared by alter-
native catalytic protocols. This study introduces an amino acid
based phosphane amide (versus Schiff base or amine systems)
as an effective chiral ligand for asymmetric conjugate
addition,and further demonstrates the important utility of
this class of modular ligands.[17] The present method comple-
ments the previously reported catalytic ACA protocols[1–4,6]
and should find utility in enantioselective organic synthesis.
[7] For enantioselective conjugate additions of sterically hindered
(tBu and cyclohexyl) radicals to unsaturated N-acyloxazolidin-
ones,see: a) M. P. Sibi,J. Ji,J. H. Wu,S. Gurtler,N. A. Porter, J.
Am. Chem. Soc. 1996, 118,9200 – 9201; b) M. P. Sibi,J. Ji, J. Org.
Chem. 1997, 62,3800 – 3801.
[8] Since control experiments showed that with Gly as AA3,the
phosphane corresponding to 7 affords less than 20% ee (5a!6),
a new route for synthesis of ligand libraries with nBu termini was
developed and utilized. See the Supporting Information for
details.
[9] See the Supporting Information for details of the screening
studies.
[10] For example,see: a) B. M. Cole,K. D. Shimizu,C. A. Krueger,
J. P. A. Harrity,M. L. Snapper,A. H. Hoveyda, Angew. Chem.
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Wirschun,J. D. Gleason,M. L. Snapper,A. H. Hoveyda, J. Am.
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Received: December 4,2002 [Z50699]
Keywords: alkyl metal compounds · asymmetric catalysis ·
.
conjugate addition · copper · enantioselectivity
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