Enantioselective synthesis of nitroalkanes bearing all-carbon quaternary stereogenic centers through Cu-catalyzed asymmetric conjugate additions

Article abstract of DOI:10.1021/ja050800f

The first examples of catalytic asymmetric conjugate addition (ACA) of alkylzinc reagents to trisubstituted nitroalkenes, leading to the formation of nitroalkanes bearing a quaternary carbon stereogenic center, are reported. Reactions are promoted in the

Full text of DOI:10.1021/ja050800f

Published on Web 03/12/2005
Enantioselective Synthesis of Nitroalkanes Bearing All-Carbon Quaternary
Stereogenic Centers through Cu-Catalyzed Asymmetric Conjugate Additions
Jing Wu, Dawn M. Mampreian, and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467
Received February 7, 2005; E-mail: amir.hoveyda@bc.edu
Discovery of methods for catalytic asymmetric conjugate addi-
tions (ACA) involving carbon nucleophiles is an important objective
in chemical synthesis.1 Nitroalkenes represent a notable class of
substrates for catalytic ACA, since the resulting nitroalkanes can
be converted to synthetically useful N- and O-containing optically
enriched organic molecules.2 We have reported a method for Cu-
catalyzed ACA of dialkylzinc reagents to cyclic nitroalkenes,
through which, after appropriate acidic workup (in situ Nef), the
corresponding small, medium, and macrocyclic ketones that contain
an R-stereogenic center can be synthesized efficiently and in >92%
ee.3 Feringa and co-workers later disclosed a protocol for Cu-
catalyzed ACA of dialkylzincs reagents to acyclic nitroalkenes that
bear a γ-acetal; optically enriched products were transformed to
R-alkyl-â-amino acids.4
with longer chains or a heteroatom functionality proceed to afford
the desired chiral nitroalkanes in good isolated yield10 and with
excellent enantioselectivity (85-96% ee). Nonetheless, longer
reaction times (entries 3 and 4) and/or higher catalyst loading (entry
3) may be required for complete conversion at the optimal
temperature (see below). The catalytic asymmetric procedure is
effective with electron deficient substrate 1b (entries 2-4) and
naphthyl-substituted 1c (entries 5 and 6).11
As the findings in entries 7-9 of Table 1 indicate, under the
conditions used effectively for catalytic ACA of 1a-1c, with
nitroalkenes 1d and 1e (R ) n-Pr and i-Pr) as substrates, reaction
efficiency and enantioselectivity suffer noticeably. Although >98%
conv is observed with Et2Zn, in the case of the less reactive
Me2Zn,12 higher temperatures are required to ensure reasonably high
conversion that can lead to lower ee. For example, when the reaction
in entry 8 is performed at -15 °C, 2i is obtained in 85% ee but
with ∼20% conv after 72 h (16 mol % 3).
Despite the above advances, as well as noteworthy observations
reported by other laboratories,5 there has been no report of an
efficient catalytic6 ACA of an alkylmetal to a nitroalkene that leads
to the formation of an all-carbon quaternary stereogenic center.7
Optically enriched organic molecules that contain a quaternary
carbon are important due to their relevance to the synthesis of
biologically active compounds.6 Moreover, in contrast to the afore-
mentioned methods that deliver a tertiary carbon stereogenic site,
protocols that lead to quaternary carbon stereogenic centers cannot
be substituted by alternative strategies involving enantioselective
hydrogenations or conjugate hydride additions.8 The absence of such
protocols is likely because efficient addition of carbon nucleophiles
to a highly substituted olefin requires an especially effective catalyst.
Herein, we disclose the first catalytic method for ACA of
alkylmetals to nitroalkenes that leads to the formation of nitroal-
kanes containing an all-carbon quaternary carbon stereogenic center.
Cu-catalyzed reactions proceed efficiently, in up to 98% ee, and
can be carried out with a variety of dialkylzinc reagents and
nitroolefins. The synthetic utility of the method is highlighted by
efficient conversion of representative optically enriched nitroalkanes
to the corresponding carboxylic acids.
We began our studies by examining the ability of chiral peptide-
based ligand 3, previously established9 to be effective in Cu-
catalyzed ACA of dialkylzinc reagents to acyclic disubstituted
nitroalkenes, to promote additions to the derived trisubstituted
nitroolefins. Nitroolefin 1a (>98% E) was employed as the test
substrate. As illustrated in eq 1, we established that in the presence
of 4 mol % 3, 2 mol % (CuOTf)2‚C6H6, and 3 equiv of Et2Zn, the
catalytic ACA proceeds at -78 °C to >98% conv in 24 h to afford
(S)-2a in 94% ee and 87% yield after silica gel chromatography.
When the catalytic ACA is performed at -30 °C, 2a is obtained in
92% ee and 89% isolated yield (>98% conv, 24 h). In the absence
of 3, there is only ∼20% conversion to 2a (under conditions
otherwise identical to eq 1).
To address the above shortcomings, we examined the ability of
a small selection of chiral phosphines to promote Cu-catalyzed ACA
in entries 7-9 of Table 1. These ligands were selected on the basis
of the hypothesis that with nitroalkenes bearing olefin substituents
larger than Me, reduced steric hindrance at the chiral binding pocket
may lead to more facile ACA. A faster reaction could then be
performed at lower temperatures, giving rise to improved product
optical purity. The effects of alteration of peptide structure
(diastereomeric 4), removal of one amino acid side chain (5 and 6)
or the AA2 moiety (7), were examined (e.g., AA2 in 5 is Gly). As
the data in Table 2 indicate, chiral phosphines 4 and 5 readily
(>98% conv at 0 °C) deliver nitroalkane 2j in 93% and 90% ee
with 84% and 48% isolated yield, respectively (versus 79% ee and
53% isolated yield with 3).
As illustrated in eq 2, similar studies indicated that chiral
phosphine 5 gives rise to the formation of 2h in 85% ee and 64%
isolated yield (versus 75% ee and 40% yield with 3). When this
Cu-catalyzed transformation is performed at lower temperature,
reaction efficiency suffers (57% conv, 86% ee after 72 h at 22 °C);
when peptide 4 is used, less improvement in asymmetric induction
is observed (80% ee). In contrast to transformations shown in entries
7 and 9 of Table 1, none of the ligands shown in Table 2 give rise
to higher enantioselectivity for the reaction in entry 8 (1e f 2i).13
With the availability of a catalytic method for enantioselective
synthesis of nitroalkanes bearing quaternary carbon stereogenic
centers, a range of other optically enriched molecules become
accessible. Reduction to the derived amines through Pd-catalyzed
With the aforementioned promising observation in hand, we set
out to establish the scope of the Cu-catalyzed protocol. The results
of these studies are summarized in Table 1. As illustrated in entries
1, 3-4, and 6 of Table 1, catalytic additions of dialkylzinc reagents
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10.1021/ja050800f CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Cu-Catalyzed ACA of Dialkylzinc Reagents Promoted by
Scheme 1. Functionization of Optically Enriched ACA Products
3a
a Reaction performed at 50 °C.
In brief, we report the first examples of catalytic ACA of
alkylmetals to acyclic nitroalkenes, leading to the formation of all-
carbon quaternary carbon stereogenic centers. The optically enriched
nitroalkanes may be transformed efficiently to synthetically versatile
optically enriched molecules, such as the derived amines, nitriles,
aldoximes, and carboxylic acids. Development of efficient methods
for synthesis and identification of optimal catalyst(s) for ACA of
trisubstituted nitroalkenes bearing a nonaryl substituent (e.g., alkyl)
is in progress.
a Reactions carried out under N2 atm. b Based on consumption of
substrate; determined by 1H NMR analysis. c Isolated yields. d Determined
by chiral GLC and HPLC; see the Supporting Information. Absolute
stereochemistry is by inference (determined for 2a; see the SI). e 16 mol %
3 and 8 mol % (CuOTf)2‚C6H6 used.
Acknowledgment. Financial support was provided by the NIH
(GM-47480).
Table 2a
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.
References
(1) (a) Krause, N.; Hoffmann-Roder, A. Synlett 2001, 171-196. (b) Alexakis,
A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221-3236. (c) Feringa, B.
L.; Naasz, R.; Imbos, R.; Arnold, L. A. In Modern Organocopper
Chemistry; Krause, N., Ed.; Wiley-VCH: Weinheim, Germany, 2002; pp
224-258.
(2) (a) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002,
1877-1894. (b) Ono, N. In The Nitro Group in Organic Synthesis; Wiley-
VCH: New York, 2001.
(3) (a) Luchaco-Cullis, C. A.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124,
8192-8193. For an overview, see: (b) Hoveyda, A. H.; Hird, A. W.;
Kacprzynski, M. A. Chem. Commun. 2004, 1779-1785.
(4) Duursma, A.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2003,
125, 3700-3701.
(5) (a) Sewald, N.; Wendisch, V. Tetrahedron: Asymmetry 1998, 9, 1341-
1344. (b) Versleijen, J. P. G.; van Leusen, A. M.; Feringa, B. L.
Tetrahedron Lett. 1999, 40, 5803-5806. (c) Ongeri, S.; Piarulli, U.;
Jackson, R. F. W.; Gennari, C. Eur. J. Org. Chem. 2001, 803-807. (d)
Alexakis, A.; Benhaim, C.; Rosset, S.; Humam, M. J. Am. Chem. Soc.
2002, 124, 5262-5263. (e) Eilitz, U.; Lebmann, F.; Seidelmann, O.;
Wendisch, V. Tetrahedron: Asymmetry 2003, 14, 189-191. (f) Choi, H.;
Hua, Z.; Ojima, I. Org. Lett. 2004, 6, 2689-2691.
(6) For noncatalytic variants, see: Schafer, H.; Seebach, D. Tetrahedron 1995,
51, 2305-2324.
(7) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
5363-5367.
a-d See footnotes for Table 1.
(8) (a) Czekelius, C.; Carreira, E. M. Angew. Chem., Int. Ed. 2003, 42, 4793-
4795. (b) Czekelius, C.; Carreira, E. M. Org. Lett. 2004, 6, 4575-4577.
(9) Mampreian, D. M.; Hoveyda, A. H. Org. Lett. 2004, 6, 2829-2832.
(10) The difference in conv vs yield is due to unidentified byproducts.
(11) Nitroalkenes were prepared based on a published procedure: Ohta, H.;
Kobayashi, N.; Ozaki, K. J. Org. Chem. 1989, 54, 1802-1804. Substrates
bearing electron-donating alkyl ether substituents cannot be prepared but
the related products can be accessed through Pd-catalyzed etherification
of aryl halides (e.g., 2c-e); see: Torraca, K. E.; Huang, X.; Parrish, C.
A.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 10770-10771.
(12) Kitamura, M.; Miki, T.; Nakano, K.; Noyori, R. Bull. Chem. Soc. Jpn.
2000, 73, 999-1014.
(13) Reactions of substrates 1a-c are less efficient and less selective with
phosphines 4-7. As an example, in the presence of 4 and 5, 2c is formed
in 89% (>98% conv) and 66% ee (13% conv) (vs 98% conv and 98% ee
with 3).
(14) For example, reduction of 2c (600 psi H2, 10% Pd(C), MeOH, 40 h) affords
the optically enriched primary amine in 63% isolated yield; see SI for
details.
hydrogenation is one well-established possibility.14 Another con-
venient protocol, outlined most recently, allows for facile conversion
of nitroalkanes to the corresponding nitriles and aldoximes, which
can undergo efficient and stereoselective [3 + 2] cycloadditions.15
Another synthetically useful functionalization involves oxidation
of the nitromethylene group to the corresponding carboxylic acid
(8-11, Scheme 1).16 These transformations proceed under mild
conditions to afford the desired carboxylic acids bearing an adjacent
quaternary carbon stereogenic center. Optically enriched carboxylic
acids, represented in Scheme 1, are not easily accessible by catalytic
asymmetric or diastereoselective alkylations of enolates that bear
a chiral auxiliary.
(15) Czekelius, C.; Carreira, E. M. Angew. Chem., Int. Ed. 2005, 42, 612-
615.
(16) Matt, C.; Wagner, A.; Mioskowski, C. J. Org. Chem. 1997, 62, 234-235.
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