Highly stereoselective synthesis of α-alkyl-α-hydroxycarboxylic acid derivatives catalyzed by a dinuclear zinc complex

Article abstract of DOI:10.1002/anie.201201116

A dinuclear zinc-ProPhenol catalyst enables highly enantioselective nitro-Michael reactions with oxazol-4(5H)-ones as nucleophilic substrates (see scheme, Nap=2-naphthyl). This work highlights the utility of the ProPhenol family of ligands. The modular nature of these ligands proved crucial in the optimization of reaction conditions to achieve excellent stereoselectivities. Copyright

Full text of DOI:10.1002/anie.201201116

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DOI: 10.1002/anie.201201116
Asymmetric Catalysis
Highly Stereoselective Synthesis of a-Alkyl-a-Hydroxycarboxylic Acid
Derivatives Catalyzed by a Dinuclear Zinc Complex**
Barry M. Trost* and Keiichi Hirano
Direct, highly diastereo- and enantioselective catalytic con-
struction of all-substituted carbon stereocenters adjacent to
carbonyl groups through addition of a-disubstituted carbonyl
compounds to unsaturated bonds is still a challenging feat,
and successful examples are limited to the use of nucleophiles
that are singly activated by a mesomeric electron-withdraw-
ing group.[1–3] The dinuclear zinc–ProPhenol complex has
shown remarkable efficiency and stereoselectivities in
carbon–carbon bond-forming processes that involve enolates,
such as aldol reactions,[4] Mannich-type reactions,[5] and nitro-
Michael reactions.[6] Despite the synthetic utility of 5H-
oxazol-4-ones as a-alkyl-a-hydroxy ester surrogates, there
have been relatively few reports[7] of their employment as
nucleophiles since we first disclosed their use in a catalytic
asymmetric allylic alkylation.[8] Herein we describe a highly
diastereo- and enantioselective nitro-Michael reaction of 5H-
oxazol-4-ones that forms all-substituted carbon stereocenters
and does not require the use of pre-functionalized enolate
precursors.[9,10]
as determined by 1H NMR spectroscopy, albeit with little
stereocontrol after brief optimization studies (d.r. = 2.4:1,
46% ee for the major diastereomer, [Eq. 1]).
An advantage of the ProPhenol ligand is its modularity,
because its diarylcarbinol substructure allows a systemic
variation (Scheme 1). Slightly electron-deficient ligands L2
and L3 improved the d.r. to 3:1 without affecting the yield and
enantioselectivity. Ligand L3, which bears a strongly electron-
withdrawing trifluoromethyl group, decreased the reactivity
of the catalyst, presumably because of its decreased Brønsted
basicity. However, in this case the diastereoselectivity was
increased to 4.1:1, albeit with a significant loss of enantiose-
lectivity. With even more electron-deficient ligand L5, the
product was obtained in poor yield but with excellent
We commenced our studies by examining the addition of
5-methyl-2-phenyloxazol-4(5H)-one to b-nitrostyrene cata-
lyzed by the dinuclear zinc–ProPhenol complex. Gratifyingly,
the desired product could be obtained in more than 95% yield
[*] Prof. Dr. B. M. Trost, Dr. K. Hirano
Department of Chemistry, Stanford University
Stanford, CA 94305-5080 (USA)
Scheme 1. Impact of the ligand structure on reactivity and stereoselec-
tivity. All reactions were run on a 0.125 mmol scale. Catalyst prepara-
tion: Et2Zn in hexanes (1m, 12.5 mL, 10 mol%) was added to a solution
of the ligand (5 mol%) in THF, and the resulting yellow solution was
stirred for 30 min at RT. Catalysis: The catalyst solution was added to
a solution of b-nitrostyrene (20.5 mg, 0.1375 mmol, 1.1 equiv) and
1 (21.9 mg, 0.125 mmol, 1.0 equiv) in propionitrile, and the reaction
E-mail: bmtrost@stanford.edu
Homepage: http://www.stanford.edu/group/bmtrost/
[**] We thank the National Science Foundation for their support of our
programs, and the postdoctoral fellowships by the Uehara Memo-
rial Foundation (for the first six months) and JSPS Postdoctoral
Research Fellowship (for the following period) to K.H. are gratefully
acknowledged. Prof. Allen Oliver (University of Notre Dame) is
gratefully acknowledged for XRD analysis.
1
was stirred for 16 h at RT. Yields were determined by H NMR
spectroscopy with mesitylene as internal standard. The diastereomeric
ratios were determined by 1H NMR analysis of the crude mixture. The
ee values were determined by HPLC analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201201116.
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diastereoselectivity. Notably, the sense of enantioinduction
was reversed. With a ligand that bears pentafluorophenyl
substituents (L6), low reaction efficiency was observed and
the major diastereomer was obtained as a racemate. A ligand
with 1-naphthyl groups (L7) gave a significantly improved
ee value (79%), although the d.r. was low (1.9:1). To our
delight, the reaction proceeded to complete conversion with
an excellent d.r. (15.6:1) and ee value (88%) by using ligand
L8, which possesses the corresponding 2-naphthyl rings.
We next optimized the aryl group of oxazolone
(Scheme 2). A methyl group as well as a tert-butyl group at
the para position of the phenyl ring decreases the diastereo-
and enantioselectivity. The para-methoxy and para-bromo
derivatives behaved similarly to the para-methyl nucleophile
Scheme 2. Optimization of the nucleophile structure. All reactions
were run on a 0.125 mmol scale under the conditions described in
Scheme 1 with L8 and different nucleophiles. Yields were determined
by 1H NMR spectroscopy with mesitylene as internal standard. The
diastereomeric ratios were determined by 1H NMR analysis of the
crude mixture. The ee values were determined by HPLC analysis.
[a] Reaction conducted in propionitrile (0.08m).
Scheme 3. Addition of 5-methyloxazole-4(5H)-one to various nitro
olefins. All reactions were run on a 0.125 mmol scale under the
conditions described in Scheme 1 with L8 (0.08m) in propionitrile.
Yields of isolated products are given. The diastereomeric ratios were
1
determined by H NMR analysis of the crude mixture. The ee values
were determined by HPLC analysis. [a] 0.5 mmol scale; reaction on
a 0.125 mmol scale: 90% yield, d.r. =8.4:1, 84% ee. [b] From the
mother liqueur of a single recrystallization. [c] Absolute configuration
established as (R,R) by single crystal X-ray analysis. [d] Yield of the
major isomer.
(3 vs. 5 and 6). Product 7 with a 3,5-dimethoxyphenyl group
was obtained with a much lower diastereoselectivity, but the
ee value was comparable to that of the parent phenyl system
(88% ee). Product 8 was obtained with d.r. = 14.0:1 and an
excellent ee value (90%) by switching to the 2-naphthyl
substituent. The oxazolone with the meta-methylphenyl
group gave product 9 with d.r. = 18.2:1 and 90% ee. When
the reaction was conducted in propionitrile under higher
dilution conditions (0.08m), even higher stereoselectivities
were obtained (d.r. > 19:1 and 93% ee).
With optimized conditions in hand, the scope of the nitro
olefins was examined (Scheme 3). Performing the reaction
with the para-tolyl substrate gave 10 in 97% yield, d.r. > 19:1,
and 92% ee, while the para-methoxy substrate gave 11 in
97% yield, d.r. = 12.8:1, and 93% ee. The inductively
electron-withdrawing chloro substituent at the para position
slightly decreased the d.r. (6.7:1) and ee value (86%), whereas
an analogous cyano group, a mesomeric electron-withdrawing
group, gave reduced selectivities (13, d.r. = 3.4:1, 75% ee).
This effect was even more pronounced by a nitro group (14,
76% yield, d.r. = 3.1:1, 64% ee). The variety of meta
substituents were well tolerated, giving the corresponding
products (15–18) in excellent yields and with high degrees of
stereoselectivity. Notably, the reaction proceeded on
0.5 mmol scale without any deleterious effect to give com-
pound 16, and its enantiopurity could be upgraded to 99% ee
through recrystallization. In contrast, substrates with ortho
substituents are more challenging. Significantly decreased
enantioselectivities were observed when the corresponding
ortho-tolyl and 1-naphthyl substrates were employed (44% ee
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for 19 and 56% ee for 20, respectively), although the
reactivity was good. The reaction with ortho-fluorophenyl
nitro olefin showed much better enantioselectivity (70% ee
for 21). This result clearly indicates that the steric bulk at the
ortho position is deleterious for enantioinduction. Heteroar-
omatic substrates were well tolerated. The 2- and 3-furyl
substrates as well as substrates that bear a thiophene moiety
gave the corresponding products (22–25) in excellent yields
with good stereoselectivities. The N-Boc-protected 3-indole
nitro olefin afforded product 26 with 84% ee despite the fact
that the substrate is ortho substituted; in this case, the
detrimental effect of ortho substitution on enantioselectivity
is diminished by the smaller ring size. Ferrocene-containing
product 27 was obtained with d.r. > 19:1 and 98% ee. The
absolute configuration of 27 was unambiguously established
as (R,R) by single crystal X-ray analysis (Figure 1).
The a,b,g,d-unsaturated nitro olefin gave product 28 in
97% yield with d.r. = 12.6:1 and 92% ee. An aromatic group
at the terminal carbon atom of the diene is not required, as
Scheme 4. Scope of 5-alkyloxazole-4(5H)-ones. All reactions were run
on a 0.125 mmol scale under the conditions described in Scheme 1
with L8 (0.08m) in propionitrile. Yields of isolated products are given.
1
The diastereomeric ratios were determined by H NMR analysis of the
crude mixture. The ee values were determined by HPLC analysis. [a] b-
nitrostyrene:oxazolone 1:1 (0.1375 mmol).
excellent enantioselectivities.
A
synthetically versatile
alkyne substrate was converted to product 35. Even the
substrate with a zincaphilic sulfide was tolerated and gave
desired product 36 with excellent stereoselectivities.
The combination of 5-allyloxazolone and a,b,g,d-unsatu-
rated nitro olefin gave diene 37, which was cleanly metathe-
sized to spirocyclic cyclopentene 38 [Eq. (2)]. The oxazolone
ring was opened to a-hydroxy carboxamide 39 with base.[11]
In summary, we have developed a highly stereoselective
addition reaction of 5-alkyloxazole-4(5H)-ones to various
nitro olefins. This process provides a range of highly
functionalized a-alkyl-a-hydroxycarboxylic acid derivatives
in high yields. It is notable that the stereoselective event was
uniquely enabled by L8, which has not yet been used as
a ligand in catalytic asymmetric transformations. This dra-
matic differential effect imparts great potential to the
ProPhenol family of ligands and emphasizes the critical role
that the modularity of this ligand may play in optimizing the
design of the chiral space for asymmetric induction. Further
studies employing such a-disubstituted nucleophiles are
currently under way and will be reported in due course.
Figure 1. Single crystal X-ray diffraction analysis of 27. Thermal ellip-
soids at 50% probability.
product 29 was obtained with high stereoselectivity. A
substrate containing a triple bond also participated in the
addition reaction, and gave 30 in 43% yield, d.r. = 1.5:1, and
86% ee.
The alkyl substituent of 5-alkyloxazole-4(5H)-ones was
also varied (Scheme 4). The 5-ethyl oxazolone afforded the
desired product 31 quantitatively, d.r. > 19:1, and 92% ee. The
even more sterically-demanding 2-isobutyloxazolone gave
product 32 quantitatively, d.r. > 19:1, and 90% ee. The benzyl-
and allyloxazolones afforded products 33 and 34 with
Experimental Section
Catalyst Preparation: (S,S)-L8 (5.2 mg, 6.25 mmol, 5 mol%) was
weighed in a flame-dried microwave vial and the vial was sealed with
a rubber septum, carefully evacuated, and back-filled with nitrogen (ꢀ
2), evacuated once again and back-filled with argon. Freshly distilled
THF (0.07 mL) was injected into this vial and Et2Zn (1m in hexanes,
12.5 mL, 12.5 mmol, 10 mol%) was added by a microsyringe at RT.
The resulting yellow solution was stirred for 30 min at RT.
Catalysis: Oxazol-4(5H)-one (0.125 mmol, 1.0 equiv) and nitro
olefin (0.138 mmol, 1.1 equiv) were weighed in a flame-dried culture
tube and the tube was sealed with a rubber septum, carefully
evacuated, and back-filled with nitrogen (ꢀ 2), evacuated once again
and back-filled with argon. Propionitrile (0.15 mL) was injected into
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the vial and the catalyst solution was subsequently added with
vigorous stirring at RT. After 16 h, the reaction was diluted with ether
(2 mL), quenched with 5% KH2PO4, and diluted with H2O (1 mL).
The mixture was stirred for 5 min at RT and the phases were
separated. The aqueous phase was extracted with ether (3 ꢀ 1.5 mL)
and the combined organic phases were concentrated. The crude
material was analyzed by 1H NMR spectroscopy in order to
determine diastereoselectivity. The recovered crude material was
purified by flash column chromatography on silica gel typically using
a mixture of petroleum ether/EtOAc = 5:1 as eluent.
[3] 3-Substituted oxindoles have been successfully utilized. For
a recent review, see: F. Zhou, Y.-X. Liu, J. Zhou, Adv. Synth.
Catal. 2010, 352, 1381, and references therein.
[4] a) B. M. Trost, D. Amans, W. M. Seganish, C. K. Chung, J. Am.
Chem. Soc. 2009, 131, 17087; b) B. M. Trost, S. Malhotra, B. A.
Fried, J. Am. Chem. Soc. 2009, 131, 1674; c) B. M. Trost, S. Shin,
J. A. Sclafani, J. Am. Chem. Soc. 2005, 127, 8602; d) B. M. Trost,
A. Fettes, B. T. Shireman, J. Am. Chem. Soc. 2004, 126, 2660;
e) B. M. Trost, V. S. C. Yeh, Org. Lett. 2002, 4, 3513; f) B. M.
Trost, H. Ito, E. R. Silcoff, J. Am. Chem. Soc. 2001, 123, 3367;
g) B. M. Trost, H. Ito, J. Am. Chem. Soc. 2000, 122, 12003.
[5] a) B. M. Trost, J. Jaratjaroonphong, V. Reutrakul, J. Am. Chem.
Soc. 2006, 128, 2778; b) B. M. Trost, L. R. Terrell, J. Am. Chem.
Soc. 2003, 125, 338.
Received: February 9, 2012
Published online: May 29, 2012
[6] B. M. Trost, S. Hisaindee, Org. Lett. 2006, 8, 6003.
[7] a) T. Misaki, K. Kawano, T. Sugimura, J. Am. Chem. Soc. 2011,
133, 5695; b) T. Misaki, G. Takimoto, T. Sugimura, J. Am. Chem.
Soc. 2010, 132, 6286. During preparation of this manuscript,
a report on the stereoselective addition of 5H-oxazol-4-ones to
a,b-unsaturated ketones appeared: c) H. Huang, K. Zhu, W. Wu,
Z. Jin, J. Ye, Chem. Commun. 2012, 48, 461.
[8] B. M. Trost, K. Dogra, M. Franzini, J. Am. Chem. Soc. 2004, 126,
1944.
[9] For the related stereoselective addition of 5-aryl-1,3-dioxolan-4-
ones to nitro olefins reported by Dixon and co-workers, see: P. S.
Hynes, D. Stranges, P. A. Stupple, A. Guarna, D. J. Dixon, Org.
Lett. 2007, 9, 2107.
[10] For asymmetric addition reactions of the isomeric 4H-oxazol-5-
ones (azlactones) to electron-deficient olefins reported by
Jørgensen and co-workers, see: J. Alemꢁn, A. Milelli, S. Cabrera,
E. Reyes, K. A. Jørgensen, Chem. Eur. J. 2008, 14, 10958.
[11] Unoptimized result. Relative stereochemistry was further es-
tablished by an nOe study. See the Supporting Information for
details.
Keywords: asymmetric catalysis · dinuclear catalysts ·
nitro-Michael reaction · oxazolones · ProPhenol ligands
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[1] For selected publications, see: aldol reactions: a) M. Terada, H.
Tanaka, K. Sorimachi, J. Am. Chem. Soc. 2009, 131, 3430; b) N.
Kumagai, S. Matsunaga, T. Kinoshita, S. Harada, S. Okada, S.
Sakamoto, K. Yamaguchi, M. Shibasaki, J. Am. Chem. Soc. 2003,
125, 2169; Mannich-type reactions: c) X. Liu, L. Deng, X. Jiang,
W. Yan, C. Liu, R. Wang, Org. Lett. 2010, 12, 876; d) L. Yin, M.
Kanai, M. Shibasaki, J. Am. Chem. Soc. 2009, 131, 9610; e) J.
Hernꢁndez-Toribio, R. Gꢂmez Arrayꢁs, J. C. Carretero, J. Am.
Chem. Soc. 2008, 130, 16150; f) D. Uraguchi, Y. Ueki, T. Ooi,
J. Am. Chem. Soc. 2008, 130, 14088.
[2] For enamine catalysis with a-branched aldehydes, see: a) F. Yu,
Z. Jin, H. Huang, T. Ye, X. Liang, J. Ye, Org. Biomol. Chem.
2010, 8, 4767; b) N. Mase, R. Thayumanavan, F. Tanaka, C. F.
Barbas III, Org. Lett. 2004, 6, 2527.
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