Catalytic enantioselective trapping of an alcoholic oxonium ylide with aldehydes: RhII/ZrIV-co-catalyzed three-component reactions of aryl diazoacetates, benzyl alcohol, and aldehydes

Article abstract of DOI:10.1002/anie.200801510

(Chemical Equation Presented) The right combination: A catalytic asymmetric multicomponent reaction has been developed in which two stereogenic carbon centers are constructed in a single step (see scheme; erythro/threo 90:10, up to 80% yield, 98% ee).This type of enantioselective three-component reaction generates α,β-dihydroxy acid derivatives in good yields and with excellent enantioselectivities. Bn =benzyl.

Full text of DOI:10.1002/anie.200801510

Angewandte
Chemie
DOI: 10.1002/anie.200801510
Multicomponent Reactions
Catalytic Enantioselective Trapping of an Alcoholic Oxonium Ylide
with Aldehydes: RhII/ZrIV-Co-Catalyzed Three-Component Reactions
of Aryl Diazoacetates, Benzyl Alcohol, and Aldehydes**
Xu Zhang, Haoxi Huang, Xin Guo, Xiaoyu Guan, Liping Yang, and Wenhao Hu*
Catalytic asymmetric multicomponent reactions (CAMCRs),
in which three or more reactants are combined in a single
chemical step to stereoselectively produce chiral molecules,
have received considerable attention.[1] In addition to low-
ering costs, saving time and energy, and being environ-
mentally friendly, CAMCRs are capable of efficiently build-
ing chiral molecules such as those with stereogenic quaternary
carbon atoms that would otherwise be inaccessible by tradi-
tional methods.[2] Although significant progress has been
made in the area of multicomponent reactions,[1d,3] there is
still a high demand for new CAMCRs to meet the increasing
need for the rapid construction of polyfunctional chiral
molecules. Herein we disclose a novel type of CAMCR in
which polyfunctional dihydroxy acid derivatives with two
stereogenic centers, one of which is a tetrasubstituted carbon
center, are constructed in a single step.
We have previously reported three-component reactions
of diazo compounds 1, alcohols 2, and aldehydes 3 to yield
racemic mixtures of dihydroxy acid frameworks with quater-
nary stereogenic centers 4 [Eq. (1)].[4c] The reaction was
proposed to proceed through the alcoholic oxonium ylide
intermediates IIa or IIb (Scheme 1), which are generated
in situ from 1 and benzyl alcohol (2) in the presence of
Rh2(OAc)4. Trapping intermediates II with aldehydes
resulted in 4; the desired process was in competition with
an irreversible intramolecular proton transfer within IIa/IIb
and thereby activating them. On the basis of this observation
and the previous success of chiral Lewis acid catalysts in
facilitating highly enantioselective aldol reactions,[5] we
envisioned that by using appropriate chiral Lewis acid co-
catalysts it might be possible to achieve asymmetric catalysis
of the target three-component reaction. In the presumed
mechanism, an alcoholic oxonium ylide II, which is formed
in situ from a diazoacetate and an alcohol, would experience a
“delayed proton transfer” and instead undergo an enantiose-
lective aldol-type addition onto an aldehyde III activated with
chiral Lewis acid to generate optically active 4 (Scheme 1).
To validate the hypothesis a number of chiral Lewis
acids,[5] such as combinations of Cu(OTf)2, Yb(OTf)3, Mg-
(ClO4)2, or Sn(OTf)2 (Tf = trifluoromethanesulfonyl) with
chiral bisoxazoline ligands and combinations of TiIV salts with
chiral binol (binol = (1,1’-bi-2-naphthyl)) derivatives, were
screened as chiral co-catalysts for the target CAMCR. None
yielded satisfactory chemo- and stereoselectivities. Never-
À
leading to the O H insertion side products 5 (Scheme 1). We
also observed that addition of a stoichiometric amount of the
[4c]
À
Lewis acid Ti(OtBu)4 suppressed the O H insertion. This
observation supported the proposed mechanism, including
the competing intramolecular process, because the Lewis acid
would have increased the electrophilicity of the aldehydes,
[*] X. Zhang, H. Huang, X. Guo, X. Guan, Prof. L. Yang, Dr. W. Hu
Department of Chemistry
East China Normal University, Shanghai 20062 (China)
Fax: (+86)21-6223-3176
E-mail: whu@chem.ecnu.edu.cn
X. Zhang, H. Huang, X. Guo, X. Guan
Chendu Institute of Organic Chemistry
China Academy of Sciences, Chendu 610041 (China)
and
Graduate School of the Chinese Academy of Sciences
Beijing (China)
[**] We are grateful for financial support from the National Science
Foundation of China (Grant No. 20772033) and for sponsorship by
the Shanghai Pujiang Program.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200801510.
Scheme 1. Proposed mechanism for the target CAMCR. MLn*=chiral
Lewis acid, Bn=benzyl.
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theless, the zirconium–binol system developed by Kobayashi
generated the desired products in 81% overall yield (erythro-
4a/threo-4a 90:10) with 98% ee for erythro-4a.
The scope and limitations of the optimized reaction
conditions were investigated and were found to be amenable
to the reaction of benzyl alcohol with other aldehydes and
diazo compounds (Table 2). Various aryl aldehydes with
and co-workers[6] was identified as the best co-catalysts for
generating the desired optically active products.
The Kobayashi research group has developed air-stable,
chiral Zr/binol/molecular sieves catalysts by combining Zr-
(OnBu)4, chiral binol ligands 6, and 5 Š molecular sieves
(M.S.) in appropriate quantities.[6b,c] We found that these
catalysts effectively catalyzed the target three-component
reactions. In the absence of a Zr/binol/M.S. co-catalyst,
Rh2(OAc)4 catalyzed the reaction of methyl phenyldiazoace-
tate (1a) with benzaldehyde and benzyl alcohol to generate
Table 2: Catalytic asymmetric aldol-type reactions of aryl diazoacetates
with BnOH and aldehydes using the Zr(OnBu)4/6d/M.S. co-catalyst.
Entry Ar1
Ar2
Yield 4
d.r.
ee
[%][b]
(erythro/threo)[c] [%][d]
À
only the O H insertion product 5 (Table 1 entry 1). In
1
2
3
4
5
6
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
81 (4a) 90:10
68 (4b) 80:20
98
96
94
95
60
96
78
94
92
96
93
96
97
89
p-MeOPh
p-BrPh
p-ClPh
p-NO2Ph
80 (4c)
89:11
Table 1: Effect of chiral ligands on Zr(OnBu)4/6/M.S.-catalyzed aldol-
type reactions of benzaldehyde and BnOH with methyl phenyl diazo-
acetate.
77 (4d) 90:10
43 (4e) 70:30
3,4-(OCH2O)Ph 82 (4 f) 83:17
7[e]
8
1-naphthyl
cinnamonyl
2-furyl
Ph
p-MeOPh
40 (4g) 90:10
78 (4h) 84:16
9
Ph
p-BrPh
p-BrPh
m-MePh Ph
m-MePh p-MeOPh
m-MePh p-BrPh
72 (4i)
70 (4j)
91:9
92:8
10
11
12
13
14
73 (4k) 93:7
60 (4l) 89:12
65 (4m) 90:10
66 (4n) 82:18
Entry
Ligand
(mol%)
T [8C]
Solvent
Yield
[%][b]
d.r.[c]
(erythro-4a/
threo-4a)
ee
[%][d]
[a] Reactions performed in DCE at 08C in the presence of Rh2(OAc)4
(1 mol%) and Zr/6d/M.S. (15 mol%). [b] Yield of isolated product after
purification by column chromatography. [c] Diastereomeric ratios were
1
2
3
4
5
6
7
8
–
25
25
25
25
25
25
25
25
0
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
DCE
–
–
–
1
6a (15)
6b (15)
6c (15)
6d (5)
6d (15)
6d (30)
6d (15)
6d (15)
6d (15)
6d (15)
6d (15)
10
30
39
30
43
54
54
81
73
87
78
85:15
60:40
85:15
62:38
80:20
91:9
84:16
90:10
87:13
87:13
88:12
10
15
80
54
90
94
91
98
96
93
94
determined by H NMR analysis of the crude reaction mixtures. [d] The
ee values were determined by HPLC on a chiral stationary phase.
[e] Zr(OnBu)4/6d 1.0:1.2.
different substituents were found to be good substrates.
Reactions with cinnamaldehyde and furfural aldehyde
afforded the corresponding products 4h and 4i, respectively,
in moderate yields and high diastereo- and enantioselectiv-
ities (Table 2, entries 8 and 9). The reaction was observed to
be somewhat sensitive to electronic effects: the reaction of an
electron-withdrawing substrate, p-nitrobenzaldehyde, gave a
lower yield and only moderate enantioselectivity (Table 2,
entry 5). The reaction did not work well with aliphatic
aldehydes, and the use of ethyl diazoacetate failed to produce
the desired product. The absolute configuration of the major
erythro-4a enantiomer was assigned as 2S,3S by comparison
with published data for the corresponding debenzylated
compound (2S,3S)-methyl 2,3-dihydroxy-2,3-diphenylpropa-
noate.[7]
9
10
11
12
0
toluene
DCE
toluene
À20
À20
[a] Reactions were performed on a 0.1 mmol scale (1a/2/3a 1:1.2:1.1) in
the presence of Rh2(OAc)4 (1 mol%) in solvent (3.0 mL) at the given
temperature in an Ar atmosphere. [b] Yield of isolated product after
purification by column chromatography. [c] Diastereomeric ratios were
1
determined by H NMR analysis of the crude reaction mixtures. [d] The
ee values were determined by HPLC on a chiral stationary phase.
contrast, the addition of 15 mol% Zr/(S)-6a/M.S.[6d] resulted
in the isolation of the desired diastereomers (erythro-4a and
threo-4a) in 10% yield, with 10% ee for the favored erythro
diastereomer (Table 1 entry 2). This result encouraged us to
screen other binol ligands, and of those (S)-3,3’-diiodobinol
6d gave the most promising results: products 4a were isolated
in 43% yield (erythro-4a/threo-4a 80:20) with 90% ee for the
major diastereomer (Table 1 entry 6). A higher yield of
erythro-4a with 94% ee was obtained when the catalyst
loading was increased to 30 mol% (Table 1, entry 7). The
effects of solvent and temperature were also investigated
(Table 1, entries 8–13), and the optimized reaction conditions
involved 1,2-dichloroethane (DCE) at 08C in the presence of
15 mol% Zr/6d/M.S. co-catalyst (Table 1, entry 9), which
The enantioselective oxonium-trapping process reported
herein is quite unique. The alcoholic oxonium ylide inter-
mediates IIa and IIb are unstable and possess extremely short
half-lives which undergo fast, irreversible proton transfer that
À
results in the formation of the undesired O H insertion side
product.[8] By employing an appropriate chiral Lewis acid co-
catalyst, we were not only able to control the reaction
pathway by efficiently trapping the oxonium ylide to form the
desired product, we were also able to achieve high diastereo-
selectivities and excellent enantioselectivities.
In conclusion, we have developed RhII/ZrIV-co-catalyzed
asymmetric three-component reactions that combine aryl
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Angewandte
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[3] For articles on multicomponent reactions, see: a) P. Wipf, C. R. J.
diazoacetates, benzyl alcohols, and aldehydes. The reaction
occurs by trapping a reactive alcoholic oxonium ylide with a
ZrIV-activated aldehyde. The reaction provides a convenient
and highly enantioselective route to the construction of an
important class of compounds for both organic and medicinal
chemistry; namely, a,b-dihydroxy acid derivatives containing
chiral tetrasubstituted carbon centers.
Stephenson, K. Okumura, J. Am. Chem. Soc. 2003, 125, 14694;
b) V. Nair, C. Rajesh, A. U. Vinod, S. Bindu, A. R. Sreekenth, L.
Balagopal, Acc. Chem. Res. 2003, 36, 899; c) I. Ugi, Pure Appl.
Chem. 2001, 73, 187; d) A. Dömling, I. Ugi, Angew. Chem. 2000,
112, 3300; Angew. Chem. Int. Ed. 2000, 39, 3168; e) A. Dömling,
Curr. Opin. Chem. Biol. 2000, 4, 318.
[4] For representative reactions for the trapping of onium ylides, see:
a) Y. Wang, Y. Zhu, Z. Chen, A. Mi, W. Hu, M. Doyle, Org. Lett.
2003, 5, 3924; b) Y. Wang, Z. Chen, A. Mi, W. Hu, Chem.
Commun. 2004, 2486; c) C. Lu, H. Liu, Z. Chen, W. Hu, A. Mi,
Org. Lett. 2005, 7, 83; d) C. Lu, H. Liu, Z. Chen, W. Hu, A. Mi,
Chem. Commun. 2005, 2624; e) H. Huang, X. Guo, W. Hu,
Angew. Chem. 2007, 119, 1359; Angew. Chem. Int. Ed. 2007, 46,
1337; f) X. Guo, H. Huang W. Hu, Org. Lett. 2007, 9, 4721.
[5] For comprehensive references of chiral Lewis acid catalyzed
reactions, see: a) Modern Aldol Reactions, Vols. 1 and 2 (Ed.: R.
Mahrwald), Wiley-VCH, Weinheim, 2004; b) Lewis Acid
Reagents-A Practial Approach (Ed.: H. Yamamoto), Oxford
University Perss, Oxford, 1999; c) for asymmetric aldol reactions,
see: M. Sauamura, Y. Ito in Catalytic Asymmetric Synthesis (Ed.:
I. Ojima), VCH, New York, 1993, Chapter 8B1, pp. 493 – 512;
d) for recent advances in asymmetric aldol addition reactions, see:
E. M. Carreira in Catalytic Asymmetric Synthesis (Ed.: I. Ojima),
VCH, New York, 1993, Chapter 8B2, pp. 513 – 541; e) G. Desi-
moni, G. Faita, K. A. Jørgensen, Chem. Rev. 2006, 106, 3561;
f) J. M. Brunel, Chem. Rev. 2005, 105, 857; g) T. D. Machajewski,
C.-H. Wong, Angew. Chem. 2000, 112, 1406; Angew. Chem. Int.
Ed. 2000, 39, 1352; h) H. Suga, K. Inoue, S. Inoue, A. Kakehi, J.
Am. Chem. Soc. 2002, 124, 14836.
[6] a) S. Kobayashi, M. Ueno in Comprehensive Asymmetric Catal-
ysis (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer,
Heidelberg, 1999, suppl. 1, p. 143 – 150; b) M. Ueno, H. Ishitani, S.
Kobayashi, Org. Lett. 2002, 4, 3395; c) T. Isoda, R. Akiyama, H.
Oymda, K. S. Kobayashi, Adv. Synth. Catal. 2006, 348, 1813; d) H.
Ishitani, M. Ueno, S. Kobayashi, J. Am. Chem. Soc. 1997, 119,
7153; e) H. Ishitani, M. Ueno, S. Kobayashi, J. Am. Chem. Soc.
2000, 122, 8180; f) S. Xue, S. Yu, Y. Deng, W. D. Wulff, Angew.
Chem. 2001, 113, 2331; Angew. Chem. Int. Ed. 2001, 40, 2271; g) Y.
Ihori, Y. Yamashita, H. Ishitani, S. Kobayashi, J. Am. Chem. Soc.
2005, 127, 15528; h) Y. Yamashita, S. Kobayashi, J. Am. Chem.
Soc. 2004, 126, 11279; i) T. Gastner, H. Ishitani, R. Akiyama, S.
Kobayashi, Angew. Chem. 2001, 113, 1949; Angew. Chem. Int. Ed.
2001, 40, 1896; j) H. Ishitani, Y. Yamashita, H. Shimizu, S.
Kobayashi, J. Am. Chem. Soc. 2000, 122, 5403.
Experimental Section
Typical experimental procedure for asymmetric aldol-type reactions
with a chiral zirconium catalyst: BnOH (12.5 mL, 0.12 mmol) was
added to a mixture of powdered Zr catalyst[6d] (0.015 mmol) in DCE
(1.00 mL) at room temperature. The mixture was stirred for 1 h
before a solution of benzadehyde (0.11 mmol) and Rh2(OAc)4
(0.5 mg, 1 mol%) in DCE (0.50 mL) was added. The resulting
mixture was stirred at room temperature for 5 min and then cooled
to 08C for 10 min before methyl phenyldiazoacetate (1a; 17.6 mg,
0.10 mmol) in DCE (1 mL) was added. The reaction mixture was
stirred for 3–4 h at 08C until the reaction was complete (as evident by
TLC) and was subsequently quenched by the addition of a saturated
aqueous solution of NaHCO3. After removal of the organic layer, the
aqueous layer was extracted with CH2Cl2 (2 ” 10 mL) and the organic
extracts were then combined, dried over anhydrous Na2SO4, and the
filtrate was concentrated under reduced pressure to give the crude
product. 1H NMR analysis was used to determine the diastereoselec-
tivity of the reaction. The crude product was then purified by flash
chromatography on silica gel (EtOAc/light petroleum 1:15) to yield
4a (29.3 mg, 81%). The optical purity was determined by HPLC on a
chiral stationary phase using a Daicel Chirapak OD-H column.
Compounds 4b–4n were prepared by similar procedures.
Received: March 31, 2008
Published online: July 21, 2008
Keywords: asymmetric catalysis · diazo compounds ·
.
Lewis acids · multicomponent reaction · ylides
[1] a) H. C. Guo, J. A. Ma, Angew. Chem. 2006, 118, 362; Angew.
Chem. Int. Ed. 2006, 45, 354; b) D. Enders, M. R. Hüttl, C.
Grondal, G. Raabe, Nature 2006, 441, 861; c) Multicomponent
Reactions; (Eds.: J. Zhu, H. BienaymØ), Wiley-VCH, Weinheim,
2005; d) D. J. Ramón, M. Yus, Angew. Chem. 2005, 117, 1628;
Angew. Chem. Int. Ed. 2005, 44, 1602.
[7] S. Scholtis, A. Ido, R. Mahrwald, Org. Lett. 2006, 8, 5353.
[8] a) Y. Sawada, T. Mori, A. Oku, J. Org. Chem. 2003, 68, 10040;
b) Y. Sawada, T. Mori, A. Oku, Chem. Commun. 2001, 1086; c) I.
Naito, A. Oku, N. Ohtani, Y. Fujiwara, Y. Tanimoto, J. Chem. Soc.
Perkin Trans. 2 1996, 725; d) H. Tomioka, N. Kobayashi, S.
Murata, T. Ohtawa, J. Am. Chem. Soc. 1991, 113, 8771.
[2] a) K. Oisaki, D. Zhao, M. Kanai, M. Shibasaki, J. Am. Chem. Soc.
2007, 129, 7439; b) B. M. Trost, C. Jiang, Synthesis 2006, 369;
c) C. J. Douglas, L. E. Overman, Proc. Natl. Acad. Sci. USA 2004,
101, 5363; d) E. J. Corey, A. Guzman-Perez, Angew. Chem. 1998,
110, 402; Angew. Chem. Int. Ed. 1998, 37, 388.
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