Asymmetric aldol reaction of glyoxal catalyzed by diarylprolinol

Article abstract of DOI:10.1002/cctc.201300247

All selection should be this- eeasy: The direct asymmetric aldol reaction of commercial aqueous glyoxal is catalyzed by trifluoromethyl-substituted diarylprolinol 1 to afford a β-formyl-β-hydroxy-α-substituted aldehyde in good yield with excellent anti selectivity and excellent enantioselectivity.

Full text of DOI:10.1002/cctc.201300247

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Y. Hayashi,* M. Kojima
&& – &&
Asymmetric Aldol Reaction of Glyoxal
Catalyzed by Diarylprolinol
All selection should be this eeasy: The
direct asymmetric aldol reaction of com-
mercial aqueous glyoxal is catalyzed by
trifluoromethyl-substituted diarylprolinol
1 to afford a b-formyl-b-hydroxy-a-sub-
stituted aldehyde in good yield with
excellent anti selectivity and excellent
enantioselectivity.
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DOI: 10.1002/cctc.201300247
Asymmetric Aldol Reaction of Glyoxal Catalyzed by
Diarylprolinol
Yujiro Hayashi*[a] and Masahiro Kojima[b]
Glyoxal, possessing two conjoined formyl groups, is a syntheti-
cally useful reagent that is commercially available as a 39%
aqueous solution.[1] If the addition of D2O to commercial aque-
chloroacetaldehyde,[11] or pyruvaldehyde,[12] and trifluoroacetal-
dehyde ethyl hemiacetal.[13] Herein, we describe the application
of this diarylprolinol catalyst to the highly enantioselective
cross-aldol reaction of glyoxal by the direct use of its commer-
cially available aqueous solution.
1
ous glyoxal is monitored by H NMR spectroscopy, several spe-
cies, including its hydrated form and dimer and trimer species,
are observed.[2] Despite these complications, it is clearly an ad-
vantage to employ this reagent directly as an aqueous solution
in synthetic organic chemistry without removing the water.
The aldol reaction is one of the most important carbon–
carbon bond-forming reactions in organic synthesis, and many
variations of the asymmetric aldol reaction have been devel-
oped with the use of chiral organometallic catalysts.[3] After the
discovery of the proline-catalyzed intermolecular aldol reaction
by List, Lerner, and Barbas in 2000,[4] the field of organocataly-
sis advanced rapidly. Asymmetric aldol reactions catalyzed by
organocatalysts are now well established in the literature.[5]
Our group has an interest in the development and applica-
tion of novel organocatalysts to asymmetric reactions. We
have found diphenylprolinol silyl ether (Figure 1) to be an ef-
We chose 3-phenylpropanal as a model nucleophilic alde-
hyde. The reaction of an aqueous solution of glyoxal (39% so-
lution) was examined under a variety of reaction conditions
(Table 1). As the obtained product readily isomerizes, the aldol
Table 1. Effect of the catalyst and solvent in the aldol reaction of 3-phe-
nylpropanal with glyoxal.[a] i) 10 mol% Cat., solvent, RT, time; ii) Ph3P=
CHCO2Et, toluene, 508C.
Entry
Catalyst
Solvent
t
[h]
Yield[b]
[%]
anti/syn[c]
ee[d]
[%]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
2
3
4
DMSO
DMF
CH3CN
1,4-dioxane
THF
THF
THF
THF
THF
48
48
64
20
25
19
10
3.5
22
15
22
39
76
75
79
68
90
98
33
29
>20:1
>20:1
>20:1
>20:1
>20:1
7:1
92
91
96
94
96
77
2:1
3:1
4:1
2:1
À51
À86
72
proline
proline
10
DMF
56
Figure 1. The organocatalysts investigated in this study.
[a] The reaction was performed with glyoxal (39% aqueous solution,
120 mL, 1.0 mmol), 3-phenylpropanal (0.5 mmol), and organocatalyst
(0.05 mmol) in the indicated solvent (0.5 mL) at room temperature for the
indicated time. Upon completion of the reaction, the aldol product was
converted into bis(a,b-unsaturated ester) 5a by treatment with Ph3P=
CHCO2Et. See the Supporting Information for details. [b] Yield of isolated
bis(a,b-unsaturated ester) 5a. [c] Determined by 1H NMR spectroscopy.
[d] Determined by HPLC analysis on a chiral phase.
fective organocatalyst in several asymmetric reactions.[6–8] Re-
cently, we found trifluoromethyl-substituted diarylprolinol to
be a superior catalyst in the aldol reaction of acetaldehyde as
a nucleophile and in a selection of cross-aldol reactions of sev-
eral aldehydes as electrophilic components,[9] for example, by
its reaction with polymeric ethyl glyoxylate,[10] aqueous
product was treated in situ with a Wittig reagent, (ethoxycar-
bonylmethylidene)triphenylphosphorane, and converted into
bis(ester) 5a through a double Wittig reaction; compound 5a
was isolated and characterized (Equation (1), Table 1). The reac-
tion proceeded in a highly diastereo- and enantioselective
manner if trifluoromethyl-substituted diarylprolinol 1 was used
as the catalyst. The solvent affected the enantioselectivity only
marginally but influenced the reactivity and yield significantly
(Table 1, entries 1–5). As the reaction proceeded smoothly in
THF in good yield and with excellent diastereo- and enantiose-
lectivities, THF was selected as a suitable solvent (Table 1,
entry 5). The reaction also proceeded in the presence of diphe-
[a] Prof. Dr. Y. Hayashi
Department of Chemistry, Graduate School of Science
Tohoku University
6-3 Aramaki-Aza Aoba, Aoba-ku, Sendai 980-8578 (Japan)
Fax: (+81)22-795-6566
E-mail: yhayashi@m.tohoku.ac.jp
Homepage: http://www.ykbsc.chem.tohoku.ac.jp/
[b] M. Kojima
Department of Industrial Chemistry
Faculty of Engineering
Tokyo University of Science
Kagurazaka, Shinjuku-ku, Tokyo 162-8601 (Japan)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201300247.
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nylprolinol 2, but the diastereo- and enantioselectivities were
lower (Table 1, entry 6). In contrast to the use of 1, correspond-
ing silyl ether 3 and diphenylprolinol silyl ether 4 afforded
product 5a as its opposite enantiomer in low to moderate
enantioselectivity (Table 1, entries 7 and 8). Proline was not ef-
fective for the present reaction (Table 1, entries 9 and 10).
Having optimized the reaction conditions, the generality of
the cross-aldol reaction was investigated (Table 2). Not only 3-
phenylpropanal, but also propanal, butanal, and 3-methylbuta-
(Table 2, entry 6). The reaction of acetaldehyde also proceeded
to afford the aldol product in 81% enantiomeric excess (ee)
(Table 2, entry 7).
As the aldol products possess two formyl moieties, several
synthetic transformations are possible. Conversion of the aldol
product into other synthetically useful compounds was thus
examined. After the aldol reaction, trimethyl orthoformate and
a catalytic amount of p-toluenesulfonic acid (TsOH) were
added in the same pot. This double acetalization proceeded
smoothly to afford bis(acetal) 6 in good yield with excellent di-
astereo- and enantioselectivities [Scheme 1, Eq. (3)].
Table 2. Cross-aldol reaction of glyoxal catalyzed by 1.[a] i) 10 mol% 1,
THF, RT, time; ii) Ph3P=CHCO2Et, toluene, 508C.
Entry
Product
t
[h]
Yield[b]
[%]
anti/syn[c]
ee[d]
[%]
1
25
79
63
74
>20:1
10:1
96
98
97
2[e]
12
30
3
16:1
Scheme 1. Conversion into synthetically useful compounds.
4
90
102
19
67
63
62
>20:1
4:1
96
85
97
When the aldol product was treated with NaBH4 in the pres-
ence of MgSO4,[14] double reduction occurred to afford triol 7
in good yield with excellent diastereo- and enantioselectivities
5[f]
[15]
[Scheme 1, Eq. (4)]. When NaBH(OAc)3 was employed as the
6
8:1
reducing reagent, the formyl group proximal to the a-alkyl
group was reduced chemoselectively, and b-hydroxy-directed
reduction proceeded predominantly without a-hydroxy-direct-
ed reduction. This provided tetrahydrofuran derivative 8 in
good yield with excellent enantioselectivity [Scheme 1, Eq. (5)].
Notably, there was no loss of the diastereo- and enantioselec-
tivities during these transformations, and the enantiopurity of
the final compounds were consistently 97% ee.
7[g]
72
71
–
81
[a] Unless indicated otherwise, the reaction was performed with glyoxal
(39% aqueous solution, 120 mL, 1.0 mmol), nucleophilic aldehyde
(0.5 mmol), and organocatalyst 1 (0.05 mmol) in THF (0.5 mL) at room
temperature for the indicated time. Upon completion of the reaction, the
aldol product was converted into its bis(a,b-unsaturated ester) by treat-
ment with Ph3P=CHCO2Et. See the Supporting Information for details.
[b] Yield of isolated bis(a,b-unsaturated ester). [c] Determined by 1H NMR
The absolute stereochemistry of the products was deter-
mined by comparison of their optical rotation values to that of
known acetal 10.[16] Acetal 10 was prepared according to
Scheme 2, Equation (6). The aldol product of glyoxal and ben-
zyloxyacetaldehyde was reduced in situ with NaBH4 to provide
triol 9, which was then treated with acetone in the presence of
TsOH to afford acetal 10.
spectroscopy. [d] Determined by HPLC analysis on
a chiral phase.
[e] Glyoxal (0.5 mmol) and propanal (1.0 mmol) were employed. [f] Cata-
lyst 2 (20 mol%) was employed. [g] Acetaldehyde (1.5 mmol) and glyoxal
(0.5 mmol) were employed.
nal, was found to be suitable nucleophilic aldehydes, and all of
these substrates afforded products 5 in excellent diastereo-
and enantioselectivities (Table 2, entries 1–4). a-Alkoxyalde-
hydes such as benzyloxyacetaldehyde could also be employed,
and the product was obtained with excellent enantioselectivity.
Notably, 20 mol% of catalyst 2 was employed in this reaction
because of the slow reaction rate and because catalyst 2 is
more nucleophilic (Table 2, entry 5). Importantly, possible side
reactions, such as b-alkoxy elimination, were not observed
The absolute configuration of the aldol adducts can be ra-
tionalized to proceed via the transition model represented in
Figure 2. First, the prolinol catalyst and aldehyde react to gen-
erate an enamine, after which glyoxal becomes activated by
hydrogen bonding to the hydroxy group of the catalyst. To
make this hydrogen-bonding interaction strong, the trifluoro-
methyl substituent on the aromatic ring of the catalyst is nec-
essary. If silyl ether 3 or 4 is employed as the catalyst, glyoxal
approaches from the opposite enantioface of the enamine as
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Scheme 2. Preparation of the known acetal 10.
Keywords: aldol reaction · asymmetric synthesis · glyoxal ·
organocatalysis · enantioselectivity
a
result of the steric repulsion
the bulky substituent
of
(TMSOAr2CÀ), which affords the op-
posite enantiomer.
[1] Glyoxal is commercially available as an aqueous solution. Aldrich: cata-
log number 128465. TCI: catalog number G0152.
In conclusion, we have devel-
[2] a) E. B. Whipple, J. Am. Chem. Soc. 1970, 92, 7183; b) K. W. Loeffler, C. A.
Koehler, N. M. Paul, D. O. De Haan, Environ. Sci. Technol. 2006, 40, 6318;
c) E. Avzianova, S. D. Brooks, Spectrochim. Acta Part A 2013, 101, 40 and
references therein.
oped
a
practical synthesis of
aldehydes
b-formyl-b-hydroxy
through an asymmetric, direct aldol
reaction of glyoxal catalyzed by dia-
rylprolinol 1. There are several note-
worthy features related to this reac-
tion.
Figure 2. The proposed transi-
tion state between enamine
and glyoxal.
[3] Modern Aldol Reactions, Vols. 1, 2 (Ed.: R. Mahrwald), Wiley-VCH, Wein-
heim, 2004.
[4] B. List, R. A. Lerner, C. F. Barbas, III, J. Am. Chem. Soc. 2000, 122, 2395.
[5] Enamine Catalysis of Intermolecular Aldol Reactions“, S. M. Yliniemela-
Sipari, A. Piisola, P. M. Pihko in Asymmetric Organocatalysis 1, Science of
Synthesis (Volume editor: B. List), Thieme, Stuttgart, 2012.
[6] Y. Hayashi, H. Gotoh, T. Hayashi, M. Shoji, Angew. Chem. 2005, 117,
4284; Angew. Chem. Int. Ed. 2005, 44, 4212.
[7] Jørgensen’s group also reported the diarylprolinol silyl ether at the
same time, see; M. Marigo, T. C. Wabnitz, D. Fielenbach, K. A. Jørgensen,
Angew. Chem. 2005, 117, 804; Angew. Chem. Int. Ed. 2005, 44, 794.
[8] Reviews of diarylprolinol silyl ether, see; a) C. Palomo, A. Mielgo, Angew.
Chem. 2006, 118, 8042; Angew. Chem. Int. Ed. 2006, 45, 7876; b) A.
Mielgo, C. Palomo, Chem. Asian J. 2008, 3, 922; c) L. W. Xu, L. Li, Z. H.
Shi, Adv. Synth. Catal. 2010, 352, 243; d) K. L. Jensen, G. Dickmeiss, H.
Jiang, L. Albrecht, K. A. Jørgensen, Acc. Chem. Res. 2012, 45, 248.
[9] a) Y. Hayashi, T. Itoh, S. Aratake, H. Ishikawa, Angew. Chem. 2008, 120,
2112; Angew. Chem. Int. Ed. 2008, 47, 2082; b) Y. Hayashi, S. Samanta, T.
Itoh, H. Ishikawa, Org. Lett. 2008, 10, 5581; c) T. Itoh, H. Ishikawa, Y. Hay-
ashi, Org. Lett. 2009, 11, 3854.
1) Synthetically useful chiral b-formyl-b-hydroxy-a-substituted
aldehydes can be prepared with excellent anti selectivity
and excellent enantioselectivity.
2) Commercially available aqueous glyoxal, in which several
species are present, is used directly without the need to
remove water prior to use.
3) Acetaldehyde can be successfully used as a nucleophilic
aldehyde.
Because the generated chiral b-formyl-b-hydroxy aldehydes
are synthetically important chiral building blocks, this method
offers efficient entry to the preparation of more complex
targets.
[10] T. Urushima, Y. Yasui, H. Ishikawa, Y. Hayashi, Org. Lett. 2010, 12, 2966.
[11] Y. Hayashi, Y. Yasui, T. Kawamura, M. Kojima, H. Ishikawa, Angew. Chem.
2011, 123, 2856; Angew. Chem. Int. Ed. 2011, 50, 2804.
[12] Y. Hayashi, Y. Yasui, M. Kojima, T. Kawamura, H. Ishikawa, Chem.
Commun. 2012, 48, 4570.
[13] Y. Hayashi, Y. Yasui, T. Kawamura, M. Kojima, H. Ishikawa, Synlett 2011,
485.
Acknowledgements
[14] Without MgSO4, the isolated yield decreased dramatically.
[15] D. A. Evans, K. T. Chapman, E. M. Carreira, J. Am. Chem. Soc. 1988, 110,
3560.
This work was supported by a Grant-in-Aid for Scientific Research
on Innovative Areas “Advanced Molecular Transformations by Or-
ganocatalysts” from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
[16] L. Ermolenko, N. A. Sasaki, J. Org. Chem. 2006, 71, 693.
Received: April 2, 2013
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