Zinc triflate-bis-oxazoline complexes as chiral catalysts: Enantioselective reduction of α-alkoxy-ketones with catecholborane

Article abstract of DOI:10.1016/S0040-4039(99)02339-4

A new methodology for the catalytic enantioselective reduction of α- alkoxy-ketones is described. The procedure employs Zn(OTf)₂-bis-oxazoline complexes (8-10 mol%) as catalysts and catecholborane as the reducing agent. The reaction, carried ou

Full text of DOI:10.1016/S0040-4039(99)02339-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1601–1605
Zinc triflate–bis-oxazoline complexes as chiral catalysts:
enantioselective reduction of α-alkoxy-ketones with
catecholborane
Marco Bandini, Pier Giorgio Cozzi,∗ Meri de Angelis and Achille Umani-Ronchi ∗
Dipartimento di Chimica‘G. Ciamician’, Università di Bologna, Via Selmi 2, 40126 Bologna, Italy
Received 21 October 1999; accepted 16 December 1999
Abstract
A new methodology for the catalytic enantioselective reduction of α-alkoxy-ketones is described. The procedure
employes Zn(OTf)2–bis-oxazoline complexes (8–10 mol%) as catalysts and catecholborane as the reducing
agent. The reaction, carried out in CH2Cl2 at 0°C, affords the α-alkoxy-alcohols in high yields and with good
enantioselectivity. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: asymmetric reactions; catalysis; ketones; reduction.
Enantioselective reduction of ketones represents one of the most important methodologies for ob-
taining enantiomerically pure compounds which are used as key intermediates in the preparation of
fine chemicals and biologically active compounds.1 The asymmetric borane reductions of α-substituted
prochiral ketones such as α-halo ketones,2a α-ketophosphonates2b and other prochiral ketones con-
taining heteroatoms,2c have been recently reported to give optically active 1,2-diols. Moreover, BI-
NAP–ruthenium complexes have been found to be highly effective in the enantioselective reduction
of chelating substrates such as β-ketoesters and β-alkoxy-ketones.3 As a part of our program devoted
to the application of the bis-oxazoline (box) ligands in asymmetric catalytic processes,4 we describe
herein a new simple and convenient method for the enantioselective reduction of α-alkoxy-ketones
employing chiral catalysts derived from Zn(OTf)2 and optically pure bis-oxazolines. The Lewis acidity
of these box–M(OTf)n complexes is well established, and highly enantioselective Diels–Alder,5a aldol
condensation,5b hetero Diels–Alder,5a Michael addition5c and carbonyl ene5a reactions based on such
catalysts, have been reported.
In almost all of these reports, two-point catalyst–substrate binding, is involved.† However, to the best
of our knowledge, the same strategy has never been applied to the catalytic enantioselective reduction
∗
Corresponding author. E-mail: pgcozzi@ciam.unibo.it (P. G. Cozzi), umani@ciam.unibo.it (A. Umani-Ronchi)
In fact, N-acyl-oxazolidinones, α-benzyloxy-aldehydes and piruvates are the substrates which give higher ees in the catalytic
†
box-Lewis acid mediated reactions.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02339-4
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of ketones. Moreover, a recent report pointed out that α-chelating ketones are not suitable substrates for
enantioselective transfer hydrogenation reductions promoted by chiral ruthenium catalysts.6 Initially, the
box ligands 1–6 (Fig. 1)7 were chosen as ligands for the reduction of the α-methoxy-acetophenone
78 with different reducing agents: catecholborane (CATBH), BH3·SMe2, NaBH4, (EtO)3SiH. The
catecholborane reductant afforded both higher yields and enantioselectivity.‡ The asymmetric reductions
were carried out at 0°C in the presence of a catalytic amount of a box–Zn(OTf)2 complex (simply
prepared by stirring a solution of box and Zn(OTf)2 in CH2Cl2 for 1 h) (Scheme 1).
Fig. 1.
Scheme 1.
The results obtained using the box-ligands 1–6 and 1.2 eq. of CATBH as reductant, are shown in Table
1.
On the basis of these results, it is important to point out that, while the box-ligands 2 and 4
(excellent ligands for several asymmetric reactions)10 afforded (S)-(+)-2-methoxy-1-phenylethanol (8)
with a modest enantioselection (entries 2 and 4, Table 1), the box bearing the benzylic substitution (1)
gave the highest enantioselectivity (ee=82%).
This methodology has been extended to several aliphatic and aromatic α-benzyloxy-11 and α-
methoxy-ketones12 synthesised following the procedures known in literature. The results obtained using
box 1 as a ligand for Zn(OTf)2, are summarised in Table 2.
The data in Table 2 provide evidence that in order to obtain a high level of enantioselection (ee>80%),
the α-methoxy substitution of the ketone is necessary. In fact, a different protecting group, such as
benzyloxy, gave lower enantioselectivity probably due to steric reasons (Table 2, entries 5–6). A second
trend is evident from the illustrated data: aromatic ketones displayed higher enantiomeric excesses
in this reaction with respect to the aliphatic analogues, probably due to π-polar interaction with the
‡
Other reducting agents catalysed the asymmetric reduction of 7 in low yield and with poor enantioselectivity.

1603
Table 1
Catalytic enantioselective reduction of α-methoxy-acetophenone promoted by Zn–box complexes in
the presence of catecholborane as reductant
Fig. 2.
benzyl substituent of the ligand. A remarkable feature of this protocol is the necessary two-point
catalyst–substrate binding. In fact, while a high level of enantioselectivity is recorded with chelating
substrates, unsubstituted ketones afforded only racemic alcohols.
At the present time, we can only speculate about the mechanism of the reaction. However, the absolute
configuration observed for the alcohol 8 appears to be in agreement with the hypothetical chelating model
proposed in Fig. 2.
In conclusion, we have developed a new methodology for the enantioselective reduction of α-alkoxy-
ketones based on chiral Zn(OTf)2–bis-oxazoline complexes. Analogous studies using other α-hetero
substituted ketones (-SR, -NR2), are now under investigation in our laboratories.
The typical procedure for the catalytic enantioselective reduction is as follows: A flame-dried flask was
charged with the bis-oxazoline 1 (26 mg, 0.078 mmol), Zn(OTf)2 (28 mg, 0.078 mmol) and anhydrous
CH2Cl2 (2 mL) under nitrogen. The solution was stirred during 1 h, cooled at 0°C and then 7 (107 µL,
0.78 mmol) was added. The mixture was then stirred for 5 minutes and CATBH (100 µL, 0.94 mmol) was
added. The solution was kept without stirring for 72 h at 0°C then diluted with Et2O (5 mL) and quenched

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Table 2
Enantioselective reduction of aliphatic and aromatic α-benzyloxy- and α-methoxy-ketones promoted
by the 1–Zn(OTf)2 catalyst
with NaOH 2N (5 mL). The organic phase was separated and the aqueous phase extracted with Et2O
(3×5 mL). The combined organic phases were dried over anhydrous Na2SO4 and evaporated in vacuo.
Finally, the crude product was purified by flash chromatography (cyclohexane:Et2O, 9:1), affording the
(S)-(+)-2-methoxy-1-phenylethanol as a colourless oil in 78% yield and with 82% ee.

1605
Acknowledgements
We would like to thank C.N.R. and M.U.R.S.T. (Progetto nazionale ‘Stereoselezione in Sintesi
Organica: Metodologie ed Applicazioni’) and Bologna University (funds for selected research topics)
for the financial support of this research.
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