Novel simple and highly modular ligands for efficient asymmetric transfer-hydrogenation of ketones

Article abstract of DOI:10.1039/b206471e

Novel simple and highly modular dipeptide-analogue ligands combined with [RuCl₂(p-cymene)]₂ were demonstrated to efficiently catalyze the reduction of ketones under hydrogen transfer conditions with enantioselectivities up to 96%.

Full text of DOI:10.1039/b206471e

Novel simple and highly modular ligands for efficient asymmetric
transfer-hydrogenation of ketones
Isidro M. Pastor, Patrik Västilä and Hans Adolfsson*
Department of Organic Chemistry, Stockholm University, SE-10691 Stockholm, Sweden.
E-mail: hansa@organ.su.se; Fax: +46 8 154908; Tel: +46 8 162479
Received (in Cambridge, UK) 4th July 2002, Accepted 24th July 2002
First published as an Advance Article on the web 13th August 2002
Novel simple and highly modular dipeptide-analogue li-
gands combined with [RuCl (p-cymene)] were demon-
slightly better conversion to (S)-1-phenylethanol (41% in 2 h,
Table 1, entry 1). The enantioselectivity was in the same range
(95% ee) as observed using ligand 2a. The conversion to the
secondary alcohol was, however, dramatically increased by
employing the diastereomeric ligand 2c (entry 2). The enantio-
selectivity of the reduction was unchanged (95%). Interestingly,
the absolute configuration of the product alcohol stayed the
same irrespectively of the chiral nature of the amino alcohol.
Thus, regardless of the configuration of the amino alcohol, we
obtained (S)-1-phenylethanol as the major product isomer.
These results suggested that the stereocenter present in the
amino acid part of the ligand was responsible for the
stereochemical outcome of the reaction. To further investigate
this, we prepared ligands 2d and 2e, starting from the non-
2
2
strated to efficiently catalyze the reduction of ketones under
hydrogen transfer conditions with enantioselectivities up to
96%.
The reduction of ketones using catalytic hydrogen-transfer
conditions with 2-propanol or formic acid as hydrogen source is
a mild and highly attractive route for the formation of secondary
6
alcohols. The combination of Ru(II)(h -arene) complexes with
chiral amino alcohols or diamine ligands have rendered some
excellent catalysts for the asymmetric reduction of ketones.1
Recently, amides derived from a-amino acids were reported as
2
efficient chiral ligands for the above transformation. In this
context, we decided to investigate the effect of a novel class of
amido-oxazoline ligands (1, Scheme 1) for the asymmetric
reduction of ketones. These ligands, recently prepared in our
laboratories, were employed in titanium-catalyzed enantiose-
natural
D
-valine. Performing the transfer-hydrogenation of
acetophenone using these ligands resulted in high enantiomeric
excess of (R)-1-phenylethanol (entries 3 and 4). Hence, the
absolute configuration of the amino acid did indeed dictate the
stereochemistry of the product.
3
lective addition of diethylzinc to aldehydes. Screening this
class of ligands in the reduction of acetophenone using various
Ru(II) precursors under transfer hydrogenation conditions
Although the stereoselectivity using either of the ligands 2b–
e remained on an equally high level, the enantiomeric ligand
pair 2c and 2d appear to be the matched cases regarding the
reactivity of the formed catalysts. The other pair of ligands (2b
and 2e) can thus be considered as the mis-matched cases
(
2-propanol) revealed that they performed rather poorly, giving
the secondary alcohol in poor yield and low enantioselectivity.
An interesting result, however, caught our attention. We
discovered that a precursor to the oxazoline ligands gave much
better selectivity than the parent ligand structure. The prepara-
tion of 1 starts with the formation of a dipeptide analogue from
a Boc-protected a-amino acid and a 1,2-amino alcohol (2).
Table 1 Enantioselective reduction of acetophenone using transfer
a
hydrogenation conditions
b
c
The coupling of N-Boc-protected
generated a ligand (Scheme 1, 2a, R1 = R2 = i-Pr) which
together with [RuCl (p-cymene)] catalyzed the reduction of
acetophenone to (S)-1-phenylethanol with modest conversion
13% in 2 h) but in good enantioselectivity (93% ee) (Scheme
). This encouraged us to further investigate other dipeptide
L
-valine with (S)-valinol
Entry
1
Ligand
Conv. (%)
Ee (%)
2b
2c
2d
2e
2f
41
78
75
32
63
62
95 (S)
95 (S)
95 (R)
95 (R)
83 (S)
83 (R)
2
2
d
2
3
4
5
6
(
2
analogues (i.e. combinations of amino acids and amino
alcohols) as ligands for the ruthenium-catalyzed reduction of
ketones under hydrogen-transfer conditions. Performing the
reduction of acetophenone with a ligand containing (S)-
phenylglycinol (2b) as the amino-alcohol part, resulted in
2g
a
Reaction conditions: acetophenone (1 eq., 0.2 M in 2-propanol), [RuCl
cymene)] (1 mol% in Ru), ligand (3 mol%) and NaOH (5 mol%). All
reactions were performed at ambient temperature for 2 h. Conversion was
2
(p-
2
b
c
determined by GLC analysis. Enantiomeric excess and absolute configura-
tion were determined by GLC (CP Chirasil DEX CB). d Conversion after 5
h; > 96% (94% ee).
Scheme 1
Scheme 2
2
046
CHEM. COMMUN., 2002, 2046–2047
This journal is © The Royal Society of Chemistry 2002

View Article Online
resulting in significantly lower conversions to the secondary
alcohol. Replacing the ruthenium source with [RuCl (ben-
zene)] in the above protocol resulted in complementary
conversions and enantioselectivities. The reaction carried out in
the presence of ligand 2c gave 81% conversion to the alcohol
and 80 enantiomeric excess ((S)-isomer) within 2 h. Employing
ligand 2d resulted in 65% conversion and 81% ee of the (R)-
isomer. The same trend was observed with the mis-matched pair
turned out to be crucial for the outcome of the reaction.
2
Removal of the protecting group from ligand 2c and thereafter
performing the reduction of acetophenone resulted in no
conversion to the alcohol. From the above results we concluded
that compounds 2c/2d are the most efficient ligands for the
asymmetric reduction of acetophenone.‡ To investigate the
scope of the transfer-hydrogenation a number of aromatic
prochiral ketones were subjected to the protocol containing
2
(
i.e. comparable low conversions and moderate enantioselectiv-
2 2
[RuCl (p-cymene)] and ligand 2c (Table 2).§ As presented in
6
ities). As observed by others, the nature of the h -arene ligand
Table 2, all the examined substrates were transformed to their
corresponding secondary alcohols with good to excellent
conversion and in high enantioselectivities. Notably, the
reduction of the electron-rich 3-methoxyacetophenone pro-
ceeded smoothly to yield the corresponding secondary alcohol
in high enantiomeric excess (entry 4, Table 2). Aromatic
ketones substituted with electron-withdrawing groups, Br, F
4
is important for the catalytic activity. In our case the ruthenium
precursor containing p-cymene provides a catalyst which is
equally active as its less hindered benzene analogue, although
the former precursor transforms into a more stereoselective
catalyst. To investigate the chiral influence of the amino alcohol
moiety of the ligands, we prepared compounds 2f and 2g from
N-Boc-protected
L
- and
D-valine, respectively, and 2-aminoe-
3
and CF , were reduced in high conversions (entries 5–7). The
thanol. Employing these ligands in the above described
procedure for the reduction of acetophenone, resulted in good
conversion albeit moderate enantioselectivity of the formed
alcohol (entries 5 and 6, Table 1). From these results it is evident
that the chiral information supplied by the amino alcohol assists
in increasing the enantiomeric excess of the product, although
the important stereochemical information comes from the
amino acid.† This implies that the structure of the active
ruthenium catalyst probably involves coordination of the amino
acid part of the ligand. The structural investigation is, however,
still under consideration. The N-Boc protection of the ligand
electrophilic nature of these substrates favor a rapid hydride
transfer, a process typically connected with low stereoselectiv-
ity. This was, however, not the case since the secondary
alcohols were obtained in excellent enantioselectivities.
In conclusion, we have demonstrated that simple dipeptide
analogues can be employed as ligands for the ruthenium-
catalyzed asymmetric transfer-hydrogenation of ketones. Al-
though the ligands contain more than one center of chirality, the
absolute configuration of the amino acid dictates the ster-
eochemical outcome of the reduction. The simplicity and high
modularity of the ligand structure, in combination with
inexpensive ligand starting material, makes this class of ligands
particularily attractive for asymmetric catalytic reactions.
This work was supported by the Swedish Natural Science
Research Foundation, The Carl Trygger Foundation and The
Wenner-gren Foundation.
Table 2 Enantioselective transfer hydrogenation of aromatic ketonesa
b
c
Entry
Substrate
Conv. (%)
E.e. (%)
Notes and references
1
2
72
65
92
95
†
This is in direct contrast to the transfer-hydrogen reduction protocols
employing chiral 1,2-amino alcohols as ligands. In these systems the
asymmetric induction originates from the chirality imposed by the amino
alcohol.
‡
It should be noted that active catalyst is formed simply by mixing the
ligand and the ruthenium-source at ambient temperature in the presence of
NaOH, thus no heating is required.
3
4
99
75
96
95
§ General experimental procedure for the reduction of ketones: ligand 2c
(
0.03 mmol), [RuCl
dissolved in 2-propanol (5 mL) in a dry Schlenck tube, under inert
atmosphere (N ). The solution was stirred for 15 min and the substrate (1
mmol) added. The reaction mixture was stirred at ambient temperature for
h and thereafter quenched by the addition of NH Cl (10 mL, sat. aq.
solution). An aliquot of the crude product was passed through a pad of silica
2 2
(p-cymene)] (0.005 mmol) and NaOH (5 mol%) were
2
2
4
and washed with Et
Chirasil DEX CB).
2
O. The resulting solution was analyzed by GLC (CP
5
6
97
83
95
94
1
R. Noyori and S. Hashiguchi, Acc. Chem. Res., 1997, 30, 97; M. J. Palmer
and M. Wills, Tetrahedron: Asymmetry, 1999, 10, 2045.
2 Amino acids: D. Carmona, F. J. Lahoz, R. Atencio, L. A. Oro, M. Pilar
Lamata, F. Viguri, E. San Jose, C. Vega, J. Reyes, F. Joó and Á. Kathó,
Chem. Eur. J., 1999, 5, 1544; A. Kathó, D. Carmona, F. Viguri, C. D.
Remacha, J. Kovács, F. Joó and L. A. Oro, J. Organomet. Chem., 2000,
5
93–594, 299; T. Ohta, S. Nakahara, Y. Shigemura, K. Hattori and I.
7
98
94
Furukawa, Appl. Organometal. Chem., 2001, 15, 699. Amino acid
amides: H. Y. Rhyoo, Y. A. Yoon, H. J. Park and Y. K. Chung,
Tetrahedron Lett., 2001, 42, 5045; H. Y. Rhyoo, H. J. Park and Y. K.
Chung, Chem. Commun., 2001, 2064; J. W. Faller and A. R. Lavoie,
Organometallics, 2001, 20, 5245.
I. M. Pastor and H. Adolfsson, Tetrahedron Lett., 2002, 43, 1743.
J. Takehara, S. Hashiguchi, A. Fujii, S. Inoue, T. Ikariya and R. Noyori,
Chem. Commun., 1996, 233.
a
Reaction conditions: substrate+ligand 2c+[Ru]+NaOH = 100+3+1+5 in
-propanol ([substrate] = 0.2 M) at ambient temperature. Reaction time: 2
h. Conversion was determined by GLC analysis. Enantiomeric excess
and absolute configuration were determined by GLC (CP Chirasil DEX
CB).
2
b
c
3
4
CHEM. COMMUN., 2002, 2046–2047
2047