Employing the structural diversity of nature: Development of modular dipeptide-analogue ligands for ruthenium-catalyzed enantioselective transfer hydrogenation of ketones

Article abstract of DOI:10.1002/chem.200304900

A library of novel dipeptideanalogue ligands based on the combination of tert-butoxycarbonyl(N-Boc)-protected a-amino acids and chiral vicinal amino alcohols were prepared. These highly modular ligands were combined with [{RuCl₂(p-cymene)}₂ and the resulting metal complexes were screened as catalysts for the enantioselective reduction of acetophenone under transfer hydrogenation conditions using 2-propanol as the hydrogen donor. Excellent enantioselectivity of 1-phenylethanol (up to 98% ee) was achieved with several of the novel catalysts. Although most of the ligands contained two stereocenters, it was demonstrated that the absolute configuration of the product alcohol was determined by the configuration of the amino acid part of the ligand. Employing ligands based on L-amino acids generated S-configured products, and catalysts based on Damino acids favored the formation of the R-configured alcohol. The combination N-Boc-L-alanine and (R)-phenylglycinol (Boc-L-Ab) or its enantiomer (N-Boc-D-alanine and (S)-phenylglycinol, Boc-D-Aa) proved to be the best ligands for the reduction process. Transfer hydrogenation of a number of aryl alkyl ketones were evaluated and excellent enantioselectivity, up to 96 % ee, was obtained.

Full text of DOI:10.1002/chem.200304900

FULL PAPER
Employing the Structural Diversity of Nature: Development of Modular
Dipeptide-Analogue Ligands for Ruthenium-Catalyzed Enantioselective
Transfer Hydrogenation of Ketones
Isidro M. Pastor, Patrik V‰stil‰, and Hans Adolfsson*[a]
Abstract: A library of novel dipeptide-
analogue ligands based on the combina-
tion of tert-butoxycarbonyl(N-Boc)-pro-
tected a-amino acids and chiral vicinal
amino alcohols were prepared. These
highly modular ligands were combined
with [{RuCl2(p-cymene)}2] and the re-
sulting metal complexes were screened
as catalysts for the enantioselective
reduction of acetophenone under trans-
fer hydrogenation conditions using
2-propanol as the hydrogen donor. Ex-
cellent enantioselectivity of 1-phenyl-
ethanol (up to 98% ee) was achieved
with several of the novel catalysts.
Although most of the ligands contained
two stereocenters, it was demonstrated
that the absolute configuration of the
product alcohol was determined by the
configuration of the amino acid part of
the ligand. Employing ligands based on
l-amino acids generated S-configured
products, and catalysts based on d-
amino acids favored the formation of
the R-configured alcohol. The combina-
tion N-Boc-l-alanine and (R)-phenyl-
glycinol (Boc-l-Ab) or its enantiomer
(N-Boc-d-alanine and (S)-phenylglyci-
nol, Boc-d-Aa) proved to be the best
ligands for the reduction process. Trans-
fer hydrogenation of a number of aryl
alkyl ketones were evaluated and ex-
cellent enantioselectivity, up to 96% ee,
was obtained.
Keywords: amino acids
alcohols asymmetric catalysis
hydrogen transfer ¥ ruthenium
¥
amino
¥
¥
Introduction
Transition-metal catalyzed transfer hydrogenation has
emerged as an efficient and practical method for the
enantioselective reduction of prochiral ketones to secondary
alcohols. In recent years, a considerable number of chiral
metal complexes have been prepared and examined as
catalysts in the reduction reaction.[1] The most successful
catalysts so far are based on [{RuCl2(arene)}2] combined with
chiral, enantiomerically pure 1,2-amino alcohols or mono-N-
sulfonated 1,2-diamines (e.g. TsDPEN).[2] The most common
hydrogen source for catalytic transfer hydrogenation of
ketones is 2-propanol, although the use of formic acid, in
particular a 5:2 formic acid/triethyl amine azeotropic mixture,
is usually the preferred terminal reductant because of the
favorable irreversible process. The latter reductant is, how-
ever, limited to only a few ruthenium catalysts. For example,
the highly efficient and selective catalyst 1, introduced by
Noyori and co-workers, reduces ketones with high enantio-
face selectivity and in high conversions using the formic acid/
triethylamine system,[3] whereas the corresponding catalyst
formed from [RuII(arene)] complexes and 1,2-amino alcohols
only give the product in the presence of a secondary alcohol,
typically 2-propanol.[4, 5] The catalytic activity (TOF), how-
ever, is generally higher when amino alcohols are employed as
ligands.[2a, 6]
We have recently introduced a novel class of ligands for
asymmetric transfer hydrogenation.[7] The dipeptide ana-
logues 2, obtained from tert-butoxycarbonyl(N-Boc)-protect-
ed a-amino acids and 1,2-amino alcohols, were combined with
[RuII(arene)] complexes to generate highly active and selec-
tive catalysts for the reduction of aryl alkyl ketones. The use of
amino acids,[8, 9] amino amides,[10, 11] and even dipeptides[8] as
ligands for the reduction process has previously been reported
but the resulting catalysts nearly all produced the secondary
alcohols with low to moderate enantioselectivity. Furokawa
and co-workers employed a number of a-amino acids as
ligands together with [{RuCl2(p-cymene)}2] as catalysts for the
reduction of acetophenone in 2-propanol and the secondary
alcohols were formed with enantioselectivity ranging from 3
81%.[8a] The use of dipeptide ligands resulted in ee values
[a] Dr. H. Adolfsson, Dr. I. M. Pastor, M. Sc. P. V‰stil‰
Department of Organic Chemistry
The Arrhenius Laboratory
Stockholm University, 106 91 Stockholm (Sweden)
Fax : ‡(46) 8-154908
E-mail: hansa@organ.su.se
Chem. Eur. J. 2003, 9, 4031 4045
DOI: 10.1002/chem.200304900
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H. Adolfsson et al.
FULL PAPER
ranging from 0 43%.[8b] Carmona and co-workers reported
on the preparation of self-assembled trimeric metal arene
complexes (Rh, Ir, and Ru) containing amino acids as
bridging ligands. These complexes were employed as catalysts
in the transfer hydrogenation of acetophenone using either
2-propanol or sodium formate as the hydrogen source. The
catalysts were reasonably active at high temperature (838C)
and the enantioselectivities ranged from 2 73%.[9] Simple
amides derived from a-amino acids have been shown to be
somewhat better ligands than the parent acids. Hence, l-
prolineamide combined with [{RuCl2(p-cymene)}2] or
[{Cp*RhCl2}2] catalyzed the reduction of aryl alkyl ketones
using 2-propanol with selectivities ranging from 35
93% ee.[10] The N-aryl prolineamides introduced by Chung
and co-workers turned out to be even more efficient ligands,
thus when combined with [RuII(arene)] complexes, high
conversions and selectivities (up to 98% ee) were obtained
in the transfer hydrogenation of a number of substituted aryl
alkyl ketones.[11] The source of hydrogen used in the latter
reductions was either the 5:2 formic acid/triethyl amine
azeotropic mixture or simply sodium formate in aqueous
solution.
ability of naturally occurring, inexpensive building blocks like
amino acids makes these compounds excellent as starting
materials. The great variety of functionality displayed by the
amino acids further increases the power of employing them in
the search for highly active and selective catalysts. The
promising initial results obtained with the dipeptide analogue
2 as a ligand for ruthenium in the transfer hydrogenation of
acetophenone invited an extended study in search of catalysts
of higher activity and selectivity. Thus, from the initial
combination of l-valine and l-valinol, we set out to prepare
a library of analogous ligands and to study the influence of
different ligand substituents in the reduction reaction.
Preparation of the ligand library: The dipeptide-like structure
of the ligand is particularly attractive since it is easily modified
by the choice of starting materials. In addition, the short and
simple route to these compounds allows them to be prepared
on a multigram scale. A library of 45 dipeptide ligands, using a
combination of nine amino acids (i.e. l-phenyl-Gly, d-phenyl-
Gly, l-Phe, l-Leu, l-Ala, d-Ala, l-Val, d-Val, and l-tLeu)
and five amino alcohols (i.e. l-phenylglycinol, d-phenylglyci-
nol, l-phenylalaninol, l-valinol, and 2-aminoethanol) was
readily obtained as outlined in Table 1. The ligands were
prepared in a straightforward two-step synthesis: N-protec-
tion of the amino acid with Boc2O, using a standard
procedure,[13] was followed by coupling with the correspond-
ing 1,2-amino alcohol. For the latter step we found that the use
of isobutyl chloroformate as coupling reagent worked partic-
ularly well.[13] The ligands were isolated in good yields
(Table 1) after recrystallization (the ligands containing 2-ami-
noethanol were, however, isolated as oils).
The results obtained by the Chung group inspired us to
investigate a class of carboxamido-oxazoline ligands (3) in the
ruthenium-catalyzed transfer hydrogenation of ketones. We
recently prepared these tetra-
dentate bisamides and employed
them in the titanium-catalyzed
enantioselective addition of di-
ethylzinc to aryl aldehydes.[12]
When used in the reduction of
acetophenone under transfer hy-
drogenation conditions with ei-
Moreover, to elucidate the importance and influence of the
different possible coordinating atoms and stereocenters of the
ligand in the activity and selectivity of the RuII catalyst during
the hydrogen transfer reaction, other ligands of potential
interest were prepared. Thus, the following carbamates
(benzyl carbamate (Z), allyl carbamate (Alloc), and 9-fluo-
renylmethyl carbamate (Fmoc)) and amides (acetamide,
trifluoroacetamide, and tosylamide) were used as protecting
groups for the N-terminal in the amino acid part. For this
study, the combination of l-valine (l-V) and (R)-phenyl-
glycinol (b) was chosen. Cleavage of the Boc group in ligand
Boc-l-Vb was also performed to obtain the compound with a
free amine functionality (l-Vb). The synthesis of the ligands
containing different carbamates was carried out in the same
way as previously outlined, initial N-protection followed by
formation of the peptide bond with R-phenylglycinol (b). The
Alloc and Fmoc protection was performed by reacting l-
valine (l-V) with allyloxy and 9-fluorenylmethyloxy chloro-
formate, respectively, under basic conditions. The Z-N-l-
valine (Z-l-V) was prepared by using N-(benzyloxycarbony-
loxy)succinimide (Scheme 1).
ther
[Ru(PPh3)3Cl2]
or
[{RuCl2(p-cymene)}2] as rutheni-
um sources, poor reactivity and
selectivity were observed. Interestingly, we discovered that a
precursor used in the preparation of ligand 3, when combined
with the [{RuCl2(p-cymene)}2] complex, catalyzed the forma-
tion of 1-phenylethanol (in 2-propanol) with significantly
better selectivity. The actual ligand employed in this crucial
experiment was the N-Boc-protected amide 2 (R1 ˆ R2 ˆ iPr);
when we analyzed the reaction mixture we found that the
secondary alcohol was formed with modest conversion (13%
after 2 h), but in good enantioselectivity (93% ee). This result
encouraged us to further investigate the effect of employing
differently substituted dipeptide-like ligands formed by the
combination of amino acids and amino alcohols. Herein we
report in detail on the formation of these modular ligands and
on the results obtained employing this ligand library in the
ruthenium-catalyzed transfer hydrogenation of prochiral
ketones.
The reaction of l-valine with a mixture of acetic acid and
acetic anhydride or with trifluoroacetic acid/trifluoroacetic
anhydride gave the corresponding acetamide (Ac-l-V) and
trifluoroacetamide (TFA-l-V) derivatives, which yielded the
ligands Ac-l-Vb and TFA-l-Vb after the typical coupling with
(R)-phenylglycinol (Scheme 2).
Results and Discussion
The structural diversity of Nature has provided us with a vast
supply of material for the preparation of chiral, enantiomeri-
cally pure ligands for asymmetric catalysis. The ready avail-
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Modular Dipeptide-Analogue Ligands
4031 4045
Table 1. Preparation of the library of N-Boc-protected ligands.[a]
Amino acid
Amino alcohol
l-PhG
d-PhG
l-F
l-L
l-A
d-A
l-V
d-V
Boc-l-PhGa (68)
Boc-d-PhGa (73)
Boc-l-Fa (82)
Boc-l-La (74)
Boc-l-Aa (83)
Boc-d-Aa (95)
Boc-l-Va (82)
Boc-d-Va (79)
Boc-l-tLa (65)
Boc-l-PhGb (77)
Boc-d-PhGb (81)
Boc-l-Fb (80)
Boc-l-Lb (84)
Boc-l-Ab (85)
Boc-d-Ab (85)
Boc-l-Vb (91)
Boc-d-Vb (85)
Boc-l-tLb (62)
Boc-l-PhGc (76)
Boc-d-PhGc (76)
Boc-l-Fc(90)
Boc-l-Lc (89)
Boc-l-Ac (81)
Boc-d-Ac (89)
Boc-l-Vc (73)
Boc-d-Vc (79)
Boc-l-tLc (63)
Boc-l-PhGd (68)
Boc-d-PhGd (82)
Boc-l-Fd (76)
Boc-l-Ld (92)
Boc-l-Ad (74)
Boc-d-Ad (68)
Boc-l-Vd (89)
Boc-d-Vd (81)
Boc-l-tLd (47)
Boc-l-PhGe (57)
Boc-d-PhGe (61)
Boc-l-Fe (59)
Boc-l-Le (80)
Boc-l-Ae (53)
Boc-d-Ae (52)
Boc-l-Ve (63)
Boc-d-Ve (58)
Boc-l-tLe (41)
l-tL
[a] The values given in parentheses refer to yields of the dipeptide analogues based on the amino acid after the two steps.
l-Vb) as outlined in Scheme 3. Although N-tosylation of
amino acids using tosyl chloride usually results in high yields
of the N-sulfonated amino acid, the use of this route for the
preparation of Ts-l-Vb did not give good results in our hands.
Asymmetric transfer hydrogenation, screening of the ligand
library: The library containing 45 ligands was evaluated in the
reduction of acetophenone using 2-propanol as hydrogen
source (0.2m of the ketone in 2-propanol). The reactions were
carried out with a substrate/ruthenium/ligand/base ratio of
100:1:3:5. The active catalyst was prepared in situ by mixing
the ligand (3 mol%), [{RuCl2(p-cymene)}2] (0.5 mol%), and
the base (NaOH, 5 mol%) in 2-propanol for 10 15 min at
room temperature. The reaction mixture usually turned a
purple or reddish color in the beginning, which sometimes
changed after few minutes to light brown. The ketone was
added to the reaction mixture and the transfer hydrogenation
was performed at room temperature for 2 h. The reactions
were quenched using ammonium chloride (aqueous solution)
and the conversion and stereochemical outcome were then
analyzed by GLC. The results are summarized in Figure 1,
which shows conversions (a) and enantioselectivity/product
configuration (b).
Scheme 1. Preparation of ligands Alloc-l-Vb, Fmoc-l-Vb, and Z-l-Vb.
From the plots in Figure 1 it is evident that structural
variations of the ligand play an important role for the activity
and selectivity of the ruthenium catalyst formed in situ.
Focusing on catalytic activity, the plot in Figure 1a shows that
using ligands containing two stereocenters, one in the amino
acid part and one in the amino alcohol, generally resulted in
lower conversion to the secondary alcohol (series a d) as
compared with the ligand combination between all N-Boc-
protected amino acids and 2-aminoethanol (series e). In the
latter series (e), the ligands derived from l- or d-phenyl-
glycine had the highest activity, resulting in almost quantita-
tive formation of the product after 2 h. When amino acids
containing other side chains were employed, lower conver-
sions were obtained. The general trend indicates that an
increased number of substituents at the b-carbon atom, which
increase the steric hindrance, have a detrimental effect on the
Scheme 2. Preparation of ligands Ac-l-Vb and TFA-l-Vb.
For the generation of the unprotected ligand (l-Vb),
compound Boc-l-Vb was treated with a 1:1 mixture of
methanol and HCl (3m aq.) at low temperature, according
to the synthetic route developed for the preparation of the C2-
symmetric oxazoline ligands.[12] This compound (l-Vb) was
also used for the preparation of the tosylamide derivative (Ts-
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H. Adolfsson et al.
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catalytic activity. This is partic-
ularly striking when comparing
ligands derived from t-leucine or
valine with those based on the
less sterically demanding alanine
or leucine; the catalytic transfer
hydrogenation employing the
latter ligands resulted in about
20% better conversion. Regard-
ing the ligands in series a d,
there are only a few combina-
tions for which comparable ac-
tivity was obtained. Moderate to
good conversion was achieved
employing phenylglycinol com-
bined with leucine, alanine, or
valine. A remarkable difference
in activity is observed compar-
ing ligands Boc-PhGa or Boc-
PhGb (phenylglycine and phe-
nylglycinol) and the highly-
productive Boc-PhGe (phenyl-
glycine and 2-aminoethanol).
Furthermore, comparing the re-
sults obtained based on the
amino alcohols employed (ser-
ies a d), the general trend of
activity goes from l-A and l-L
(high) to l-V (moderate) and
l-tL (poor). These results con-
firm the observation that steric
hindrance is of high importance
for catalytic activity (with
2-aminoethanol the tendency
is not so obvious). Another
interesting observation that
can be made from Figure 1a is
the distinct difference in activ-
ity between diastereomeric li-
gands. When ligand Boc-l-Ab
and its mirror image, ligand
Boc-d-Aa, were employed in
the transfer hydrogenation re-
action, excellent conversions
were obtained, however the
use of the diasteromeric ligands
Boc-d-Ab and Boc-l-Aa only
resulted in moderate formation
of the product alcohol. The
same trend can be seen when
comparing ligands derived from
valine and phenylglycinol. This
matched/mismatched scenario
is most often observed when
comparing the stereoselective
outcome of a catalytic reaction
involving diastereomeric li-
gands. Here, however, this ef-
fect is most pronounced in the
Scheme 3. Preparation of the ligands l-Vb and Ts-l-Vb.
Figure 1. a) Conversion of acetophenone after 2 h using the ligand library presented in Table 1. b) Enantio-
selectivity and product configuration of 1-phenylethanol using the different ligands.
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Modular Dipeptide-Analogue Ligands
4031 4045
catalytic activity, as will be discussed below. To summarize the
results concerning catalytic activity, the structure of the
catalyst is highly sensitive towards steric hindrance imposed
by the coordinating ligand. Furthermore, the proper combi-
nation of the two stereocenters present in most of the ligands
is of high importance for the outcome of the reaction.
located in the amino alcohol (R-phenylglycinol), the R-
configured product was obtained. In contrast, when the same
amino alcohol is combined with an l-amino acid, for example
l-alanine, a dramatic switch in selectivity was observed.
Performing the catalytic reaction with ligand Boc-l-Ab gave a
94% ee of the S isomer. At first sight, it appears that the
stereocenter present in the amino alcohol part of the ligand is
completely overruled by the chirality present in the amino
acid. On closer examination, however, it becomes evident that
the amino alcohol actually amplifies the selectivity obtained
with this particular ligand (cf. in reactions using ligand Boc-l-
Ae, 90% ee of the (S)-1-phenylethanol was obtained). Using
Boc-Ga gave, as expected, complementary results to Boc-Gb
(60% conversion and 63% ee of the S enantiomer after 2 h).
On the basis of these results, it is evident that the choice of
amino acid is important for the activity and enantioselectivity
of the active catalyst. Nevertheless, improvements both in
activity and selectivity of the catalytic process can be
accomplished by combining the amino acid with a proper
amino alcohol.
The stereoselectivity obtained by using the library of
ligands is depicted in Figure 1b. With a few exceptions, high
enantioface selectivity (>85% ee) was attained with most
combinations of amino acids and amino alcohols. It is
noteworthy that, regardless of the chiral information provided
by the 1,2-amino alcohol, the absolute configuration of the
product was, in all entries, determined by the stereocenter
present in the amino acid part of the ligand. Hence, ligands
based on natural amino acids generated products of S
configuration and when an unnatural amino acid was present
in the ligand, the R-configured product was obtained. The
highly active (in terms of conversion) catalysts generated
from the ligand combination of N-Boc-phenylglycine and
2-aminoethanol (Boc-l-PhGe and Boc-d-PhGe) and
[{RuCl2(p-cymene)}2], produced the secondary alcohol with
only moderate enantioelectivity (50%). Excellent product ee
values were reached by using the leucine based ligands Boc-l-
La, Boc-l-Lc, and Boc-l-Ld (97 98%). The low chemical
yields obtained with these catalysts, however, make them less
interesting. On the other hand, employing ligands based on
alanine and phenylglycinol (Boc-Aa and Boc-Ab) resulted in
catalysts that reduced acetophenone in high yield and with
good enantioselectivity. The matched/mismatched relation-
ship observed for the catalytic activity was only slightly visible
in the stereodifferentiation. In fact, the least productive
enantiomeric ligand pair turned out to be somewhat more
selective, although the difference is certainly insignificant.
With the above results in hand, we concluded that the best
ligands in the above library for the ruthenium-catalyzed
reduction of acetophenone under transfer hydrogenation
conditions are the enantiomers Boc-d-Aa and Boc-l-Ab.
In addition to the above catalytic experiments, we thought
it would be interesting to prepare and examine ligands lacking
a chiral center in the amino acid moiety (i.e. starting from
glycine, G). For these experiments we chose phenylglycinol as
the amino alcohol, since the results in Figure 1 show that
ligands containing this particular group were superior, espe-
cially with respect to the selectivity. Following the synthetic
procedure described above for N-Boc protection and then
coupling with the amino alcohol, ligands Boc-Ga and Boc-Gb
were isolated in 65 and 63% yield, respectively.
Asymmetric transfer hydrogenation, ligand structure versus
catalytic activity: As observed above, when screening the
ligand library, the side-chain structure of the pseudopeptides
plays an important role in determining the activity and
selectivity displayed by the ruthenium catalyst. In connection
to the results obtained by using Boc-protected peptide
analogues as ligands, we set out to investigate how changes
in the functional groups would affect the catalytic activity
(Table 2). Initially we focused on using ligands in which the
Boc group had been replaced by other carbamates. Catalytic
transfer hydrogenation of acetophenone using ligands pro-
tected either with allyl carbamate (Alloc) or with benzyl
carbamate (Z) proceeded smoothly and generated the
secondary alcohol in good conversion and enantioselectivity
(Table 2, entries 2 and 4). Employing the Fmoc-protected
ligand resulted in practically no product formation (Table 2,
entry 3).
Table 2. Ruthenium-catalyzed transfer hydrogenation of acetophenone.[a]
Effects of ligand functional group variation.
Entry
Ligand
Conversion [%][b]
Enantioselectivity [%][c]
1
2
3
4
5
6
7
8
9
Boc-l-Vb
Alloc-l-Vb
Fmoc-l-Vb
Z-l-Vb
Ac-l-Vb
TFA-l-Vb
L-Vb
78
81
< 1
80
< 2
6
< 2
< 2
4
95
93
93
66
Ts-l-Vb
4
7
10
11
5
6
< 2
< 2
Employing ligand Boc-Gb in the reduction of acetophe-
none (using the same conditions as above) resulted in
conversion to the R alcohol with moderate yield (56%) and
enantioselectivity (64% ee) (reaction monitored after 2 h).
Interestingly, when the chiral information was uniquely
[a] Reaction conditions: Acetophenone (1 equiv, 0.2m in 2-propanol),
[{RuCl2(p-cymene)}2] (1 mol% in Ru), ligand (3 mol%), and NaOH
(5 mol%). All reactions were performed at ambient temperature for 2 h.
[b] Conversion was determined by GLC analysis. [c] Enantiomeric excess
was determined by GLC (CP Chirasil DEX CB).
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H. Adolfsson et al.
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Changing the protecting group on the N-terminal to a
carboxamide functionality resulted in ligands that performed
poorly in the catalytic reaction (Table 2, entries 5 and 6).
Furthermore, running the reduction with ligands containing
an unprotected (Table 2, entry 7) or a sulfonate-protected
(Table 2, entry 8) N-terminal gave virtually no product. A
possible explanation for the poor reactivity observed using
Fmoc-l-Vb could be found in the result obtained with the
unprotected ligand l-Vb. Owing to the base-lability of the
Fmoc-protecting group it is highly plausible that ligand l-Vb
was rapidly formed during the reduction reaction. Thus, we
can conclude that a stable carbamate, positioned at the
N-terminal, is a necessary prerequisite for a productive ligand.
For the C-terminal, the hydroxyl functionality turned out to
be of equal importance. Low conversion and ee of the product
alcohol was obtained when the O-methylated ligand 4 was
employed in the catalytic reaction (Table 2, entry 9). Addi-
tionally, the use of ligands 5 and 6 did not yield the desired
product (Table 2, entries 10 and 11). The latter results
demonstrate the importance of employing ligands with proper
functional groups at both termini.
ketones gave comparable results to those obtained using
RuII-based catalysts.[14] The RhIII catalysts were prepared from
[{Cp*RhCl2}2] and monotosylated diamine ligands, and the
reductions were, as in the case of the corresponding RuII-
catalyzed reactions, performed by using either 2-propanol or
formic acid as the hydrogen source. To examine whether this
would also be applicable in our system, we prepared the
analogous RhIII catalyst by mixing Boc-l-Vb with
[{Cp*RhCl2}2] and base (NaOH) in 2-propanol. Using this
catalyst for the reduction of acetophenone (in 2-propanol) at
room temperature resulted in 50% conversion and a moder-
ate 80% ee of the (S)-1-phenylethanol after 2 h. The use of
the diastereomeric ligand (Boc-l-Va), which was less active
with the RuII precursor, resulted in only 8% conversion and
28% ee of the S product. Similar results were obtained when
the pair of ligands derived from d-valine were employed in
the catalytic reaction together with the rhodium precursor,
although in these cases an excess of the R enantiomer of the
alcohol was formed.
Nature of the catalyst: To further our understanding of the
structure of the active catalyst, or rather the pre-catalyst,
attempts were made to obtain a crystalline sample of the
ruthenium complex. This process was, however, unsuccessful,
and we decided to examine the catalytic mixture by means of
spectroscopic methods. Thus, using 1H NMRspectroscopy (in
CD3OD) we observed that simply mixing ligand Boc-l-Vb
and [{RuCl2(p-cymene)}2] in a 2:1 ratio (L/Ru 1:1) resulted in
a spectrum in which the signal from the proton on the
carbamate nitrogen was absent. Upon addition of one
equivalent of NaOH, the proton signal of the amide disap-
peared. These observations indicate that an initial complex-
ation reaction occurs, forming a postulated ruthenium com-
plex 7 (Scheme 4),[15] in which the deprotonated carbamate
and the amide functionality coordinate to the metal. The
removal of the amide proton upon addition of base then
allows for the formation of complex 8a.[16] In the latter
complex we believe that the alcohol functionality plays an
important role in generating an 18-electron complex, hence
stabilizing the ruthenium catalyst. This is in direct contrast to
the Noyori catalyst ([{Ru(p-cymene)Cl2}2] and (S,S)- or (R,R)-
TsDPEN)), which generates a 16-electron complex upon
addition of base.[3]
Asymmetric transfer hydrogenation, influence of the metal
precursor: Variation of the arene moiety in the RuII precursor
has been demonstrated to influence the outcome of the
transfer hydrogenation reaction.[6] Performing the reduction
of acetophenone with [{RuCl2(benzene)}2] and either of the
ligands, Boc-l-Vb or Boc-d-Va, resulted in conversions
comparable to those obtained using the p-cymene complex
(ca. 75% conversion after 2 h). The enantioselectivity, how-
ever, dropped significantly to 81% ee of (S)-1-phenylethanol
using Boc-l-Vb and 80% ee of the R enantiomer using Boc-d-
Va.
Regarding the mechanism of this transfer hydrogenation, it
is likely that the reaction proceeds by the concerted route
recently proposed by Noyori and co-workers.[17] According to
this mechanism, there is a simultaneous transfer of a hydride
It has previously been reported that the use of RhIII
complexes as catalysts in the transfer hydrogenation of
Scheme 4. Proposed route for the formation of the pre-catalyst.
4036
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Modular Dipeptide-Analogue Ligands
4031 4045
and a proton between the hydrogen donor/substrate and the
ruthenium complex. The formation of a catalytically active
ruthenium hydride from 8a must be preceded by the release
of one of the coordinating groups of the ligand. Hence, the
existence of an equilibrium, as depicted in Scheme 5,[15] is a
necessary prerequisite for the catalytic system.
complexes have been conducted it would only be speculative
to propose a more detailed mechanism.
Asymmetric transfer-hydrogenation, scope of the reaction:
With the results from the ligand optimization study described
above, we continued with an examination of the substrate
scope. The enantiomeric pair of ligands Boc-l-Ab and Boc-d-
Aa was chosen for this study, since using these compounds
gave the best results in terms of activity and selectivity during
the reduction of acetophenone. Even though the screening of
the library was performed using a 3:1 ligand/Ru ratio, we
established that a 1.1:1 ligand/metal ratio gave the same
results in terms of catalytic activity and, most importantly, that
the enantioselectivity was unaffected. Thus, unless otherwise
stated, using a ratio of substrate/ligand/[RuII]/NaOH in
200:1.1:1:5 in 2-propanol (concentration of the ketone
0.2m), a number of different aryl alkyl ketones were reduced
at room temperature (Table 3).
As seen in Table 3, enantiomeric excess and the reaction
rate in the transfer hydrogenation of various alkyl aryl
ketones were found to depend on both steric and electronic
factors. The reduction of acetophenone gave the secondary
alcohol in high yield and ee using only 0.5 mol% of the
ruthenium catalyst. Introducing substituents in the ortho
position of the substrate, (Table 3, entries 3 5) significantly
slowed down the rate of the reaction, probably because of
increased steric hindrance, and we had to double the amount
of catalyst to reach acceptable yields. In the case of
2-methylacetophenone, excellent enantioselectivity was ob-
tained (entries 3 and 4), whereas the more electron-rich
2-methoxy-acetophenone was reduced in moderate ee (Ta-
ble 3, entry 5). A plausible explanation for the poor reactivity
and selectivity obtained with the latter substrate can be found
in deactivation of the catalyst by substrate coordination, in
which the chiral ligand gets displaced by the substrate.[18]
Performing the transfer hydrogenation reaction with aryl
methyl ketones substituted in either the meta- or para-
position resulted in considerably better yields and selectivity.
Hence, 3-substituted acetophenones were readily reduced in
high yield and enantioselectivity regardless of the nature of
the substituent (Table 3, entries 6 9). The possibility for
substrate chelation using 3-methoxyacetophenone is com-
pletely lost, and this particular ketone was reduced in good
yield and in excellent enantioselectivity (Table 3, entry 7).
The para-substituted substrates were smoothly reduced to
their corresponding secondary alcohols (Table 3, entries 10
13). The lower reactivity observed for 4-methoxyacetophe-
none as compared with its 3-substituted analogue is most
likely due to electronic effects (Table 3, entries 11 and 12).
Interestingly, somewhat poorer selectivity was obtained using
Either of the two 16-electron complexes, 9 or 10, can in
principle react to form the active ruthenium hydride, but at
this stage it is difficult to predict which one is operating in the
system. An intricate balance in ligand acidity seems, however,
to be operating. As described above, ligands containing
protecting groups other than carbamates at the N-terminal,
gave ruthenium complexes with little or no catalytic activity.
Thus, an overly acidic proton at the N-terminal (e.g. using
ligand Ts-l-Vb) would favor a complex with a structure
similar to 9. This 16-electron complex could generate a
ruthenium hydride species upon reaction with 2-propanol,
although the low activity observed with ligand Ts-l-Vb
indicates this process to be unfavorable. Removal of the
N-protecting group (i.e. using ligand l-Vb) would also favor
a complex similar to 9 because of the enhanced coordinat-
ing ability of the primary amine. This ligand also turned out
to generate a catalyst with low activity. Furthermore, removal
of the hydroxyl functionality strongly affected the activity
of the catalyst. Using ligand 4 would again favor the forma-
tion of a ruthenium complex with a structure closely related to
9, but the low activity observed with this catalyst de-
monstrates the importance of the alcohol functionality. The
above observations would indicate that the ruthenium hy-
dride is formed from complex 10, although this is not
consistent with the absolute configuration of the product
alcohol.
Regardless of the configuration of the stereocenter present
in the amino alcohol part of the ligand, we achieved the S-
configured secondary alcohol as the major isomer when the
ligands were based on l-amino acids. Performing the reaction
with ligands based on d-amino acids gave the corresponding
R-configured alcohol. This strongly indicates coordination of
the amide and the carbamate in the active catalyst. The
additional stereocenters created upon the formation of
complexes 9 and 10 (i.e. amide and carbamate nitrogens and
the ruthenium center), could certainly influence the observed
selectivity. However, the strong correlation between the
absolute configuration of the amino acid and the product
formed indicates that the configuration of these centers is
strictly controlled by the ligand. Furthermore, if either of
complexes 9 or 10 is the active 16-electron species in the
catalytic reaction, it is clear that the hydride is transferred to
ruthenium, but the site of protonation is less obvious. Until
further studies concerning the structure of these ruthenium
Scheme 5. Postulated pre-catalyst equilibrium.
Chem. Eur. J. 2003, 9, 4031 4045
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4037

H. Adolfsson et al.
FULL PAPER
Table 3. Enantioselective transfer hydrogenation of aromatic ketones[a]
Entry
Ketone
Ligand
t [h]
Yield [%][b]
ee [%][c]
1
2
Boc-l-Ab
Boc-d-Aa
5
5
95
91
93 (S)
93 (R)
3[d]
4[d]
Boc-l-Ab
Boc-d-Aa
10
10
74
74
96 (S)
96 (R)
5[d]
Boc-l-Ab
10
57
84 (S)
6
7
Boc-l-Ab
Boc-l-Ab
5
5
89
85
92 (S)
91 (S)
8
9
Boc-l-Ab
Boc-d-Aa
5
5
93
93
89 (S)
88 (R)
10
Boc-l-Ab
5
85
91 (S)
11
12
Boc-l-Ab
Boc-d-Aa
10
10
63
65
95 (S)
96 (R)
13
Boc-l-Ab
2.5
90
88 (S)
14
Boc-l-Ab
Boc-l-Ab
Boc-l-Ab
5
10
14
91
53
38
95 (S)
86 (S)
84 (S)
15[e]
16
17
18
Boc-l-Ab
Boc-l-Vb
5
5
85
80
87 (S)
95 (S)
[a] Reaction conditions: Ketone (1 equiv, 0.2 m in 2-propanol), [{RuCl2(p-cymene)}2] (0.5 mol% in Ru), ligand (0.55 mol%), and NaOH (2.5 mol%). All
reactions were performed at ambient temperature. [b] Yields of isolated product. [c] Enantiomeric excess and absolute configuration were determined by
GLC (CP Chirasil DEX CB). [d] Reaction conditions: [{RuCl2(p-cymene)}2] (1.0 mol% in Ru), ligand (1.1 mol%), and NaOH (5 mol%). [e] Reaction
conditions: [{RuCl2(p-cymene)}2] (2.0 mol% in Ru), ligand (2.2 mol%), and NaOH (10 mol%).
either 3-methyl or 4-methylacetophenone as compared with
the 2-substituted compound. This can possibly be explained
by additional positive steric interactions between the catalyst
and the substrate. Ketones possessing electron-withdrawing
groups in meta- and para-position (Table 3, entries 8 and 13)
reacted readily although they produced the alcohol pro-
ducts in slightly lower enantiomeric excess. We have previ-
ously reported that higher enantioselectivity was obtained in
the reduction of 4-bromoacetophenone using ligand Boc-l-
Vb (95% ee, 97% conversion after 2 h using 1 mol%
catalyst).[7] This shows that certain ligands are better suited
for specific substrates, and the power of having easy access to
a variety of ligand structures makes this approach especially
attractive.
Propiophenone reacted readily under the optimized con-
ditions, and the corresponding secondary alcohol was ob-
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¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Chem. Eur. J. 2003, 9, 4031 4045

Modular Dipeptide-Analogue Ligands
4031 4045
tained in good yield and in high enantioselectivity (Table 3,
entry 14). The sterically more demanding isobutyrophenone,
turned out to be a considerably more problematic substrate.
Even though we used 2 mol% of the catalyst, the product
alcohol was obtained in mediocre yield and in moderate
enantioselectivity (Table 3, entry 15). The reduction of 1-tet-
ralone resulted in poor yield and moderate ee of the
corresponding secondary alcohol (Table 3, entry 16). Surpris-
ingly, the reduction of 2-acetonaphthone resulted in the
formation of the alcohol product in moderate enantioselec-
tivity (Table 3, entry 17). Again, changing the ligand to Boc-l-
Vb resulted in a catalyst that performed considerably better,
and (S)-1-(2-naphthyl)ethanol could be obtained in high
enantioselectivity (Table 3, entry 18). Comparing the out-
come of the reactions using the two different catalysts, it is
evident that the interaction between ligand and substrate has
a noticeable effect on the enantioselectivity. This further
implies that certain ligands may be a better match with
specific ketones and thus result in better reactivity and
selectivity.
Experimental Section
General procedure for the preparation of library ligands, exemplified by
the preparation of tert-butyl N-[(1S)-1-({[(1R)-2-hydroxy-1-phenylethyl]-
amino}carbonyl)-2-methylpropyl]carbamate
(Boc-l-Vb):
NaOH
(66 mmol, 2.6 g), followed by Boc2O (33 mmol, 7.3 g) was added to a
stirred solution of l-valine (30 mmol, 3.56 g) in THF/H2O (50 mL of each
solvent) at room temperature and the resulting mixture was stirred for 18 h.
THF was removed under vacuum and the aqueous layer was extracted with
CH2Cl2 (40 mL). The aqueous layer was acidified with HCl (1n) to pH 4,
and then extracted with CH2Cl2 (4 Â 25 mL). The organic phase was dried
over Na2SO4 and the solvent was evaporated under vacuum. The resulting
crude N-Boc-l-valine was used without further purification in the next step.
N-methylmorpholine (NMM, 35 mmol, 3.93 mL) and isobutylchlorofor-
mate (35 mmol, 4.62 mL) were slowly added to a solution of the N-Boc-
protected valine in THF (60 mL) at À158C (a white solid was formed
during the addition of the iBuOCOCl). The reaction mixture was stirred for
45 min at À158C, and then the (R)-phenylglycinol (30 mmol, 4.25 g) was
added and the resulting mixture was stirred at room temperature for
another 3 h. The mixture was filtered through silica gel (5 cm  5 cm) and
eluted with ethyl acetate (400 mL). The solvent was concentrated under
vacuum and the resulting solid was recrystallized from CH2Cl2/n-pentane,
giving the pure product.
Boc-l-Vb: (9.2 g, 91% yield). m.p. 153 1548C; 1H NMR(300 MHz,
CDCl3): d ˆ 0.91 (m, 6H), 1.43 (s, 9H), 2.08 (m, 1H), 3.43 (brs, 1H), 3.77
(dd, J ˆ 11.4 and 6.9 Hz, 1H), 3.85 (dd, J ˆ 11.4 and 4.4 Hz, 1H), 3.99 (deft,
J ˆ 7.6 Hz, 1H), 5.10 (dt, J ˆ 7.0 and 4.2 Hz, 1H), 5.44 (brd, J ˆ 8.3 Hz, 1H),
7.30 ppm (m, 6H); 13C NMR(75 MHz, CDCl 3): d ˆ 18.2, 19.5, 28.5 (3C),
31.1, 55.9, 60.6, 66.1, 80.3, 127.0 (2C), 127.8, 128.8 (2C), 139.2, 156.6,
To demonstrate that both isomers of the product can be
obtained we performed a few reactions using ligand Boc-d-Aa
(Table 3, entries 4, 9, and 12). As can be seen in Table 3, the
same degree of enantioselectivity was obtained using this
ligand.
‡
‡
172.6 ppm; (MALDI-TOF): m/z: 374.161 [M À K] , 359.172 [M À Na] ,
‡
337.172 [M À H] ; elemental analysis calcd (%) for C18H28N2O4: C 64.26, H
8.39, N 8.33; found: C 64.33, H 8.20, N 8.20.
tert-Butyl N-((1S)-2-{[(1S)-2-hydroxy-1-phenylethyl]amino}-2-oxo-1-phe-
nylethyl)carbamate (Boc-l-PhGa): m.p. 125 1268C; 1H NMR
(300 MHz, CDCl3): d ˆ 1.40 (s, 9H), 2.53 (brs, 1H), 3.75 (d, J ˆ 5.7 Hz,
2H), 5.01 (m, 1H), 5.21 (m, 1H), 5.72 (brd, J ˆ 6.6 Hz, 1H), 6.75 (brd, J ˆ
7.5 Hz, 1H), 7.18 7.43 ppm (m, 10H); 13C NMR(75 MHz, CDCl 3): d ˆ 28.5
(3C), 56.2, 58.9, 66.1, 80.7, 126.9 (2C), 127.4 (2C), 128.1, 128.7, 129.1 (2C),
129.3 (2C), 138.1, 138.8, 155.6, 170.8 ppm; (MALDI-TOF): m/z: 409.026
Conclusions
We have demonstrated that novel N-Boc protected dipeptide
analogues function as efficient ligands for the ruthenium-
catalyzed asymmetric transfer hydrogenation of aryl alkyl
ketones. The ligands were prepared in a straightforward
manner from commercially available a-amino acids and 1,2-
amino alcohols. When combined with [{RuCl2(p-cymene)}2],
several of these ligands generated highly enantioselective
catalysts, although the most successful ligand combination
proved to be Boc-l-Ab or its enantiomer Boc-d-Aa. Interest-
ingly, of the two stereogenic centers present in the ligand
structure, it was the chirality originating from the amino acid
that determined the absolute configuration of the product
alcohol. Thus, by the proper choice of amino acid, either S- or
R-configured product alcohols could be obtained in high
enantiomeric excess. The presence of appropriate protecting
groups at the N-terminal along with a free hydroxyl group at
the C-terminal of the ligands turned out to be of utmost
importance for a successful outcome of the catalytic process.
High conversion to and enantioselectivity of the secondary
alcohol were only achieved when ligands containing carba-
mates resistant to basic reaction conditions (e.g Boc, Z, and
Alloc) were employed. We are currently investigating why
these structural features are so important for this new class of
ligands in the ruthenium-catalyzed asymmetric transfer hy-
drogenation of ketones.
‡
‡
‡
[M À K] , 393.055 [M À Na] , 371.095 [M À H] ; elemental analysis calcd
(%) for C21H26N2O4: C 68.09, H 7.07, N 7.56; found: C 68.02, H 7.07, N 7.37.
tert-Butyl N-((1S)-2-{[(1R)-2-hydroxy-1-phenylethyl]amino}-2-oxo-1-phe-
nylethyl)carbamate (Boc-l-PhGb): m.p. 160 1618C; 1H NMR(300 MHz,
CDCl3): d ˆ 1.39 (s, 9H), 2.83 (brs, 1H), 3.75 (dd, J ˆ 11.2 and 5.8 Hz, 1H),
3.86 (dd, J ˆ 11.2 and 4.1 Hz, 1H), 5.06 (m, 1H), 5.33 (brs, 1H), 5.84 (brd,
J ˆ 6.2 Hz, 1H), 6.91 (brs, 1H), 6.99 (m, 2H), 7.20 (m, 3H), 7.28 7.39 ppm
(m, 5H); 13C NMR(75 MHz, CDCl ): d ˆ 28.5 (3C), 55.8, 59.0, 66.1, 80.6,
3
126.6 (2C), 127.6 (2C), 127.8, 128.6, 128.8 (2C), 129.1 (2C), 138.1, 138.8,
‡
155.7, 170.8 ppm; (MALDI-TOF): m/z: 409.060 [M À K] , 393.088 [M À
‡
‡
Na] , 371.128 [M À H] .
tert-Butyl N-((1S)-2-{[(1S)-1-benzyl-2-hydroxyethyl]amino}-2-oxo-1-phe-
1
nylethyl)carbamate (Boc-l-PhGc): m.p. 117 1188C; H NMR(300 MHz,
CDCl3): d ˆ 1.42 (s, 9H), 2.69 (brs, 1H), 2.84 (m, 2H), 3.47 3.65 (m, 2H),
4.13 (m, 1H), 5.07 (m, 1H), 5.61 (brd, J ˆ 7.0 Hz, 1H), 6.26 (brd, J ˆ 7.6 Hz,
1H), 7.14 (m, 3H), 7.21 7.32 ppm (m, 7H); 13C NMR(75 MHz, CDCl 3):
d ˆ 28.5 (3C), 37.0, 53.5, 58.9, 63.7, 80.8, 126.9, 127.4 (2C), 128.7, 128.9 (2C),
129.3 (2C), 129.4 (2C), 137.7, 138.0, 155.6, 170.7 ppm; (MALDI-TOF): m/z:
‡
‡
‡
423.072 [M À K] , 407.099 [M À Na] , 385.135 [M À H] .
tert-Butyl N-((1S)-2-{[(1S)-1-(hydroxymethyl)-2-methylpropyl]amino}-2-
oxo-1-phenylethyl)-carbamate (Boc-l-PhGd): m.p. 127 1288C; H NMR
1
(300 MHz, CDCl3): d ˆ 0.87 (d, J ˆ 6.6 Hz, 3H), 0.92 (d, J ˆ 6.8 Hz, 3H),
1.42 (s, 9H), 1.85 (m, 1H), 2.69 (brt, J ˆ 5.8 Hz, 1H), 3.56 (m, 2H), 3.65 (m,
1H), 5.15 (brd, J ˆ 5.2 Hz, 1H), 5.76 (d, J ˆ 6.3 Hz, 1H), 6.26 (brd, J ˆ
8.9 Hz, 1H), 7.29 7.46 ppm (m, 5H); 13C NMR(75 MHz, CDCl 3): d ˆ 19.0,
19.7, 28.5 (3C), 29.0, 57.8, 59.4, 63.3, 80.6, 127.4 (2C), 128.6, 129.2 (2C),
As a final remark, we believe that the simplicity with which
these novel and highly modular ligands can be prepared, in
combination with their efficiency in generating the desired
product isomer should make this reduction process attractive
for the enantioselective formation of secondary alcohols.
‡
138.1, 155.7, 171.1 ppm; (MALDI-TOF): m/z: 375.086 [M À K] , 359.129
‡
‡
[M À Na] , 337.164 [M À H] .
tert-Butyl N-((1S)-2-[(2-hydroxyethyl)amino]-2-oxo-1-phenylethyl)carba-
mate (Boc-l-PhGe): After filtration an oil was obtained and further
purification was done by column chromatography (silica gel, pentane/ethyl
Chem. Eur. J. 2003, 9, 4031 4045
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¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4039

H. Adolfsson et al.
FULL PAPER
acetate mixtures): 1H NMR(300 MHz, CDCl 3): d ˆ 1.41 (s, 9H), 2.53 (brs,
1H), 3.24 3.50 (m, 2H), 3.60 3.90 (m, 2H), 5.20 (m, 1H), 5.80 (brs, 1H),
6.54 (brs, 1H), 7.25 7.40 ppm (m, 5H); 13C NMR(75 MHz, CDCl 3): d ˆ
28.5 (3C), 42.7, 58.8, 61.8, 80.5, 127.4 (2C), 128.6, 129.2 (2C), 138.3, 155.6,
2H), 3.37 3.49 (m, 2H), 4.08 (m, 1H), 4.26 (m, 2H), 5.05 (brs, 1H), 5.97
(brd, J ˆ 7.6 Hz, 1H), 7.10 7.34 ppm (m, 10H); 13C NMR(75 MHz,
CDCl3): d ˆ 28.5 (3C), 37.0, 38.9, 53.0, 56.4, 63.5, 80.6, 126.8, 127.3, 128.8
(2C), 129.0 (2C), 129.4 (2C), 129.5 (2C), 136.9, 137.6, 155.7, 171.5 ppm;
‡
‡
‡
‡
171.4 ppm; (MALDI-TOF): m/z: 333.135 [M À K] , 317.165 [MNa] .
(MALDI-TOF): m/z: 437.180[M À K] , 421.219[M À Na] , 399.230[M À
‡
H] .
tert-Butyl N-((1R)-2-{[(1S)-2-hydroxy-1-phenylethyl]amino}-2-oxo-1-phe-
nylethyl)carbamate (Boc-d-PhGa): m.p. 160 1618C; 1H NMR(300 MHz,
CDCl3): d ˆ 1.39 (s, 9H), 2.85 (brs, 1H), 3.71 3.78 (m, 1H), 3.81 3.88 (m,
1H), 5.06 (m, 1H), 5.33 (brs, 1H), 5.85 (brd, J ˆ 6.1 Hz, 1H), 6.98 (m, 2H),
7.20 (m, 3H), 7.27 7.39 ppm (m, 5H); 13C NMR(75 MHz, CDCl 3): d ˆ 28.5
(3C), 55.8, 58.9, 66.1, 80.6, 126.6 (2C), 127.5 (2C), 127.8, 128.6, 128.8 (2C),
129.2 (2C), 138.1, 138.8, 155.7, 170.8 ppm; (MALDI-TOF): m/z: 409.093
tert-Butyl N-((1S)-1-benzyl-2-{[(1S)-1-(hydroxymethyl)-2-methylpropyl]-
amino}-2-oxoethyl)-carbamate (Boc-l-Fd): m.p. 131 1328C; 1H NMR
(300 MHz, CDCl3): d ˆ 0.82 (d, J ˆ 6.8 Hz, 3H), 0.88 (d, J ˆ 6.8 Hz, 3H),
1.43 (s, 9H), 1.77 (m, 1H), 2.21 (brs, 1H), 3.02 (dd, J ˆ 13.6 and 8.0 Hz,
1H), 3.12 (dd, J ˆ 13.6 and 6.5 Hz, 1H), 3.48 (d, J ˆ 4.4 Hz, 2H), 3.62 (m,
1H), 4.30 (m, 1H), 5.15 (brd, J ˆ 7.4 Hz, 1H), 5.89 (brd, J ˆ 8.6 Hz, 1H),
7.22 7.36 ppm (m, 5H); 13C NMR(75 MHz, CDCl 3): d ˆ 18.8, 19.6, 28.5
(3C), 29.0, 38.6, 56.7, 57.5, 63.6, 80.6, 127.3, 129.0 (2C), 129.5 (2C), 137.1,
‡
‡
‡
[M À K] , 393.122 [M À Na] , 371.159 [M À H] .
tert-Butyl N-((1R)-2-{[(1R)-2-hydroxy-1-phenylethyl]amino}-2-oxo-1-phe-
nylethyl)carbamate (Boc-d-PhGb): m.p. 132 1338C; 1H NMR(300 MHz,
CDCl3): d ˆ 1.40 (s, 9H), 2.52 (brs, 1H), 3.76 (d, J ˆ 4.9 Hz, 2H), 5.02 (dt,
J ˆ 7.4 and 4.9 Hz, 1H), 5.21 (brs, 1H), 5.71 (brd, J ˆ 6.3 Hz, 1H), 6.72
(brd, J ˆ 7.4 Hz, 1H), 7.22 7.41 ppm (m, 10H); 13C NMR(75 MHz,
CDCl3): d ˆ 28.5 (3C), 56.2, 59.0, 66.1, 80.7, 126.9 (2C), 127.4 (2C), 128.1,
128.7, 129.0 (2C), 129.3 (2C), 138.1, 138.8, 155.6, 170.7 ppm; (MALDI-
‡
155.8, 171.9 ppm; (MALDI-TOF): m/z: 389.269 [M À K] , 373.261 [M À
‡
‡
Na] , 351.270 [M À H] .
tert-Butyl N-((1S)-1-benzyl-2-[(2-hydroxyethyl)amino]-2-oxoethyl)carba-
1
mate (Boc-l-Fe): m.p. 103 1048C; H NMR(300 MHz, CDCl ): d ˆ 1.40
3
(s, 9H, s), 2.79 (brs, 1H), 3.04 (d, J ˆ 7.3 Hz, 2H), 3.31 (m, 2H), 3.49 3.65
(m, 2H), 4.33 (m, 1H), 5.27 (brd, J ˆ 7.6 Hz, 1H), 6.51 (m, 1H), 7.18
7.34 ppm (m, 5H); 13C NMR(75 MHz, CDCl 3): d ˆ 28.5 (3C), 39.0, 42.5,
56.4, 61.8, 80.6, 127.2, 128.9 (2C), 129.5 (2C), 136.9, 155.8, 172.5 ppm;
‡
‡
‡
TOF: m/z: 409.146 [M À K] , 393.187 [M À Na] , 371.203 [M À H] ;
elemental analysis calcd (%) for C21H26N2O4: C 68.09, H 7.07, N 7.56;
found: C 67.98, H 7.05, N 7.53.
‡
‡
(MALDI-TOF): m/z: 347.141 [M À K] , 331.157 [M À Na] , 309.183 [M À
‡
H] .
tert-Butyl N-((1R)-2-{[(1S)-1-benzyl-2-hydroxyethyl]amino}-2-oxo-1-phe-
nylethyl)carbamate (Boc-d-PhGc): m.p. 145 1468C; 1H NMR(300 MHz,
CDCl3): d ˆ 1.39 (s, 9H), 2.66 2.80 (m, 3H), 3.54 (dd, J ˆ 11.2 and 5.4 Hz,
1H), 3.66 (dd, J ˆ 11.2 and 4.1 Hz, 1H), 4.20 (m, 1H), 5.13 (brs, 1H), 5.80
(d, J ˆ 6.7 Hz, 1H), 6.21 (brs, 1H), 6.95 (m, 2H), 7.21 (m, 3H), 7.27
7.33 ppm (m, 5H); 13C NMR(75 MHz, CDCl 3): d ˆ 28.5 (3C), 37.0, 53.0,
58.9, 63.9, 80.5, 126.7, 127.4 (2C), 128.5, 128.7 (2C), 129.2 (2C), 129.3 (2C),
tert-Butyl N-[(1S)-1-({[(1S)-2-hydroxy-1-phenylethyl]amino}carbonyl)-3-
methylbutyl]carbamate (Boc-l-La): m.p. 106 1078C; 1H NMR(300 MHz,
CDCl3): d ˆ 0.91 (d, J ˆ 4.2 Hz, 3H), 0.93 (d, J ˆ 4.2 Hz, 3H), 1.41 (s, 9H),
1.47 (m, 1H), 1.67 (m, 2H), 3.15 (deft, J ˆ 6.1 Hz, 1H), 3.74 3.90 (m, 2H),
4.17 (m, 1H), 5.01 (m, 1H), 5.07 (brs, 1H), 7.17 7.35 ppm (m, 6H);
13C NMR(75 MHz, CDCl 3): d ˆ 22.2, 23.1, 24.9, 28.4 (3C), 40.8, 53.5, 55.9,
66.3, 80.5, 126.8 (2C), 127.8, 128.9 (2C), 139.1, 156.2, 173.0 ppm; (MALDI-
‡
137.3, 138.2, 155.6, 170.7 ppm; (MALDI-TOF: m/z: 423.162 [M À K] ,
‡
‡
‡
‡
‡
407.187 [M À Na] , 385.200 [M À H] .
TOF): m/z: 389.205 [M À K] , 373.246 [M À Na] , 351.230 [M À H] ;
elemental analysis calcd (%) for C19H30N2O4: C 65.12, H 8.63, N 7.99;
found: C 65.12, H 8.75, N 7.99.
tert-Butyl N-((1R)-2-{[(1S)-1-(hydroxymethyl)-2-methylpropyl]amino}-2-
1
oxo-1-phenylethyl)-carbamate (Boc-d-PhGd): m.p. 138 1398C; H NMR
(300 MHz, CDCl3): d ˆ 0.65 (d, J ˆ 6.6 Hz, 3H), 0.81 (d, J ˆ 6.6 Hz, 3H),
1.41 (s, 9H), 1.73 (m, 1H), 3.22 (brs, 1H), 3.59 (m, 1H), 3.64 3.78 (m, 2H),
5.23 (brs, 1H), 5.92 (d, J ˆ 6.6 Hz, 1H), 6.39 (brs, 1H), 7.32 (m, 3H),
7.40 ppm (m, 2H); 13C NMR(75 MHz, CDCl 3): d ˆ 18.5, 19.6, 28.5 (3C),
29.3, 57.3, 59.0, 63.4, 80.4, 127.4 (2C), 128.5, 129.1 (2C), 138.5, 155.6,
tert-Butyl N-[(1S)-1-({[(1R)-2-hydroxy-1-phenylethyl]amino}carbonyl)-3-
methylbutyl]carbamate (Boc-l-Lb): m.p. 155 1568C; 1H NMR(300 MHz,
CDCl3): d ˆ 0.90 (m, 6H), 1.43 (s, 9H), 1.49 (m, 1H), 1.63 (m, 2H), 3.37 (m,
1H), 3.76 3.89 (m, 2H), 4.18 (m, 1H), 5.07 (m, 1H), 5.29 (d, J ˆ 8.1 Hz,
1H), 7.19 7.36 ppm (m, 6H); 13C NMR(75 MHz, CDCl 3): d ˆ 22.2, 23.1,
24.9, 28.5 (3C), 41.3, 53.7, 55.9, 66.2, 80.5, 126.9 (2C), 127.9, 128.9 (2C),
‡
‡
171,2 ppm; (MALDI-TOF): m/z: 375.163 [M À K] , 359.187 [M À Na] ,
‡
‡
337.187 [M À H] .
139.2, 156.4, 173.4 ppm; (MALDI-TOF): m/z: 389.159 [M À K] , 373.176
‡
‡
[M À Na] , 351.203 [M À H] .
tert-Butyl N-((1R)-2-[(2-hydroxyethyl)amino]-2-oxo-1-phenylethyl)carba-
mate (Boc-d-PhGe): After filtration an oil was obtained and further
purification was done by column chromatography (silica gel, pentane/ethyl
acetate mixtures): 1H NMR(300 MHz, CDCl 3): d ˆ 1.43 (s, 9H), 2.53 (brs,
1H), 3.23 3.53 (m, 2H), 3.59 3.90 (m, 2H), 5.26 (m, 1H), 5.78 (brs, 1H),
6.48 (brs, 1H), 7.27 7.46 ppm (m, 5H); 13C NMR(75 MHz, CDCl 3): d ˆ
28.5 (3C), 42.7, 58.8, 63.9, 80.6, 127.4 (2C), 128.6, 129.2 (2C), 138.3, 155.6,
tert-Butyl N-[(1S)-1-({[(1S)-1-benzyl-2-hydroxyethyl]amino}carbonyl)-3-
methylbutyl]carbamate (Boc-l-Lc): m.p. 126 1278C; 1H NMR
(300 MHz, CDCl3): d ˆ 0.89 (d, J ˆ 4.0 Hz, 3H), 0.91 (d, J ˆ 4.0 Hz, 3H),
1.39 (m, 1H), 1.43 (s, 9H), 1.51 1.69 (m, 2H), 2.88 (d, J ˆ 7.3 Hz, 2H), 3.28
(m, 1H), 3.52 3.69 (m, 2H), 3.98 4.21 (m, 2H), 5.02 (brs, 1H), 6.65 (brd,
J ˆ 8.4 Hz, 1H), 7.17 7.31 ppm (m, 5H); 13C NMR(75 MHz, CDCl ): d ˆ
3
‡
‡
171.4 ppm; (MALDI-TOF): m/z: 333.136 [M À K] , 317.170 [MNa] .
22.1, 23.0, 24.9, 28.5 (3C), 37.1, 41.3, 53.1, 53.7, 63.6, 80.5, 126.7, 128.7 (2C),
129.4 (2C), 138.0, 156.1, 173.1 ppm; (MALDI-TOF): m/z: 403.170 [M À
tert-Butyl N-((1S)-1-benzyl-2-{[(1S)-2-hydroxy-1-phenylethyl]amino}-2-
oxoethyl)carbamate (Boc-l-Fa): m.p. 130 1318C. 1H NMR(300 MHz,
CDCl3): d ˆ 1.40 (s, 9H), 2.58 (brs, 1H), 3.05 (m, 2H), 3.66 (m, 2H), 4.37
(m, 1H), 4.95 (m, 1H), 5.18 (d, J ˆ 7.5 Hz, 1H), 6.59 (brd, J ˆ 6.9 Hz, 1H),
‡
‡
‡
K] , 387.210 [M À Na] , 365.217 [M À H] .
tert-Butyl N-[(1S)-1-({[(1S)-1-(hydroxymethyl)-2-methylpropyl]amino}-
carbonyl)-3-methylbutyl]carbamate (Boc-l-Ld): m.p. 145 1468C;
1H NMR(300 MHz, CDCl 3): d ˆ 0.94 (m, 12H), 1.44 (s, 9H), 1.44 1.55
(m, 1H), 1.62 1.76 (m, 2H), 1.89 (m, 1H), 2.81 (t, J ˆ 5.6 Hz, 1H), 3.58
3.76 (m, 3H), 4.06 (m, 1H), 4.96 (brd, J ˆ 7.5 Hz, 1H), 6.44 ppm (brd, J ˆ
8.1 Hz, 1H); 13C NMR(75 MHz, CDCl 3): d ˆ 18.8, 19.7, 22.2, 23.1, 25.0, 28.5
(3C), 29.2, 40.7, 53.8, 57.5, 64.1, 80.6, 156.2, 173.5 ppm; (MALDI-TOF):
7.13 7.35 ppm (m, 10H); 13C NMR(75 MHz, CDCl ): d ˆ 28.4 (3C), 38.7,
3
55.9, 56.4, 66.1, 80.6, 126.9 (2C), 127.2, 127.9, 128.9 (2C), 129.0 (2C), 129.5
(2C), 136.9, 138.8, 155.7, 171.6 ppm; (MALDI-TOF) (m/z) 423.168[M À
‡
‡
‡
K] , 407.184[M À Na] , 385.224[M À H] .
tert-Butyl N-((1S)-1-benzyl-2-{[(1R)-2-hydroxy-1-phenylethyl]amino}-2-
oxoethyl)carbamate (Boc-l-Fb): m.p. 147 1488C; 1H NMR(300 MHz,
CDCl3): d ˆ 1.40 (s, 9H), 2.68 (brs, 1H), 3.05 (d, J ˆ 7.1 Hz, 2H), 3.76 (dd,
J ˆ 11.5 and 6.3 Hz, 1H), 3.83 (dd, J ˆ 11.5 and 4.1 Hz, 1H), 4.37 (m, 1H),
5.03 (m, 1H), 5.23 (brs, 1H), 6.64 (brs, 1H), 7.05 7.32 ppm (m, 10H);
13C NMR(75 MHz, CDCl 3): d ˆ 28.5 (3C), 38.6, 55.8, 56.6, 66.2, 80.7, 126.8
(2C), 127.1, 127.9, 128.9 (2C), 129.5 (4C), 136.6, 138.6, 156.0, 172.0 ppm;
‡
‡
‡
m/z: 355.134 [M À K] , 339.180 [M À Na] , 317.200 [M À H] .
tert-Butyl N-((1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-3-methylbutyl)-
carbamate (Boc-l-Le): After filtration an oil was obtained and further
purification was done by column chromatography (silica gel, pentane/ethyl
1
acetate mixtures): H NMR(300 MHz, CDCl ): d ˆ 0.91 (m, 6H), 1.41 (s,
3
9H), 1.44 1.54 (m, 1H), 1.55 1.74 (m, 2H), 3.25 3.37 (m, 2H), 3.38 3.50
(m, 1H), 3.68 (m, 2H), 4.11 (m, 1H), 5.26 (brs, 1H), 7.02 ppm (m, 1H);
13C NMR(75 MHz, CDCl 3): d ˆ 22.1, 23.1, 24.9, 28.5 (3C), 41.6, 42.5, 53.6,
‡
‡
(MALDI-TOF): m/z: 423.133 [M À K] , 407.186 [M À Na] , 385.183 [M À
‡
H] ; elemental analysis calcd (%) for C22H28N2O4: C 68.73, H 7.34, N 7.29;
‡
found: C 68.54, H 7.44, N 7.16.
61.9, 80.4, 156.3, 174.1 ppm; (MALDI-TOF): m/z: 313.160 [M À K] ,
‡
‡
297.160 [M À Na] , 275.196 [M À H] .
tert-Butyl N-((1S)-1-benzyl-2-{[(1S)-1-benzyl-2-hydroxyethyl]amino}-2-
oxoethyl)carbamate (Boc-l-Fc): m.p. 117 1188C; 1H NMR(300 MHz,
CDCl3): d ˆ 1.41 (s, 9H), 2.33 (brs, 1H), 2.69 2.83 (m, 2H), 2.92 3.01 (m,
tert-Butyl N-((1S)-2-{[(1S)-2-hydroxy-1-phenylethyl]amino}-1-methyl-2-
oxoethyl)carbamate (Boc-l-Aa): m.p. 114 1158C; 1H NMR(300 MHz,
4040
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 4031 4045

Modular Dipeptide-Analogue Ligands
4031 4045
CDCl3): d ˆ 1.34 (d, J ˆ 7.1 Hz, 3H), 1.42 (s, 9H), 3.14 (m, 1H), 3.74 3.90
(m, 2H), 4.20 (m, 1H), 5.02 (m, 1H), 5.18 (brs, 1H), 7.17 (brs, 1H), 7.21
7.41 ppm (m, 5H); 13C NMR(75 MHz, CDCl 3): d ˆ 18.0, 28.5 (3C), 50.5,
55.9, 66.3, 80.6, 126.9 (2C), 127.9, 128.9 (2C), 139.1, 156.0, 173.2 ppm;
d ˆ 0.92 (d, J ˆ 6.8 Hz, 3H), 0.96 (d, J ˆ 6.8 Hz, 3H), 1.37 (d, J ˆ 7.0 Hz,
3H), 1.44 (s, 9H), 1.87 (m, 1H), 3.54 3.78 (m, 4H), 4.19 (m, 1H), 5.51 (brs,
1H), 6.71 ppm (brs, 1H); 13C NMR(75 MHz, CDCl ): d ˆ 18.7, 18.8, 19.7,
3
28.5 (3C), 29.2, 50.6, 57.2, 63,5, 80.4, 156.0, 173.9 ppm; (MALDI-TOF):
‡
‡
‡
‡
‡
(MALDI-TOF): m/z: 347.101 [M À K] , 331.158 [MNa] .
m/z: 313.094 [M À K] , 297.107 [M À Na] , 275.162 [M À H] .
tert-Butyl N-((1S)-2-{[(1R)-2-hydroxy-1-phenylethyl]amino}-1-methyl-2-
oxoethyl)carbamate (Boc-l-Ab): m.p. 111 1128C; 1H NMR(300 MHz,
CDCl3): d ˆ 1.34 (3H, d, J ˆ 7.1 Hz), 1.43 (s, 9H), 3.44 (m, 1H), 3.72 3.90
(m, 2H), 4.24 (m, 1H), 5.07 (m, 1H), 5.43 (brd, J ˆ 7.4 Hz, 1H), 7.21
7.37 ppm (m, 6H); 13C NMR(75 MHz, CDCl 3): d ˆ 18.5, 28.5 (3C), 50.6,
55.8, 66.2, 80.5, 126.9 (2C), 127.9, 128.9 (2C), 139.1, 156.2, 173.5 ppm;
tert-Butyl N-{(1R)-2-[(2-hydroxyethyl)amino]-1-methyl-2-oxoethyl}carba-
mate (Boc-d-Ae): After filtration an oil was obtained and further
purification was done by column chromatography (silica gel, pentane/ethyl
acetate mixtures): 1H NMR(300 MHz, CDCl 3): d ˆ 1.37 (d, J ˆ 7.2 Hz,
3H), 1.44 (s, 9H), 3.24 (brs, 1H), 3.31 3.52 (m, 2H), 3.70 (m, 2H), 4.17 (m,
1H), 5.36 (brs, 1H), 6.97 ppm (m, 1H); 13C NMR(75 MHz, CDCl 3): d ˆ
18.7, 28.5 (3C), 42.5, 50.6, 61.9, 80.5, 156.0, 174.1 ppm; (MALDI-TOF):
‡
‡
(MALDI-TOF): m/z: 347.119 [M À K] , 331.157 [M À Na] , 309.181 [M À
‡
‡
‡
‡
H] ; elemental analysis calcd (%) for C16H24N2O4: C 62.32, H 7.84, N 9.08;
m/z: 271.098 [M À K] , 255.126 [M À Na] , 233.136 [M À H] .
found: C 62.42, H 7.93, N 9.10.
tert-Butyl N-[(1S)-1-({[(1S)-2-hydroxy-1-phenylethyl]amino}carbonyl)-2-
methylpropyl]carbamate (Boc-l-Va): m.p. 126 1278C; 1H NMR
(300 MHz, CDCl3): d ˆ 0.93 (d, J ˆ 6.6 Hz, 3H), 0.98 (d, J ˆ 6.9 Hz, 3H),
1.42 (s, 9H), 2.10 (m, 1H), 2.96 (brs, 1H), 3.75 3.88 (m, 3H), 3.92 (m, 1H),
5.04 (m, 1H), 5.23 (brd, J ˆ 8.1 Hz, 1H), 7.06 (brs, 1H), 7.23 7.37 ppm (m,
5H); 13C NMR(75 MHz, CDCl 3): d ˆ 18.3, 19.6, 28.5 (3C), 30.7, 56.0, 60.8,
66.3, 80.4, 126.9 (2C), 127.9, 128.9 (2C), 139.1, 156.4, 172.4 ppm; (MALDI-
tert-Butyl N-((1S)-2-{[(1S)-1-benzyl-2-hydroxyethyl]amino}-1-methyl-2-
oxoethyl)carbamate (Boc-l-Ac): m.p. 113 1148C; 1H NMR(300 MHz,
CDCl3): d ˆ 1.29 (d, J ˆ 7.1 Hz, 3H), 1.44 (s, 9H), 2.87 (d, J ˆ 7.3 Hz, 2H),
3.16 (t, J ˆ 5.8 Hz, 1H), 3.51 3.60 (m, 1H), 3.62 3.71 (m, 1H), 4.01 4.21
(m, 2H), 5.10 (d, J ˆ 6.9 Hz, 1H), 6.58 (d, J ˆ 8.0 Hz, 1H), 7.17 7.32 ppm
(m, 5H); 13C NMR(75 MHz, CDCl ): d ˆ 18.4, 28.5 (3C), 37.1, 50.7, 53.0,
3
‡
‡
‡
63.6, 80.6, 126.8, 128.7 (2C), 129.4 (2C), 138.0, 155.8, 173.2 ppm; (MALDI-
TOF): m/z: 375.113 [M À K] , 359.141 [M À Na] , 337.169 [M À H] .
‡
‡
TOF): m/z: 361.139 [M À K] , 345.158 [MNa] .
tert-Butyl N-[(1S)-1-({[(1S)-1-benzyl-2-hydroxyethyl]amino}carbonyl)-2-
methylpropyl]-carbamate (Boc-l-Vc): m.p. 144 1458C; 1H NMR
(300 MHz, CDCl3): d ˆ 0.82 (brd, J ˆ 6.7 Hz, 3H), 0.89 (d, J ˆ 6.8 Hz,
3H), 1.43 (s, 9H), 2.07 (m, 1H), 2.87 (m, 2H), 3.16 (brs, 1H), 3.56 (dd, J ˆ
11.2 and 5.0 Hz, 1H), 3.64 (dd, J ˆ 11.2 and 3.8 Hz, 1H), 3.83 (m, 1H), 4.17
(m, 1H), 5.09 (d, J ˆ 8.2 Hz, 1H), 6.53 (brs, 1H), 7.16 7.30 ppm (m, 5H);
tert-Butyl N-((1S)-2-{[(1S)-1-(hydroxymethyl)-2-methylpropyl]amino}-1-
methyl-2-oxoethyl)-carbamate (Boc-l-Ad): m.p. 83 848C; 1H NMR
(300 MHz, CDCl3): d ˆ 0.92 (d, J ˆ 6.8 Hz, 3H), 0.95 (d, J ˆ 6.8 Hz, 3H),
1.37 (d, J ˆ 7.0 Hz, 3H), 1.44 (s, 9H), 1.90 (m, 1H), 3.13 (t, J ˆ 5.7 Hz, 1H),
3.58 3.76 (m, 3H), 4.14 (m, 1H), 5.20 (brd, J ˆ 6.5 Hz, 1H), 6.59 ppm (1H,
brd, J ˆ 8.3 Hz); 13C NMR(75 MHz, CDCl 3): d ˆ 18.0, 18.8, 19.7, 28.5 (3C),
29.1, 50.7, 57.3, 63.8, 80.6, 156.1, 173.7 ppm; (MALDI-TOF): m/z: 313.114
13C NMR(75 MHz, CDCl ): d ˆ 17.9, 19.4, 28.5 (3C), 30.7, 37.1, 53.0, 60.7,
3
63.7, 80.4, 126.8, 128.8 (2C), 129.4 (2C), 137.9, 156.2, 172.1 ppm; (MALDI-
‡
‡
‡
‡
‡
‡
[M À K] , 297.163 [M À Na] , 275.163 [M À H] ; elemental analysis calcd
(%) for C13H26N2O4: C 56.91, H 9.55, N 10.21; found: C 57.02, H 9.73, N
10.21.
TOF): m/z: 389.117 [M À K] , 373.158 [M À Na] , 351.181 [M À H] .
tert-Butyl N-[(1S)-1-({[(1S)-1-(hydroxymethyl)-2-methylpropyl]amino}-
carbonyl)-2-methylpropyl]carbamate (Boc-l-Vd): m.p. 149 1508C;
1H NMR(300 MHz, CDCl 3): d ˆ 0.91 1.01 (m, 12H), 1.45 (s, 9H), 1.89
(m, 1H), 2.17 (m, 1H), 2.71 (def t, J ˆ 5.7 Hz, 1H), 3.60 3.77 (m, 3H), 3.84
(dd, J ˆ 8.1 and 6.6 Hz, 1H), 5.04 (brs, 1H), 6.22 ppm (brs, 1H); 13C NMR
(75 MHz, CDCl3): d ˆ 18.2, 19.0, 19.6, 19.7, 28.5 (3C), 29.0, 30.4, 57.4, 61.0,
tert-Butyl N-{(1S)-2-[(2-hydroxyethyl)amino]-1-methyl-2-oxoethyl}carba-
mate (Boc-l-Ae): After filtration an oil was obtained and further
purification was done by column chromatography (silica gel, pentane/ethyl
acetate mixtures): 1H NMR(300 MHz, CDCl 3): d ˆ 1.37 (d, J ˆ 7.2 Hz,
3H), 1.44 (s, 9H), 3.17 (brs, 1H), 3.31 3.52 (m, 2H), 3.70 (m, 2H), 4.17 (m,
1H), 5.35 (brs, 1H), 6.96 ppm (brs, 1H); 13C NMR(75 MHz, CDCl 3): d ˆ
18.7, 28.5 (3C), 42.5, 50.6, 61.8, 80.5, 156.0, 174.1 ppm; (MALDI-TOF):
‡
63.7, 80.3, 156.3, 172.6 ppm; (MALDI-TOF): m/z: 341.141 [M À K] ,
‡
‡
325.176 [M À Na] , 303.194 [M À H] .
tert-Butyl N-((1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-methylpropyl)-
carbamate (Boc-l-Ve): After filtration an oil was obtained and further
‡
‡
‡
m/z: 271.098 [M À K] , 255.126 [M À Na] , 233.149 [M À H] .
tert-Butyl N-((1R)-2-{[(1S)-2-hydroxy-1-phenylethyl]amino}-1-methyl-2-
oxoethyl)carbamate (Boc-d-Aa): m.p. 112 1138C; 1H NMR(300 MHz,
CDCl3): d ˆ 1.36 (d, J ˆ 6.9 Hz, 3H), 1.43 (s, 9H), 3.04 (brs, 1H), 3.81 (dd,
J ˆ 11.5 and 6.3 Hz, 1H), 3.88 (dd, J ˆ 11.5 and 4.1 Hz, 1H), 4.21 (m, 1H),
5.07 (m, 1H), 5.25 (brs, 1H), 7.07 (brs, 1H), 7.24 7.38 ppm (m, 5H);
13C NMR(75 MHz, CDCl 3): d ˆ 18.3, 28.5 (3C), 50.6, 55.9, 66.4, 80.6, 126.9
(2C), 128.0, 129.0 (2C), 139.0, 156.1, 173.4 ppm; (MALDI-TOF): m/z:
purification was done by column chromatography (silica gel, pentane/ethyl
1
acetate mixtures): H NMR(300 MHz, CDCl ): d ˆ 0.95 (6H, m), 1.44 (s,
3
9H), 2.10 (1H, m), 3.15 (brs, 1H), 3.31 3.53 (2H, m), 3.65 3.76 (2H, m),
3.88 (1H, m), 5.34 (brd, J ˆ 8.7 Hz, 1H), 6.96 ppm (brs, 1H); 13C NMR
(75 MHz, CDCl3): d ˆ 19.2, 19.5, 28.5 (3C), 31.0, 42.5, 60.6, 62.0, 80.4, 156.4,
‡
‡
173.0 ppm; (MALDI-TOF): m/z: 299.099 [M À K], 283.129 [M À Na],
‡
261.141 [M À H].
‡
‡
‡
347.136 [M À K] , 331.171 [M À Na] , 309.175 [M À H] ; elemental analysis
calcd (%) for C16H24N2O4: C 62.32, H 7.84, N 9.08; found: C 62.20, H 7.93, N
9.00.
tert-Butyl N-[(1R)-1-({[(1S)-2-hydroxy-1-phenylethyl]amino}carbonyl)-2-
methylpropyl]-carbamate (Boc-d-Va): m.p. 156 1578C; 1H NMR
(300 MHz, CDCl3): d ˆ 0.88 0.94 (m, 6H), 1.43 (9H, s), 2.08 (m, 1H),
3.36 (1H, brs), 3.85 (m, 2H), 3.99 (1H, def t, J ˆ 7.4 Hz), 5.10 (m, 1H), 5.40
(brd, J ˆ 7.8 Hz, 1H), 7.19 (1H, brs), 7.23 7.38 ppm (m, 5H); 13C NMR
(75 MHz, CDCl3): d ˆ 18.2, 19.6, 28.5 (3C), 31.1, 55.9, 60.7, 66.2, 80.4, 127.0
(2C), 127.9, 128.9 (2C), 139.2, 156.7, 172.6 ppm; (MALDI-TOF): m/z:
tert-Butyl N-((1R)-2-{[(1R)-2-hydroxy-1-phenylethyl]amino}-1-methyl-2-
oxoethyl)carbamate (Boc-d-Ab): m.p. 119 1208C; 1H NMR(300 MHz,
CDCl3): d ˆ 1.36 (3H, d, J ˆ 7.1 Hz), 1.43 (9H, s), 2.76 (brs, 1H), 3.79 3.91
(m, 2H), 4.20 (m, 1H), 5.04 (m, 2H), 7.06 (brs, 1H), 7.23 7.37 ppm (m,
5H); 13C NMR(75 MHz, CDCl 3): d ˆ 17.9, 28.5 (3C), 50.6, 56.0, 66.5, 80.8,
126.9 (2C), 128.0, 129.0 (2C), 139.0, 156.0, 173.1 ppm; (MALDI-TOF):
‡
‡
‡
375.153 [M À K] , 359.172 [M À Na] , 337.200 [M À H] ; elemental analysis
calcd (%) for C18H28N2O4: C 64.26, H 8.39, N 8.33; found: C 64.43, H 8.50,
N 8.38.
‡
‡
‡
m/z: 347.117 [M À K] , 331.116 [M À Na] , 309.170 [M À H] .
tert-Butyl N-((1R)-2-{[(1S)-1-benzyl-2-hydroxyethyl]amino}-1-methyl-2-
oxoethyl)carbamate (Boc-d-Ac): m.p. 122 1238C; 1H NMR(300 MHz,
CDCl3): d ˆ 1.23 (d, J ˆ 6.8 Hz, 3H), 1.41 (s, 9H), 2.78 2.93 (2H, m), 3.08
(brs, 1H), 3.53 (dd, J ˆ 11.3 and 5.2 Hz, 1H), 3.67 (dd, J ˆ 11.3 and 3.6 Hz,
1H), 4.07 (m, 1H), 4.18 (m, 1H), 5.19 (brd, J ˆ 7.4 Hz, 1H), 6.50 (brd, J ˆ
8.2 Hz, 1H), 7.17 7.31 ppm (m, 5H); 13C NMR(75 MHz, CDCl 3): d ˆ 18.5,
28.5 (3C), 37.2, 50.6, 52.9, 63.9, 80.5, 126.8, 128.8 (2C), 129.4 (2C), 137.8,
tert-Butyl N-[(1R)-1-({[(1R)-2-hydroxy-1-phenylethyl]amino}carbonyl)-
2-methylpropyl]-carbamate (Boc-d-Vb): m.p. 69 708C; 1H NMR
(300 MHz, CDCl3): d ˆ 0.94 (d, J ˆ 6.9 Hz, 3H), 1.00 (d, J ˆ 6.9 Hz, 3H),
1.44 (s, 9H), 2.17 (m, 2H), 3.82 3.97 (m, 3H), 4.96 5.11 (m, 2H), 6.73 (m,
1H), 7.24 7.41 ppm (m, 5H); 13C NMR(75 MHz, CDCl 3): d ˆ 19.2, 19.6,
18.5 (3C), 30.7, 56.0, 60.8, 66.4, 80.4, 126.9 (2C), 128.0, 129.0 (2C), 139.0,
‡
156.3, 172.3 ppm; (MALDI-TOF): m/z: 375.165 [M À K] , 359.191 [M À
‡
‡
‡
156.0, 173.4 ppm; (MALDI-TOF): m/z: 361.129 [M À K] , 345.179 [M À
Na] , 337.202 [M À H] .
‡
‡
Na] , 323.196 [M À H] .
tert-Butyl N-[(1R)-1-({[(1S)-1-benzyl-2-hydroxyethyl]amino}carbonyl)-2-
methylpropyl]-carbamate (Boc-d-Vc): m.p. 131 1328C; 1H NMR
(300 MHz, CDCl3): d ˆ 0.77 0.92 (m, 6H), 1.43 (s, 9H), 1.93 (m, 1H),
2.81 (dd, J ˆ 13.8 and 7.9 Hz, 1H), 2.91 (dd, J ˆ 13.8 and 7.1 Hz, 1H), 3.14
(brs, 1H), 3.54 (dd, J ˆ 11.2 and 5.1 Hz, 1H), 3.69 (dd, J ˆ 11.2 and 3.6, 1H),
tert-Butyl N-((1R)-2-{[(1S)-1-(hydroxymethyl)-2-methylpropyl]amino}-1-
methyl-2-oxoethyl)-carbamate (Boc-d-Ad): After filtration an oil was
obtained and further purification was done by column chromatography
(silica gel, pentane/ethyl acetate mixtures): 1H NMR(300 MHz, CDCl 3):
Chem. Eur. J. 2003, 9, 4031 4045
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4041

H. Adolfsson et al.
FULL PAPER
3.73 3.84 (m, 1H), 4.25 (m, 1H), 5.24 (brd, J ˆ 8.1 Hz, 1H), 6.41 (brd, J ˆ
8.1 Hz, 1H), 7.17 7.31 ppm (m, 5H); 13C NMR(75 MHz, CDCl 3): d ˆ 18.2,
19.3, 28.5 (3C), 30.9, 37.2, 53.0, 60.9, 64.1, 80.4, 126.8, 128.8 (2C), 129.4
the aqueous layer was acidified with HCl (3m) and then extracted with
CH2Cl2 (4 Â 10 mL). The organic phase was dried over Na2SO4 and the
solvent was evaporated under vacuum. The resulting crude Alloc-l-V
(860 mg) was used without further purification in the next step.
‡
(2C), 137.8, 156.5, 172.4 ppm; (MALDI-TOF): m/z: 389.200 [M À K],
‡
‡
373.202 [M À Na], 351.219 [M À H].
N-methylmorpholine (NMM, 4.7 mmol, 541 mL) and isobutylchlorofor-
mate (4.7 mmol, 635 mL) were slowly added to a solution of Alloc-l-V in
THF (15 mL) at À158C (a white solid was forming during the addition of
the iBuOCOCl). The reaction mixture was stirred for 45 min at À158C, and
then (R)-phenylglycinol (4.3 mmol, 609 mg) was added and the resulting
mixture was stirred at room temperature for an additional 3 h. The mixture
was filtered through silica gel (5 cm, 5 cm Æ) and eluted with ethyl acetate
(100 mL). The solvent was concentrated under vacuum and the resulting
solid was recrystallized from CH2Cl2/n-pentane, giving the pure product
(1.3 g, 81% yield). m.p. 186 1878C; 1H NMR(300 MHz, CDCl 3): d ˆ 0.92
(m, 6H), 2.06 (m, 1H), 3.37 (brs, 1H), 3.71 3.91 (m, 2H), 4.09 (m, 1H),
4.42 4.60 (m, 2H), 5.08 (m, 1H), 5.16 5.32 (m, 2H), 5.72 (brd, J ˆ 8.7 Hz,
1H), 5.80 5.94 (m, 1H), 7.20 7.39 ppm (m, 6H); 13C NMR(75 MHz,
CDCl3): d ˆ 18.2, 19.5, 31.5, 55.7, 60.9, 66.0, 66.2, 118.1, 127.0 (2C), 127.9,
128.9 (2C), 132.7, 139.2, 157.1, 172.2 ppm; (MALDI-TOF): m/z: 359.112
t-Butyl N-[(1R)-1-({[(1S)-1-(hydroxymethyl)-2-methylpropyl]amino}car-
bonyl)-2-methylpropyl]-carbamate
(Boc-d-Vd):
m.p.
146 1478C;
1H NMR(300 MHz, CDCl 3): d ˆ 0.91 1.01 (12H, m), 1.44 (9H, s), 1.86
(1H, m), 2.10 (1H, m), 3.22 (brs, 1H), 3.60 (1H, m), 3.65 3.79 (2H, m),
3.83 (1H, m), 5.25 (1H, brd, J ˆ 7,8 Hz), 6.38 ppm (1H, brd, J ˆ 8.9 Hz);
13C NMR(75 MHz, CDCl 3): d ˆ 18.3, 19.1, 19.6, 19.8, 28.5 (3C), 29.1, 30.6,
57.5, 61.2, 63.7, 80.4, 156.6, 172.8 ppm; (MALDI-TOF): m/z: 341.169 [M À
‡
‡
‡
K] , 325.203 [M À Na] , 303.197 [M À H] .
tert-Butyl N-((1R)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-methylpropyl)-
carbamate (Boc-d-Ve): After filtration an oil was obtained and further
purification was done by column chromatography (silica gel, pentane/ethyl
1
acetate mixtures): H NMR(300 MHz, CDCl ): d ˆ 0.92 (m, 6H), 1.43 (s,
3
9H), 2.11 (m, 1H), 2.78 (brs, 1H), 3.30 3.52 (m, 2H), 3.71 (m, 2H), 3.83
3.94 (m, 1H), 5.18 (m, 1H), 6.71 ppm (brs, 1H); 13C NMR(75 MHz,
CDCl3): d ˆ 19.2, 19.5, 28.5 (3C), 30.9, 42.5, 60.7, 62.1, 80.4, 156.4,
‡
‡
‡
[M À K] , 343.140 [M À Na] , 321.156 [M À H] .
‡
‡
9H-9-fluorenylmethyl N-[(1S)-1-({[(1R)-2-hydroxy-1-phenylethyl]ami-
no}carbonyl)-2-methylpropyl]carbamate (Fmoc-l-Vb): Over a period of
30 min, 9-fluorenylmethyl chloroformate (5.5 mmol, 1.47 mg) in THF
(5 mL), and diisopropylethylamine (5.5 mmol, 961 mL) were simultane-
ously added to a stirred solution of l-valine (5 mmol, 593 mg) and Na2CO3
(5 mmol, 530 mg) in THF/H2O (5 mL/10 mL) at 08C. The resulting mixture
was stirred for an additional 2 h at room temperature. The reaction mixture
was extracted with Et2O (10 mL) and the aqueous layer was acidified with
HCl (3m) and extracted with CH2Cl2 (4 Â 10 mL). The organic phase was
dried over Na2SO4 and the solvent was evaporated under vacuum. The
resulting white solid of Fmoc-l-V (1.3 g) was used without further
purification in the next step.
173.0 ppm; (MALDI-TOF): m/z: 299.149 [M À K] , 283.161 [M À Na] ,
‡
261.194 [M À H] .
tert-Butyl N-[(1S)-1-({[(1S)-2-hydroxy-1-phenylethyl]amino}carbonyl)-
2,2-dimethylpropyl]-carbamate (Boc-l-tLa): After filtration an oil was
obtained and further purification was done by column chromatography
(silica gel, pentane/ethyl acetate mixtures): 1H NMR(300 MHz, CDCl 3):
d ˆ 1.09 (s, 9H), 1.43 (s, 9H), 3.84 3.90 (m, 3H), 5.07 (dt, J ˆ 7.2 and
4.8 Hz, 1H), 5.18 (m, 1H), 6.44 (brd, J ˆ 7.2 Hz, 1H), 7.26 7.39 ppm (m,
5H); 13C NMR(75 MHz, CDCl 3): d ˆ 26.9, 28.5 (3C), 34.5, 56.2, 63.0, 66.7,
80.2, 126.9 (2C), 128.1, 129. 1 (2C), 138.8, 156.2, 171.5 ppm; (MALDI-
‡
‡
‡
TOF): m/z: 389.130 [M À K] , 373.159 [M À Na] , 351.195 [M À H] .
tert-Butyl N-[(1S)-1-({[(1R)-2-hydroxy-1-phenylethyl]amino}carbonyl)-
2,2-dimethylpropyl]-carbamate (Boc-l-tLb): m.p. 177 1788C; 1H NMR
(300 MHz, CDCl3): d ˆ 0.98 (s, 9H), 1.43 (s, 9H), 2.94 (brs, 1H), 3.78 3.93
(m, 3H), 5.10 (m, 1H), 5.31 (brd, J ˆ 8.4 Hz, 1H), 6.64 (brd, J ˆ 7.8 Hz,
1H), 7.24 7.39 ppm (m, 5H); 13C NMR(75 MHz, CDCl 3): d ˆ 26.9 (3C),
28.5 (3C), 34.5, 56.0, 63.2, 66.2, 80.4, 127.1 (2C), 128.0, 129.0 (2C), 139.2,
N-methylmorpholine (NMM, 4.2 mmol, 483 mL) and isobutylchlorofor-
mate (4.2 mmol, 567 mL) were slowly added to a solution of the Fmoc-l-V
in THF (15 mL) at À158C (a white solid was formed during the addition of
the i-BuOCOCl). The reaction mixture was stirred for 45 min at À158C,
and then (R)-phenylglycinol (3.8 mmol, 537 mg) was added and the
resulting mixture was stirred at room temperature for a further 3 h. The
mixture was filtered through silica gel (5 cm, 5 cm Æ) and eluted with ethyl
acetate (100 mL). The solvent was evaporated and the resulting solid was
recrystallized from CH2Cl2/n-pentane, giving the pure product Fmoc-l-Vb
(1.4 g, 65% yield). m.p. 204 2058C; 1H NMR(300 MHz, CDCl 3): d ˆ 0.92
(d, J ˆ 6.9 Hz, 6H), 2.10 (m, 1H), 2.88 (brs, 1H), 3.35 3.90 (m, 2H), 4.05
(m, 1H), 4.18 (deft, J ˆ 6.9 Hz, 1H), 4.27 4.43 (m, 2H), 5.08 (m, 1H), 5.58
(m, 1H), 6.92 (brs, 1H), 7.23 7.31 (m, 7H), 7.38 (m, 2H), 7.55 (d, J ˆ 7.5 Hz,
2H), 7.75 ppm (m, 2H); 13C NMR(75 MHz, CDCl 3): d ˆ 17.8, 19.2, 31.2,
47.1, 55.7, 60.7, 65.2, 67.0, 119.9 (2C), 125.0 (2C), 126.7 (2C), 127.1 (2C),
127.6, 127.7 (2C), 128.5 (2C), 139.1, 141.3 (2C), 143.7 (2C), 157.1,
‡
156.5, 171.8 ppm; (MALDI-TOF): m/z: 389.181 [M À K] , 373.206 [M À
‡
‡
Na] , 351.236 [M À H] ; elemental analysis calcd (%) for C19H30N2O4: C
65.12, H 8.63, N 7.99; found: C 65.35, H 8.75, N 7.80.
tert-Butyl
N-[(1S)-1-({[(1S)-1-benzyl-2-hydroxyethyl]amino}carbonyl)-
2,2-dimethylpropyl]-carbamate (Boc-l-tLc): m.p. 199 2008C; 1H NMR
(300 MHz, CDCl3): d ˆ 0.95 (s, 9H), 1.44 (s, 9H), 1.95 (brs, 1H), 2.88 (d,
J ˆ 7.2 Hz, 1H), 3.57 (dd, J ˆ 11.1 and 5.1 Hz, 1H), 3.66 3.77 (m, 2H), 4.19
(m, 1H), 5.15 (brs, 1H), 5.97 (brs, 1H), 7.16 7.33 ppm (m, 5H); 13C NMR
(75 MHz, CDCl3): d ˆ 26.8 (3C), 28.6 (3C), 34.3, 37.2, 53.1, 63.3, 63.9, 80.2,
126.9, 128.9 (2C), 129.4 (2C), 137.7, 156.1, 171.3 ppm; (MALDI-TOF): m/z:
‡
‡
‡
403.211 [M À K] , 387.289 [M À Na] , 365.256 [M À H] .
‡
‡
172.3 ppm; (MALDI-TOF): m/z: 496.986 [M À K] , 481.080 [M À Na] ,
‡
t-Butyl N-[(1S)-1-({[(1S)-1-(hydroxymethyl)-2-methylpropyl]amino}car-
bonyl)-2,2-dimethyl-propyl]carbamate (Boc-l-tLd): m.p. 139 1408C;
1H NMR(300 MHz, CDCl 3): d ˆ 0.95 (m, 6H), 1.03 (s, 9H), 1.44 (s, 9H),
1.90 (m, 1H), 2.70 (brs, 1H), 3.62 3.78 (m, 3H), 3.80 (d, J ˆ 8.7 Hz, 1H),
5.22 (brd, J ˆ 8.7 Hz, 1H), 6.05 ppm (brd, J ˆ 9.0 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d ˆ 19.1, 19.7, 26.9 (3C), 28.5 (3C), 29.1, 34.2, 57.5, 63.3,
458.967 [M À H] .
Benzyl
N-[(1S)-1-({[(1R)-2-hydroxy-1-phenylethyl]amino}carbonyl)-2-
methylpropyl]carbamate (Z-l-Vb): N-(Benzyloxycarbonyloxy)succini-
mide (2 mmol, 508 mg) was added to a solution of l-valine (2 mmol,
237 mg) and NaHCO3 (2 mmol, 169 mg) in H2O/acetone (3 mL of each
solvent) and the reaction mixture was stirred overnight at room temper-
ature. The reaction mixture was extracted with CH2Cl2 (2 Â 5 mL) and the
aqueous layer was acidified with HCl (3m) and then extracted with EtOAc
(3 Â 10 mL). The organic phase was dried over Na2SO4 and the solvent was
evaporated under vacuum. The resulting crude product of Z-l-V (377 mg)
was used without further purification in the next step.
‡
63.9, 80.2, 156.3, 171.9 ppm; (MALDI-TOF): m/z: 355.179 [M À K] ,
‡
‡
339.197 [M À Na] , 317.225 [M À H] .
tert-Butyl N-((1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpro-
pyl)carbamate (Boc-l-tLe): After filtration an oil was obtained and further
purification was done by column chromatography (silica gel, pentane/ethyl
acetate mixtures): 1H NMR(300 MHz, CDCl 3): d ˆ 1.01 (s, 9H), 1.43 (s,
9H), 3.30 3.53 (m, 3H), 3.71 (m, 2H), 3.87 (m, 1H), 5.46 (brd, J ˆ 9.3 Hz,
N-Methylmorpholine (NMM, 1.8 mmol, 203 mL) and isobutylchlorofor-
mate (1.8 mmol, 236 mL) were slowly added to a solution of the Z-l-V in
THF (7 mL) at À158C (a white solid was formed during the addition of the
iBuOCOCl). The reaction mixture was stirred for 45 min at À158C, and
then (R)-phenylglycinol (1.5 mmol, 212 mg) was added and the resulting
mixture was stirred at room temperature for another 3 h. The mixture was
filtered through silica gel (5 cm, 5 cm Æ) and eluted with ethyl acetate
(80 mL). The solvent was concentrated under vacuum and the resulting
solid was recrystallized from CH2Cl2/n-pentane, giving the pure product Z-
l-Vb (530 mg, 72% yield). m.p. 198 1998C; 1H NMR(300 MHz, CDCl 3):
d ˆ 0.89 (m, 6H), 2.04 (m, 1H)), 3.74 (dd, J ˆ 11.5 and 6.7 Hz, 1H), 3.82
1H), 6.86 ppm (brs, 1H); 13C NMR(75 MHz, CDCl ): d ˆ 26.8 (3C), 28.5
3
(3C), 34.5, 42.4, 62.0, 62.8, 80.2, 156.5, 172.3 ppm; (MALDI-TOF): m/z:
‡
‡
313.149 [M À K] , 297.194 [MNa] .
Allyl
N-[(1S)-1-({[(1R)-2-hydroxy-1-phenylethyl]amino}carbonyl)-2-
methylpropyl]carbamate (Alloc-l-Vb): Allyl chloroformate (5 mmol,
547 mL) and NaOH (5 mL, 1m, aq.) were slowly added to a stirred solution
of l-valine (5 mmol, 593 mg) in basic water (5 mL, aq. NaOH 1m) at 08C.
The resulting mixture was stirred for an additional 30 min at room
temperature. The reaction mixture was extracted with Et2O (10 mL) and
4042
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 4031 4045

Modular Dipeptide-Analogue Ligands
4031 4045
(dd, J ˆ 11.5 and 4.4 Hz, 1H), 3.98 (m, 1H), 4.99 5.15 (m, 3H), 7.22
7.36 ppm (m, 10H); 13C NMR(75 MHz, CDCl 3): d ˆ 18.1, 19.4, 31.3, 55.7,
60.7, 65.7, 67.3, 126.9 (2C), 127.8, 128.1 (2C), 128.3 (2C), 128.7, 128.8 (2C),
(1.2 mmol, 170 mL) were added to a solution of L-Vb (1 mmol, 236 mg) in
CH2Cl2 (8 mL) at 08C. The reaction mixture was stirred for 5 h at room
temperature. The crude product was washed with HCl (1m, 2 Â 5 mL) and
the acidic phase was washed with CH2Cl2 (10 mL). The combined organic
phases were dried over Na2SO4 and the solvent was removed under
vacuum. The solid was recrystallized from Et2O, giving the product Ts-l-Vb
(280 mg, 72% yield). m.p. 193 1948C; 1H NMR(300 MHz, CDCl 3): d ˆ
0.82 (m, 6H), 1.93 (brs, 1H), 2.09 (m, 1H), 2.43 (s, 3H), 3.53 (dd, J ˆ 8.1 and
5.1 Hz, 1H), 3.71 (m, 2H), 4.90 (m, 1H), 5.29 (d, J ˆ 7.5 Hz, 1H), 6.60 (brd,
J ˆ 7.5 Hz, 1H), 7.20 7.25 (m, 2H), 7.27 7.38 (m, 5H), 7.75 ppm (d, J ˆ
8.4 Hz, 2H); 13C NMR(75 MHz, CDCl 3): d ˆ 17.4, 19.4, 21.8, 31.5, 56.0,
62.4, 66.3, 126.8 (2C), 127.7 (2C), 128.2, 129.1 (2C), 129.9 (2C), 136.6,
‡
136.3, 139.2, 157.1, 172.1 ppm; (MALDI-TOF): m/z: 409.111 [M À K] ,
‡
‡
393.121 [M À Na] , 371.110 [M À H] .
N-1-[(1R)-2-hydroxy-1-phenylethyl]-(2S)-2-(acetylamino)-3-methylbuta-
namide (Ac-l-Vb): Acetic anhydride (6 mmol, 566 mL) was added to a
solution of l-valine (5 mmol, 593 mg) in acetic acid (3 mL) and the
resulting mixture was stirred for 1.5 h. Toluene (10 mL) was added,
resulting in the formation of a precipitate. The solid was filtered, washed
with toluene (20 mL), and dried under vacuum. The solid product of Ac-l-
V (635 mg) was used in the next step without further purification.
‡
138.6, 144.2, 171.0 ppm; (MALDI-TOF): m/z: 429.077 [M À K] , 413.113
N-Methylmorpholine (NMM, 4.4 mmol, 506 mL) and isobutylchlorofor-
mate (4.4 mmol, 594 mL) were slowly added to a solution of the Ac-l-V in
THF (15 mL) at À158C (a white solid was formed during the addition of
the iBuOCOCl). The reaction mixture was stirred for 45 min at À158C,
then (R)-phenylglycinol (4 mmol, 565 mg) was added and the resulting
mixture was stirred at room temperature for an additional 3 h. The mixture
was filtered through silica gel (5 cm, 5 cm Æ) and eluted with ethyl acetate
(400 mL). The solvent was concentrated under vacuum and the resulting
solid was recrystallized from CH2Cl2/n-pentane, giving the pure product
Ac-l-Vb (735 mg, 53% yield). m.p. 229 2308C; 1H NMR(300 MHz,
CDCl3): d ˆ 0.86 (d, J ˆ 6.6 Hz, 3H), 0.90 (d, J ˆ 6.6 Hz, 3H), 2.00 (m, 1H),
2.03 (s, 3H), 3.72 3.82 (m, 3H), 4.17 (m, 1H), 5.01 (m, 1H), 7.24 7.41 (m,
6H), 7.94 ppm (brd, J ˆ 7.8 Hz, 1H); 13C NMR(75 MHz, CDCl 3): d ˆ 18.3,
19.2, 22.7, 31.0, 55.8, 59.2, 65.3, 126.8 (2C), 127.6, 128.6 (2C), 139.2, 171.8,
‡
‡
[M À Na] , 391.125 [M À H] .
tert-Butyl N-(2-{[(1S)-2-hydroxy-1-phenylethyl]amino}-2-oxoethyl)carba-
mate (Boc-Ga): This compound was prepared according to the general
procedure for the preparation of the library ligands. Purification of the
crude was done by column chromatography (silica gel, pentane/ethyl
acetate mixtures) (570 mg, 65% yield). 1H NMR(300 MHz, CDCl 3): d ˆ
1.42 (s, 9H), 2.41 (s, 1H), 3.68 3.88 (m, 4H), 5.07 (m, 1H), 5.58 (brs, 1H),
7.21 7.35 ppm (m, 6H); 13C NMR(75 MHz, CDCl 3): d ˆ 28.5 (3C), 44.6,
55.8, 66.0, 80.6, 126.9 (2C), 127.9, 128.9 (2C), 139.9, 156.7, 170.4 ppm;
‡
‡
(MALDI-TOF): m/z: 333.064 [M À K] , 317.106 [M À Na] , 295.130 [M À
‡
H] .
tert-Butyl N-(2-{[(1R)-2-hydroxy-1-phenylethyl]amino}-2-oxoethyl)carba-
mate (Boc-Gb): This compound was prepared according to the general
procedure for the preparation of the library ligands. Purification of the
crude was done by column chromatography (silica gel, pentane/ethyl
acetate mixtures) (554 mg, 63% yield). 1H NMR(300 MHz, CDCl 3): d ˆ
1.42 (s, 9H), 2.76 (brs, 1H), 3.69 3.95 (m, 4H), 5.05 (m, 1H), 5.69 (brs,
1H), 7.21 7.34 (m, 5H), 7.41 ppm (brd, J ˆ 7.5 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d ˆ 28.4 (3C), 44.4, 55.7, 65.8, 80.5, 126.8 (2C), 127.8,
128.8 (2C), 139.0, 156.6, 170.5 ppm; (MALDI-TOF): m/z: 333.156 [M À
‡
‡
172.1 ppm; (MALDI-TOF): m/z: 317.085 [M À K] , 301.181 [M À Na] ,
‡
279.179 [M À H] .
N-1-[(1R)-2-hydroxy-1-phenylethyl]-(2S)-3-methyl-2-[(2,2,2-trifluoroace-
tyl)amino]butanamide (TFA-l-Vb): Trifluoroacetic anhydride (6 mmol,
880 mL) was added to a solution of l-valine (5 mmol, 593 mg) in trifluoro-
acetic acid (3 mL) and the resulting mixture was stirred for 1.5 h. Toluene
(10 mL) was added and a precipitate was formed. The solid was filtered,
washed with toluene (20 mL) and dried under vacuum. The solid product
TFA-l-V (690 mg) was used in the next step without further purification.
‡
‡
‡
K] , 317.191 [M À Na] , 295.204 [M À H] .
tert-Butyl N-[(1S)-1-({[(1R)-2-methoxy-1-phenylethyl]amino}carbonyl)-
2-methylpropyl]carbamate (4):
A solution of Boc-l-Vb (0.6 mmol,
N-Methylmorpholine (NMM, 3.6 mmol, 414 mL) and isobutylchlorofor-
mate (3.6 mmol, 486 mL) were slowly added to a solution of the TFA-l-V in
THF (15 mL) at À158C (a white solid was formed during the addition of
the iBuOCOCl). The reaction mixture was stirred for 45 min at À158C,
then (R)-phenylglycinol (3.3 mmol, 466 mg) was added and the resulting
mixture was stirred at room temperature for another 3 h. The mixture was
filtered through silica gel (5 cm, 5 cm Æ) and eluted with ethyl acetate
(400 mL). The solvent was concentrated under vacuum and the resulting
solid was recrystallized from CH2Cl2/n-pentane, giving the pure product
TFA-l-Vb (700 mg, 42% yield). m.p. 206 2078C; 1H NMR(300 MHz,
CDCl3): d ˆ 0.89 (d, J ˆ 6.8 Hz, 3H), 2.10 (m, 1H), 3.73 (dd, J ˆ 11.8 and
6.9 Hz, 1H), 3.82 (dd, J ˆ 11.8 and 4.5 Hz, 1H), 4.31 (m, 1H), 5.00 (m, 1H),
7.24 7.38 ppm (m, 5H); 13C NMR(75 MHz, CDCl 3): d ˆ 18.8, 19.6, 32.0,
57.3, 60.9, 65.9, 117.4 (q, J ˆ 286.2 Hz), 128.2 (2C), 128.5, 129.4 (2C), 141.0,
200 mg) in DMSO (2 mL) was slowly added to a 08C solution of NaH
(0.72 mmol, 48 mg 60% oil dispersion) in DMSO (5 mL). After 10 min,
MeI (0.66 mmol, 42 mL) was added and the reaction mixture was stirred for
an additional 30 min. Water (10 mL) and CH2Cl2 (15 mL) were added and
the organic phase was washed with water (2 Â 5 mL). The combined
aqueous phases were washed with CH2Cl2 (10 mL) and dried over Na2SO4.
The solvent was then evaporated and the crude product was purified by
column chromatography (silica gel, CHCl3) (130 mg, 62% yield). 1H NMR
(300 MHz, CDCl3): d ˆ 0.88 (d, J ˆ 6.9 Hz, 3H), 0.92 (d, J ˆ 6.9 Hz, 3H),
1.44 (s, 9H), 2.12 (m, 1H), 3.34 (s, 3H), 3.65 (m, 2H), 3.95 (m, 1H), 5.02
5.22 (m, 2H), 6.65 (brd, J ˆ 7.5 Hz, 1H), 7.21 7.34 ppm (m, 5H); 13C NMR
(75 MHz, CDCl3): d ˆ 17.8, 19.5, 28.5 (3C), 52.7, 59.2, 60.1, 75.0, 80.0, 127.0
(2C), 127.7, 128.7 (2C), 139.9, 156.1, 171.3 ppm; (MALDI-TOF): m/z:
‡
‡
‡
‡
389.184 [M À K] , 373.208 [M À Na] , 351.228 [M À H] .
158.8 (q, J ˆ 37.7), 172.1 ppm; (MALDI-TOF): m/z: 371.020 [M À K] ,
‡
‡
355.124 [M À Na] , 333.090 [M À H] .
N1-[(1R)-2-hydroxy-1-phenylethyl](2R)-2-phenylbutanamide (5): N-
Methylmorpholine (NMM, 1.2 mmol, 135 mL) and isobutylchloroformate
(1.2 mmol, 158 mL) were slowly added to a solution of the (R)-2-phenyl-
butyric acid (1 mmol, 166 mg) in THF (5 mL) at À158C (a white solid was
formed during the addition of the iBuOCOCl). The reaction mixture was
stirred for 45 min at À158C, then (R)-phenylglycinol (1 mmol, 141 mg) was
added and the resulting mixture was stirred at room temperature for
another 3 h. The mixture was filtered through silica gel (5 cm, 5 cm Æ) and
eluted with ethyl acetate (70 mL). The solvent was concentrated under
vacuum and the resulting solid was recrystallized from CH2Cl2/n-pentane,
giving the pure product 5 (215 mg, 76% yield). m.p. 119 1208C; 1H NMR
(300 MHz, CDCl3): d ˆ 0.91 (t, J ˆ 7.5 Hz, 3H), 1.73 1.89 (m, 1H), 2.12
2.28 (m, 2H), 3.32 (t, J ˆ 7.6 Hz, 1H), 3.84 (d, J ˆ 4.5 Hz, 2H), 5.03 (dt, J ˆ
7.2 and 4.5 Hz, 1H), 6.08 (brd, J ˆ 7.2 Hz, 1H), 7.05 (m, 2H), 7.22 7.36 ppm
N-1-[(1R)-2-hydroxy-1-phenylethyl]-(2S)-2-amino-3-methylbutanamide
(L-Vb): The N-Boc-protected amide Boc-l-Vb (10 mmol, 3.36 g) was
dissolved in a 1:1 mixture of MeOH and HCl (3m, aq., 40 mL of each
solvent) and the mixture was stirred for 3 h at 08C. MeOH was removed
under vacuum keeping the bath at 308C and the resulting aqueous phase
was basified using NaOH (50% solution) (note: the addition was done
slowly to avoid an increase of the temperature. We strongly recommend the
use of an ice bath). The basic phase (pH 14) was extracted with CH2Cl2
(5 Â 20 mL). The combined organic phases were dried over K2CO3 and the
solvent was removed under vacuum to yield the deprotected amide L-Vb as
a white solid (2.3 g, 98% yield). m.p. 134 1358C; 1H NMR(300 MHz,
CDCl3): d ˆ 0.84 (d, J ˆ 6.9 Hz, 3H), 0.89 (d, J ˆ 6.9 Hz, 3H), 2.31 (m, 1H),
2.48 (brs, 3H), 3.31 (d, J ˆ 4.2 Hz, 1H), 3.86 (m, 2H), 5.06 (m, 1H), 7.26
7.40 (m, 5H), 8.04 ppm (brd, J ˆ 6.9 Hz, 1H); 13C NMR(75 MHz, CDCl 3):
d ˆ 16.5, 19.8, 31.2, 56.6, 60.3, 67.5, 127.0 (2C), 128.1, 129.1 (2C), 139.1,
(m, 8H); 13C NMR(75 MHz, CDCl ): d ˆ 12.5, 26.5, 55.4, 56.1, 67.0, 126.6
3
(2C), 127.5, 128.0, 128.2 (2C), 129.0 (2C), 129.1 (2C), 139.0, 139.9,
‡
‡
‡
‡
174.2 ppm; (MALDI-TOF): m/z: 322.184 [M À K] , 306.269 [M À Na] ,
175.2 ppm; (MALDI-TOF): m/z: 275.174 [M À K] , 259,102 [M À Na] ,
‡
‡
284.246 [M À H] .
237.193 [M À H] .
N-1-[(1R)-2-hydroxy-1-phenylethyl]-(2S)-3-methyl-2-{[(4-methylphenyl)-
sulfonyl]amino}butanamide (Ts-l-Vb): TsCl (1 mmol, 194 mg) and Et3N
tert-Butyl N-[(1S)-2-methyl-1-({(1R)-1-phenylethyl]amino}carbonyl)pro-
pyl]carbamate (6): N-Methylmorpholine (NMM, 3.5 mmol, 393 mL) and
Chem. Eur. J. 2003, 9, 4031 4045
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4043

H. Adolfsson et al.
FULL PAPER
isobutylchloroformate (3.5 mmol, 462 mL) were slowly added to a solution
of Boc-l-V (3 mmol, 652 mg) in THF (10 mL) at À158C (a white solid was
formed during the addition of the i-BuOCOCl). The reaction mixture was
stirred for 45 min at À158C, then (R)-1-phenylethylamine (2.8 mmol,
386 mL) was added and the resulting mixture was stirred at room
temperature for an additional 3 h. The mixture was filtered through silica
gel (5 cm, 5 cm Æ) and eluted with ethyl acetate (100 mL). The solvent was
removed under vacuum and the resulting solid was recrystallized from
CH2Cl2/n-pentane, giving the pure product 6 (419 mg, 47% yield). m.p.
125 1268C; 1H NMR(300 MHz, CDCl 3): d ˆ 0.92 (d, J ˆ 6.9 Hz, 3H), 0.97
(d, J ˆ 6.6 Hz, 3H), 1.42 (s, 9H), 1.49 (d, J ˆ 7.2 Hz, 3H), 2.15 (m, 1H), 3.84
(m, 1H), 4.94 5.18 (m, 2H), 6.27 (brd, J ˆ 7.8 Hz, 1H), 7.22 7.38 ppm (m,
5H); 13C NMR(75 MHz, CDCl 3): d ˆ 18.2, 19.6, 22.1, 28.5 (3C), 30.7, 49.0,
60.5, 80.1, 126.3 (2C), 127.6, 128.9 (2C), 143.1, 156.1, 170.8 ppm; (MALDI-
(S)-1-(3-fluorophenyl)ethanol: Rf ˆ 0.20; yield: 0.650 g (93% yield,
89% ee); tR(R isomer) ˆ 7.22 min, tR(S isomer) ˆ 8.12 min. [a]D ˆ À29.6
(c ˆ 0.998 in MeOH) (lit. [a]D ˆ ‡38.5 (c ˆ 0.998 in MeOH)).[23]
(R)-1-(3-fluorophenyl)ethanol: Rf ˆ 0.20; yield: 0.653 g (93% yield,
88% ee); tR(R isomer) ˆ 7.22 min, tR(S isomer) ˆ 8.12 min; [a]D ˆ ‡32.4
(c ˆ 0.998 in MeOH) (lit. [a]D ˆ ‡38.5 (c ˆ 0.998 in MeOH)).[21]
(S)-1-(4-methylphenyl)ethanol: Rf ˆ 0.20; yield: 0.580 g (85% yield,
91% ee); tR(R isomer) ˆ 8.33 min, tR(S isomer) ˆ 9.50 min; [a]D ˆ À40.2
(c ˆ 0.994 in MeOH) (lit. [a]D ˆ À43.5 (c ˆ 0.994 in MeOH)).[20]
(S)-1-(4-methoxyphenyl)ethanol: Rf ˆ 0.11; yield: 0.479 g (63% yield,
95% ee); tR(R isomer) ˆ 11.17 min, tR(S isomer) ˆ 11.21 min.
(R)-1-(4-methoxyphenyl)ethanol: Rf ˆ 0.11; yield: 0.494 g (65% yield,
96% ee); tR(R isomer) ˆ 11.17 min, tR(S isomer) ˆ 11.21 min.
‡
‡
‡
TOF): m/z: 359.181 [M À K] , 343.217 [M À Na] , 321.223 [M À H] .
(S)-1-(4-bromophenyl)ethanol: Rf ˆ 0.15; yield: 0.904 g (90% yield,
88% ee); (CP Chirasil DEX CB, Hold 1108C for 2 mins, rate 18CminÀ1
to 1258C, rate 208CminÀ1 to 2008C and hold for 3 min): tR(R isomer) ˆ
18.73 min, tR(S isomer) ˆ 19.01 min; [a]D ˆ À28.7 (c ˆ 0.436 in MeOH) (lit.
[a]D ˆ ‡31.3 (c ˆ 0.436 in MeOH, R isomer)).[24]
General procedure for the transfer hydrogenation of acetophenone using
the ligand library: Ligand (0.03 mmol), [{RuCl2(p-cymene)}2]
(0.005 mmol),[19] and NaOH (5 mol%) were dissolved in 2-propanol
(5 mL) in a dry Schlenck tube under inert atmosphere (N2). The solution
was stirred for 15 min and acetophenone (1 mmol) was added. The reaction
mixture was stirred at ambient temperature. Aliquots were taken at
different time intervals and quenched with NH4Cl (1 mL, aq. sat.),
extracted with EtOAc (1 mL), passed through a pad of silica and washed
with EtOAc. The resulting solution was analyzed by GLC (CP Chirasil
DEX CB conditions: hold 1108C for 10 min, rate 808CminÀ1 to 2008C and
hold for 5 min): tR(R isomer) ˆ 6.21 min, tR(S isomer) ˆ 6.77 min.
(S)-1-phenylpropan-1-ol: Eluent: pentane/EtOAc 20:1; Rf ˆ 0.17; yield:
0.620 g (91% yield, 95% ee); GLC (CP Chirasil DEX CB, Hold 1108C for
8 mins, rate 808CminÀ1 to 2008C and hold for 5 min): tR(R isomer) ˆ
8.53 min, tR(S isomer) ˆ 8.59 min; [a]D ˆ À32.9 (c ˆ 1.00 in MeOH) (lit.
[a]D ˆ À28 (c ˆ 1 in MeOH)).[25]
(S)-2-methyl-1-phenylpropan-1-ol: Ligand (0.11 mmol), [{RuCl2(p-cym-
ene)}2] (0.050 mmol), and NaOH (10.0 mol%). Eluent: pentane/EtOAc
30:1; Rf ˆ 0.20; yield: 0.396 g (53% yield, 86% ee); (CP Chirasil DEX CB,
Hold 1108C for 20 mins, rate 808CminÀ1 to 2008C and hold for 5 min): tR(R
isomer) ˆ 14.59 min, tR(S isomer) ˆ 14.98 min; [a]D ˆ À46.1 (c ˆ 1.00 in
diethyl ether)(lit. [a]D ˆ À49.1 (c ˆ 0.828 in diethyl ether)).[20]
General procedure for the transfer hydrogenation of aromatic ketones
using Boc-l-Ab and Boc-d-Aa as ligands: Ligand (0.0275 mmol),
[{RuCl2(p-cymene)}2] (0.0125 mmol), and NaOH (2.5 mol%) were dis-
solved in 2-propanol (25 mL) in
a dry Schlenck tube under inert
(S)-1,2,3,4-tetrahydronaphthalen-1-ol: Eluent: pentane:EtOAc 20:1; Rf ˆ
0.36; yield: 0.280 g (38% yield, 84% ee); GLC (CP Chirasil DEX CB, Hold
808C for 10 min, rate 58CminÀ1 to 1108C and hold for 10 min, rate
208CminÀ1 to 2008C and hold for 5 min): tR(R isomer) ˆ 28.89 min, tR(S
isomer) ˆ 29.00 min.
(S)-1-(2-naphthyl)ethanol: Rf ˆ 0.16; yield: 0.620 g (85% yield, 87% ee);
GLC (CP Chirasil DEX CB, Hold 1108C for 20 mins, rate 108CminÀ1 to
2008C and hold for 5 min): tR(R isomer) ˆ 27.42 min, tR(S isomer) ˆ
27.52 min; [a]D ˆ À32.6 (c ˆ 2.00 in MeOH) (lit. [a]D ˆ À25 (c ˆ 2.2 in
MeOH)).[23]
atmosphere (N2). The solution was stirred for 15 min and ketone (5 mmol)
was added. The reaction mixture was stirred at ambient temperature. The
reaction was quenched with NH4Cl (15 mL, aq. sat.) and water (10 mL) and
extracted with EtOAc (4 Â 15 mL). The organic phase was dried with
Na2SO4 and evaporated. Purification was done with Silica column using
pentane/EtOAc (8:1) as eluent. The product alcohol was analyzed by GLC
(CP Chirasil DEX CB, Hold 1108C for 10 min, rate 808CminÀ1 to 2008C
and hold for 5 min).
(S)-1-phenylethanol: Rf ˆ 0.24; Isolated yield: 0.590 g (95% yield,
93% ee); tR(R isomer) ˆ 6.21 min, tR(S isomer) ˆ 6.77 min.
(R)-1-phenylethanol: Rf ˆ 0.24; yield: 0.565 g (91% yield, 93% ee); tR(R
isomer) ˆ 6.21 min, tR(S isomer) ˆ 6.77 min.
Acknowledgements
(S)-1-(2-methylphenyl)ethanol: Ligand (0.055 mmol), [{RuCl2(p-cym-
ene)}2] (0.025 mmol), and NaOH (5.0 mol%). Eluent: pentane/EtOAc
20:1; Rf ˆ 0.16; yield: 0.503 g (74% yield, 96% ee); tR(R isomer) ˆ
10.47 min, tR(S isomer) ˆ 10.76 min; [a]D ˆ À63.0 (c ˆ 1.01 in EtOH) (lit.
[a]D ˆ À58.9 (c ˆ 1.01 in EtOH)).[20]
We are grateful to the Swedish Research Council and the Carl Trygger
Foundation for financial support. I. M. Pastor is grateful to the Wenner
Gren Foundation for a post-doctoral fellowship. We thank Dr. A. B˘gevig
for valuable comments and suggestions.
(R)-1-(2-methylphenyl)ethanol: Ligand (0.055 mmol), [{RuCl2(p-cym-
ene)}2] (0.025 mmol), and NaOH (5.0 mol%). Eluent: pentane/EtOAc
20:1; Rf ˆ 0.16; yield: 0.501 g (74% yield, 96% ee); tR(R isomer) ˆ
10.47 min, tR(S isomer) ˆ 10.76 min; [a]D ˆ ‡61.9 (c ˆ 1.01 in EtOH) (lit.
[a]D ˆ À58.9 (c ˆ 1.01 in EtOH)).[18]
(S)-1-(2-methoxyphenyl)ethanol: Ligand (0.055 mmol), [{RuCl2(p-cym-
ene)}2] (0.025 mmol), and NaOH (5.0 mol%). Eluent: pentane/EtOAc
30:1; Rf ˆ 0.09; yield: 0.430 g (57% yield, 84% ee); (CP Chirasil DEX CB,
Hold 1108C for 2 mins, rate 18CminÀ1 to 1258C, rate 208CminÀ1 to 2008C
and hold for 3 min): tR(S isomer) ˆ 13.23 min, tR(R isomer) ˆ 14.87 min;
[a]D ˆ À23.9 (c ˆ 2.00 in CHCl3) (lit. [a]D ˆ 32.3 (c ˆ 2.00 in CHCl3, R
isomer)).[21]
[1] T. Ohkuma, R. Noyori in Comprehensive Asymmetric Catalysis I
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30, 97 102; b) M. J. Palmer, M. Wills, Tetrahedron: Asymmetry 1999,
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(S)-1-(3-methylphenyl)ethanol: Eluent: pentane/EtOAc 20:1; Rf ˆ 0.11;
yield: 0.606 g (89% yield, 92% ee); tR(R isomer) ˆ 10.07 min, tR(S isomer)
ˆ 10.23 min.
(S)-1-(3-methoxyphenyl)ethanol: Rf ˆ 0.13; yield: 0.645 g (85% yield,
91% ee); (CP Chirasil DEX CB, Hold 1108C for 2 mins, rate 18CminÀ1
to 1258C, rate 208CminÀ1 to 2008C and hold for 3 min): tR(R isomer) ˆ
16.30 min, tR(S-isomer) ˆ 16.99 min. [a]D ˆ À30.9 (c ˆ 1.00 in MeOH) (lit.
[a]D ˆ À34.9 (c ˆ 0.849 in MeOH)).[22]
4044
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 4031 4045

Modular Dipeptide-Analogue Ligands
4031 4045
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¬
¬
¬
¬
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[15] Please observe that only one of two possible diastereomers of the
postulated ruthenium complexes is depicted in Schemes 4 and 5.
[16] In previous reports on (h6-arene)RuII complexes with peptide ligands,
coordination of the amide nitrogen was demonstrated. For some X-ray
[24] K. Naemura, R. Fukuda, M. Murata, M. Konishi, K. Hirose, Y. Tobe,
Tetrahedron: Asymmetry 1995, 6, 2385 2394.
[25] M. Bakker, A. S. Spruijt, F. van Rantwijk, R. A. Sheldon, Tetrahe-
dron: Asymmetry 2000, 11, 1801 1808.
Received: February 28, 2003 [F4900]
Chem. Eur. J. 2003, 9, 4031 4045
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4045