Modular furanoside pseudodipeptides and thioamides, readily available ligand libraries for metal-catalyzed transfer hydrogenation reactions: Scope and limitations

Article abstract of DOI:10.1002/adsc.201100766

Two new highly modular carbohydrate-based, pseudodipeptide and thioamide ligand libraries have been synthesized for the rhodium- and ruthenium-catalyzed asymmetric transfer hydrogenation (ATH) of prochiral ketones. These series of ligands can be prepared efficiently from easily accessible D-xylose and D-glucose. The ligand libraries contain two main ligand structures (pseudodipeptide and thioamide) that have been designed by making systematic modifications to one of the most successful ligand families developed for the ATH. As well as studying the effect of these two ligand structures on the catalytic performance, we also evaluated the effect of modifying several of the ligand parameters. We found that the effectiveness of the ligands at transferring the chiral information in the product can be tuned by correctly choosing the ligand components (ligand structure and ligand parameters). Excellent enantioselectivities (ees up to 99%) were therefore obtained in both enantiomers of the alcohol products using a wide range of substrates. Copyright

Full text of DOI:10.1002/adsc.201100766

FULL PAPERS
DOI: 10.1002/adsc.201100766
Modular Furanoside Pseudodipeptides and Thioamides,
Readily Available Ligand Libraries for Metal-Catalyzed Transfer
Hydrogenation Reactions: Scope and Limitations
Mercedes Coll,a Katrin Ahlford,b Oscar Pꢀmies,a Hans Adolfsson,b,*
and Montserrat Diꢁgueza,*
a
Departament de Quꢂmica Fꢂsica i Inorgꢀnica, Universitat Rovira i Virgili, C/Marcel·lꢂ Domingo s/n, 43007 Tarragona,
Spain
Fax : (+34)-97-755-9563; phone: (+34)-97-755-8780; e-mail: montserrat.dieguez@urv.cat
Department of Organic Chemistry, Stockholm University, Arrheniuslaboratoriet SE-106 91 Stockholm, Sweden
b
Fax : (+46)-(0)8-15-4908; phone: (+46)-(0)8-16-2484; e-mail: hansa@organ.su.se
Received: October 7, 2011; Revised: November 10, 2011; Published online: February 9, 2012
Abstract: Two new highly modular carbohydrate- on the catalytic performance, we also evaluated the
based, pseudodipeptide and thioamide ligand libra- effect of modifying several of the ligand parameters.
ries have been synthesized for the rhodium- and We found that the effectiveness of the ligands at
ruthenium-catalyzed asymmetric transfer hydrogena- transferring the chiral information in the product can
tion (ATH) of prochiral ketones. These series of li- be tuned by correctly choosing the ligand compo-
gands can be prepared efficiently from easily accessi- nents (ligand structure and ligand parameters). Ex-
ble d-xylose and d-glucose. The ligand libraries con- cellent enantioselectivities (ees up to 99%) were
tain two main ligand structures (pseudodipeptide therefore obtained in both enantiomers of the alco-
and thioamide) that have been designed by making hol products using a wide range of substrates.
systematic modifications to one of the most success-
ful ligand families developed for the ATH. As well Keywords: asymmetric catalysis; carbohydrates; ke-
as studying the effect of these two ligand structures tones; rhodium; ruthenium; transfer hydrogenation
Introduction
that of the Ru catalysts.[4] In the mid 1990s, Noyori
and co-workers found that ruthenium h6-arene com-
Fine chemicals and natural product chemistry rely on plexes in combination with vicinal amino alcohol or
enantiomerically pure compounds. The discovery of diamine ligands served as efficient catalysts for the re-
synthetic routes for preparing these compounds is one duction of ketones and ketimines, respectively, under
of the most persistently pursued goals in chemistry. ATH conditions.[5] Since then, many types of chiral li-
Asymmetric catalysis is one of the most attractive ap- gands have been developed, some of which have been
proaches, because it can provide very high reactivity successfully applied in selective transfer hydrogena-
and selectivity, and is environmentally friendly.[1] In tion.[6] In this context, Adolfssonꢃs group reported
this respect, the enantioselective reduction of prochi- that amino acid-derived pseudodipeptides 1[6i,7] and
ral ketones has acquired greater importance, since the thioamides 2[6j,8] (Figure 1) in combination with Ru or
resulting enantioenriched secondary alcohols are key Rh half-sandwich complexes are excellent catalysts
intermediates for the preparation of a large number for the ATH of aryl alkyl ketones. These ligands are
of biologically active compounds.[2] Asymmetric trans- based on the combination of different N-Boc-protect-
fer hydrogenation (ATH) has proven to be an effi- ed a-amino acids and b-amino alcohols (for type 1) or
cient, mild and versatile method for this particular on thioamides (for type 2), respectively. Both showed
transformation, in which the use of molecular hydro- the advantage of possessing a modular ligand building
gen or highly reactive hydride reagents can be avoid- block: the amino acid part.
ed.[3] Nowadays, most transfer hydrogenations are per-
Despite all these important contributions, ligands
formed using transition metal complexes, mainly based on simple starting materials and that have high
based on ruthenium, rhodium or iridium.[3] Recently, modularity still need to be further explored. For this
the use of iron-based catalysts has also shown inter- purpose, carbohydrates are particularly advantageous
esting results, but their scope is still low compared to thanks to their low price and easy modular construc-
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Mercedes Coll et al.
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gands 3 (Figure 1) in which the b-amino alcohol part
is replaced by a readily available sugar b-amino alco-
hol moiety. These new carbohydrate-based pseudodi-
peptide ligands 3 were the first successful sugar-based
ligands applied in the Ru-catalyzed asymmetric trans-
fer hydrogenation of several ketones.[10] Despite this
success, the use of other carbohydrate-based pseudo-
dipeptide ligands or carbohydrate-based thioamides
has yet to be reported. Therefore, a systematic study
of the possibilities offered by carbohydrate-based
pseudodipeptides and thioamides as new ligands for
ATH reactions was persued. To this end, in this paper
we prepared and evaluated two new carbohydrate-
based libraries of 36 potential pseudodipeptides and
36 potential thioamide ligands (Figure 2 and
Figure 3). The first set (ligands L1–L4a–i) is based on
the previous sugar-based pseudodipeptide ligands 3,
in which a 1,3-amino alcohol sugar core was used in-
Figure 1. General structure of pseudodipeptide ligands 1,
thioamide ligands 2 and sugar-based pseudodipeptide li-
gands 3.
tions.[9] Although they have been successfully used in stead of a classical 1,2-amino alcohol motif (Figure 2).
other enantioselective reactions, they have only very In the second set (carbohydrate-thioamide L5–L8a–
recently shown their huge potential as a source of i ligands), the peptide bond in the previous ligands
highly effective chiral ligands in this process.[10,11] In L1–L4a–i was converted to
thioamide group
a
this context and based on previous successful ligands (Figure 3). As well as being prepared from commer-
1, we have recently reported new pseudodipeptide li- cially available d-glucose or d-xylose, both ligand li-
Figure 2. Furanoside pseudodipeptide ligand library L1–L4a–i.
Figure 3. Furanoside-based thioamide ligand library L5–L8a–i.
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Modular Furanoside Pseudodipeptides and Thioamides, Readily Available Ligand Libraries
braries also have the advantage of a flexible ligand Compounds 4–7 were easily made in few steps from
scaffold that enables various ligand parameters to be the corresponding d-xylose or d-glucose.[12] These
easily tuned so that the catalyst performance can be compounds (4–7) were chosen as intermediates for
maximized. With these libraries, then, we investigated preparing ligands because the various elements that
the effect of systematically varying the position of the make it possible to study the position in which the a-
amino acids/thioamide groups at either C-5 (ligands amino acid/thioamide is coupled (at either C-5 or C-
L1/L2 and L5/L6) or C-3 (ligands L3/L4 and L7/L8) 3) and the configuration of C-3 of the sugar amino al-
of the furanoside backbone, the configuration at C-3 cohol can be easily incorporated. Initially, we synthe-
of the furanoside backbone and substituents/configu- sized the pseudodipeptide ligand library L1–L4a–i by
rations (a–i) in the amino acid/thioamide moieties. By coupling a series of N-Boc-protected amino acids with
carefully selecting the ligand components we achieved the corresponding amino alcohols 4–7 using isobutyl
both enantiomers of the desired alcohols in high chloroformate in the presence of N-methylmorpholine
enantioselectivities and activities for a wide range of (Scheme 1, step i).[6i] In this step the desired diversity
substrates.
in the substituents and configuration of the amino
acid part was also attained (a–i). Then, we synthesized
thioamide ligands L5–L8a–h from the previously ob-
tained pseudodipeptide ligands L1–L4a–i in a two-
step procedure. The first step was the benzoylation of
the hydroxy group attached at either C-3 (L1 and L2)
or C-5 (L3 and L4) of the furanoside backbone (8–11,
Scheme 1, step ii). The second step is the formation of
Results and Discussion
Synthesis of Pseudodipeptide L1–L4a–i and
Thioamide L5–L8a–i Ligand Libraries
The sequence for synthesizing pseudodipeptide L1– the desired thioamide ligands L5–L8a–i by treating
L4a–i and thioamide L5–L8a–i ligand libraries is illus- the corresponding benzoyl-protected pseudodipeptide
trated in Scheme 1. These ligand libraries were pre- compounds with Lawessonꢃs reagent (Scheme 1, step
pared from the corresponding easily accessible 1,3- iii).[6j] It should be pointed out that under the condi-
amino alcohol sugar derivatives (4–7, Scheme 1). tions described in this paper Lawessonꢃs reagent was
Scheme 1. Synthesis of pseudodipeptide ligand library L1–L4a–i and thioamide ligand library L5–L8a–i. Reaction conditions:
(i) i-BuOCOCl/NMM/THF/À158C; (ii) BzCl/Py/CH2Cl2/08C to room temperature; (iii) Lawessonꢃs reagent/THF/608C.
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Mercedes Coll et al.
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unable to produce the desired thioamides when tert- ing entries 2–4 we can conclude that the catalyst deac-
butyl groups (e) were present in the a-amino acid tivates quickly under the reaction conditions. This be-
moiety.
haviour can be explained by the previous mechanistic
All the ligands were isolated by purification on studies with pseudodipeptide ligands 1,[7g] which pro-
neutral silica gel (12–87% yield). They were stable at posed compound 12 as the key species responsible for
room temperature and characterized by 1H and the catalytic activity (Figure 4). In this compound,
13C NMR spectroscopy. The spectral assignments (see pseudodipeptide ligands are coordinated to the metal
Experimental Section) were based on information through all of the ligand functionalities. Therefore,
1
from H-1H and 13C-1H correlation measurements and the alcohol functionality and the peptide nitrogen of
were as expected for these C1 ligands.
the ligand coordinate as anions (note that the reaction
proceeds under basic conditions) and the carbamate
binds in a neutral fashion (Figure 4). Our pseudodi-
peptide ligand library L1–L4a–i differs from previous
successful pseudodipeptide ligands 1 in the fact that
1,3-amino alcohols are used instead of the previously
described 1,2-amino alcohols. This change should
result in the formation of a reaction intermediate 12
Asymmetric Transfer Hydrogenation
Asymmetric Transfer Hydrogenation of
Acetophenone
In a first set of experiments, we used the Ru- and Rh- in which the coordination of the alcohol as an alkox-
catalyzed transfer hydrogenation of acetophenone S1 ide forms a six-membered chelate, which is less fav-
to study the potential of both ligand libraries. S1 was
chosen as a model substrate because the reaction was
performed with a wide range of ligands, which ena-
bled the efficiency of the various ligand systems to be
compared directly.[3–5] In all cases, the catalysts were
generated in situ from the corresponding ligand and
either
[RuCl
(p-cymene)]2
or
[RhCl2Cp*]2
ACHTUNGTREN(NUNG III) chloride
[pentamethylcyclopentadienylrhodium
dimer].
Initially we investigated the pseudo-dipeptide
ligand library L1–L4a–i. The results are summarized
in Table 1. Activities and enantioselectivities were
low for both Ru- and Rh-catalytic systems. Compar-
Figure 4. Proposed key reaction intermediate 12 in the ATH
of ketones using pseudodipeptide ligands 1 and L1–L4a–i,
respectively.
Table 1. Selected results for the Ru- and Rh-catalyzed asymmetric transfer hydrogenation reaction of S1 using pseudodipep-
tide ligands L1–L4a–i.[a]
Entry
Ligand
Catalyst precursor
[RuCl2A(p-cymene)2]2
Temperature [8C]
% Conversion (Time [h])[b]
% ee[b]
1
2
3
4
5
6
7
8
L1a
L1a
L1a
L1a
L2a
L2a
L3a
L4a
L1b
L1f
L1h
L1a
L2a
G
G
25
50
50
50
25
50
25
25
50
50
50
25
25
3 (2)
18 (R)
12 (R)
12 (R)
11 (R)
16 (S)
14 (S)
3 (S)
A
U
11 (1)
13 (3)
14 (10)
3 (2)
3 (1)
1 (2)
6 (2)
12 (1)
9 (1)
10 (1)
5 (24)
3 (24)
A
CHTUNGTRENNUNG
A
CHTUNGTRENNUNG
A
CHTUNGTRENNUNG
A
U
A
U
A
U
0
9
A
U
11 (R)
12 (R)
4 (S)
14 (R)
6 (S)
10
11
12
13
A
CHTUNGTRENNUNG
A
U
R
AHCTUNGTRENNUNG
[a]
Reaction conditions: S1 (1 equiv., 0.2M in 2-propanol/THF: 1/1), [RuCl2ACHTUNGRTNE(UNG p-cymene)]2 (0.25 mol%) or [RhCl2Cp*]2
(0.25 mol%), ligand (0.55 mol%), NaO-i-Pr (5 mol%), LiCl (10 mol%) at room temperature.
Conversion and enantiomeric excess was determined by GC (CP Chirasil DEX CB).
[b]
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Modular Furanoside Pseudodipeptides and Thioamides, Readily Available Ligand Libraries
oured than when 1,2-amino alcohols are used (which
form a more stable five-membered chelate), thus fa-
vouring catalyst decomposition after only a few turn-
overs (Figure 4).[13]
In our efforts to improve catalytic performance and
take advantage of our modular ligand systems we
went on to develop and screen the thioamide ligand
library L5–L8a–i. Recently, thioamide-based ligands 2
(Figure 1) have demonstrated their potential utility in
the ATH of several aryl alkyl ketones, affording the
desired alcohols in a range of 59–97% ee.[6j,8] Our new
Figure 5. Proposed key reaction intermediate 13 in the ATH
of ketones using thioamide ligands 2.
ligand library L5–L8a–i was designed on the basis of the effect of the catalyst precursor. We found it had
previous mechanistic studies with successful thio- an important effect on both the activity and enantio-
ACHTUNGTRENNUNGamide ligands 2 that showed that this type of ligand selectivity of the reaction (Table 2, entries 1–8). Re-
coordinates to the metal in a bidentate fashion, sults were best therefore with the catalyst precursor
through the carbamate nitrogen and the thioamide [RhCl2Cp*]2. The other ligands were then screened
sulfur atoms, to form a five-membered ring (Fig- using [RhCl2Cp*]2 as the optimum source of metal.
ure 5).[8a] In order to obtain the same coordination
We then moved on to investigate the effect of the
pattern we developed the thioamide ligands L5–L8a–i ligand parameters on the catalytic performance. The
in which the hydroxy group is protected to prevent its results indicate that enantioselectivity is highly affect-
coordination to the metal in the form of alkoxide. ed by the position of the thioamide group at either C-
The enantioselectivity, then, is expected to be high.
5 or C-3 of the furanoside backbone, the configura-
The results using ligands L5–L8a–i are summarized tion of C-3 and the substituents/configurations in the
in Table 2. With ligands L5–L7a, we first investigated thioamide moiety.
Table 2. Selected results for the Ru- and Rh-catalyzed asymmetric transfer hydrogenation reaction of S1 using thioamide li-
gands L5–L8a–i.[a]
Entry
Ligand
Catalyst precursor
[RuCl2A(p-cymene)2]2
% Conversion (Time [h])[b]
% ee[b]
1
2
3
4
5
6
7
8
L5a
L5a
L6a
L6a
L7a
L7a
L8a
L8a
L5b
L5c
L5d
L5f
L5g
L5h
L5i
G
G
39 (2)
64 (1)
24 (2)
59 (1)
10 (2)
72 (1)
29 (2)
53 (1)
67 (1)
65 (1)
59 (1)
74 (1)
44 (1)
63 (1)
64 (1)
52 (1)
55 (1)
25 (1)
59 (1)
45 (1)
82 (R)
86 (R)
80 (R)
92 (R)
79 (R)
97 (R)
91 (R)
94 (R)
70 (R)
76 (R)
88 (R)
69 (R)
5 (S)
91 (S)
67 (S)
90 (R)
98 (R)
93 (S)
93 (R)
88 (R)
[RhCl2Cp*2]2
[RuCl2A(p-cymene)2]2
[RhCl2Cp*2]2
[RuCl2A(p-cymene)2]2
[RhCl2Cp*2]2
[RuCl2A(p-cymene)2]2
A
CHTUNGTRENNUNG
A
CHTUNGTRENNUNG
A
CHTUNGTRENNUNG
[RhCl2Cp*2]2
[RhCl2Cp*2]2
[RhCl2Cp*2]2
[RhCl2Cp*2]2
[RhCl2Cp*2]2
[RhCl2Cp*2]2
[RhCl2Cp*2]2
[RhCl2Cp*2]2
[RhCl2Cp*2]2
[RhCl2Cp*2]2
[RhCl2Cp*2]2
[RhCl2Cp*2]2
[RhCl2Cp*2]2
9
10
11
12
13
14
15
16
17
18
19[c]
20[c]
L7b
L7d
L7h
L7a
L8a
[a]
Reaction conditions: S1 (1 equiv., 0.2M in 2-propanol/THF: 1/1), [RuCl2ACHTUNGRTNE(UNG p-cymene)]2 (0.25 mol%) or [RhCl2Cp*]2
(0.25 mol%), ligand (0.55 mol%), NaO-i-Pr (5 mol%), LiCl (10 mol%) at room temperature.
Conversion and enantiomeric excess was determined by GC (CP Chirasil DEX CB).
No LiCl was added.
[b]
[c]
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Interestingly, we found a cooperative effect be- by the absolute configuration of the substituent in the
tween the position of the thioamide group and the thioamide moiety (Table 2, entries 2 vs. 14 and 6 vs.
configuration of carbon atom C-3 of the furanoside 18). Both enantiomers of the reduction products can
backbone (Table 2, entries 2, 4, 6 and 8). The results therefore be accessed in high enantioselectivity
indicate that the matched combination is achieved simply by changing the absolute configuration of the
with ligands L7, which have the thioamide moiety at- thioamide substituent.
tached to C-3 and an S configuration of carbon atom
The best results were therefore obtained with li-
C-3 (entry 6).
gands L7a and L7d (Table 2, entries 6 and 17, ees up
We next studied the effect of the substituents and to 98%). Interestingly, catalytic systems Rh-L7a and
configuration of the thioamide moiety with ligands Rh-L7b provided higher enantioselectivities than
L5a–i. Systematic variation of the electronic and those obtained using previously described Rh-2 cata-
steric properties of thioamide substituents indicated lysts (ees up to 96%).[8c]
that enantioselectivities were mainly controlled by the
Finally, we also evaluated the efficiency of these
steric properties of these substituents and were higher catalysts without the addition of LiCl (entries 19 and
when more sterically demanding substituents were 20). The results are in line with the decrease in activi-
present (i.e., i-Buꢀi-Pr>Bn>PhꢀMe). Little effect ty and enantioselectivity previously observed using
of the thioamide substituents on activity was ob- thioamide ligands 2, which, as expected, agrees with a
served. In addition, the presence of a chiral thioamide similar coordination mode and mechanism for the
substituent is crucial if levels of enantioselectivity are asymmetric transfer hydrogenation reaction. The
to be high (Table 2, entries 2, 9–12 vs. 13). We also higher ees obtained using our sugar-based ligands (see
found that the sense of enantioselectivity is governed also results in Table 3, vide infra) are therefore most
Table 3. Selected results for the Rh-catalyzed asymmetric transfer hydrogenation reaction of several aryl-alkyl ketones using
thioamide ligands L5–L8a–i.[a]
Entry
Substrate
R1
R2
Ligand
% Conversion (Time [h])[b]
% ee[b]
1
2
3
4
5
6
7
8
S1
S1
S2
S2
S2
S3
S3
S4
S4
S5
S5
S5
S6
S6
S6
S7
S7
S7
S8
S8
S9
S9
S10
S10
S11
C6H5
C6H5
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
L7a
L7d
L7a
L7d
L7h
L7a
L7d
L7a
L7d
L7a
L7d
L7h
L7a
L7d
L7h
L7a
L7d
L7h
L7a
L7d
L7a
L7d
L7a
L7d
L7a
85 (3)
72 (3)
68 (3)
60 (3)
49 (3)
94 (2)
78 (2)
95 (2)
85 (2)
90 (1)
91 (2)
88 (3)
87 (3)
65 (3)
59 (3)
87 (24)
69 (24)
54 (24)
18 (24)
12 (24)
76 (24)
71 (24)
68 (24)
67 (24)
15 (24)
97 (R)
98 (R)
98 (R)
98 (R)
94 (S)
97 (R)
97 (R)
97 (R)
98 (R)
96 (R)
97 (R)
95 (S)
99 (R)
99 (R)
97 (S)
95 (R)
95 (R)
93 (S)
37 (S)
34 (S)
96 (R)
97 (R)
98 (R)
98 (R)
41 (R)
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Br-C6H4
4-Br-C6H4
4-F-C6H4
9
4-F-C6H4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
4-CF3-C6H4
4-CF3-C6H4
4-CF3-C6H4
1-naphthyl
1-naphthyl
1-naphthyl
3-MeO-C6H4
3-MeO-C6H4
3-MeO-C6H4
2-MeO-C6H4
2-MeO-C6H4
C6H5
C6H5
C6H5
C6H5
Et
i-Pr
i-Pr
Me
4-MeO-C6H4-CH2CH2
[a]
Reaction conditions: ketone (1 equiv., 0.2M in 2-propanol/THF: 1/1), [RhCl2Cp*]2 (0.25 mol%), ligand (0.55 mol%),
NaO-i-Pr (5 mol%), LiCl (10 mol%) at room temperature.
Conversion and enantiomeric excess was determined by GC (CP Chirasil DEX CB).
[b]
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Modular Furanoside Pseudodipeptides and Thioamides, Readily Available Ligand Libraries
likely due to interactions between the ligand and the moiety is advantageous. These results are among the
Cp* of the starting complex when the Rh hydride is best that have been reported.[3]
formed, and/or delivered to the substrate.
Conclusions
Asymmetric Transfer Hydrogenation of Different
Aryl Alkyl Ketones
Two new highly modular carbohydrate-based, pseudo-
dipeptide and thioamide ligand libraries have been
To further study the potential of these readily avail- synthesized for the Rh- and Ru-catalyzed asymmetric
able ligands, we evaluated them in the ATH of other transfer hydrogenation of several ketones. Both
ketones S2–S10. The results are summarized in ligand libraries have the advantage that they can be
Table 3. In general, the trends were the same as for efficiently prepared from commercial a-amino acids,
the ATH of S1. Results were best with ligands L7a d-xylose and d-glucose, inexpensive natural chiral
and L7d. Again, both enantiomers of the secondary feedstocks. These ligand libraries contain two main
alcohol product were accessible in high enantioselec- ligand structures (pseudodipeptides and thioamides)
tivities (ees up to 99%, that is, Table 3, entries 3–5 that have been designed by systematically modifying
and 10–15). We found that activities were best when one of the most successful ligand families developed
electron-withdrawing groups at the para position were for this process. As well as studying the effect of
present (entries 6–12 vs. 3–5). However, enantioselec- these two ligand structures on the catalytic perfor-
tivity was hardly affected by the presence of electron- mance, we also evaluated the effect of modifying sev-
withdrawing or electron-donating groups at the para eral ligand parameters (the position of the amino
position of the phenyl group (entries 1–12). This be- acids/thioamide groups at either C-5 or C-3 of the fur-
haviour contrasts with the electronic effect on enan- anoside backbone, the configuration at C-3 of the fur-
tioselectivity observed for previous thioamide li- anoside backbone and substituents/configurations in
gands.[6j,8] Therefore, several para-substituted aryl ke- the amino acids/thioamide moieties). By carefully se-
tones, including those containing 2-naphthyl groups, lecting the ligand components, we have developed the
can be efficiently reduced using Rh-L7a and Rh-L7d first carbohydrate-based thioamide ligand library that
catalytic systems (ees ranging from 97% to 99%). The provides high enantioselectivity in a broad range of
catalytic performance (activity and enantioselectivity) aryl alkyl ketones (ees up to 99%). It should be noted
of the reaction was influenced by steric factors on the that both enantiomers of alcohol products can be ob-
aryl substituent. Although enantioselectivity was tained with high enantioselectivities by simply chang-
hardly affected by the presence of meta-substituents ing the absolute configuration of the thioamide sub-
in the phenyl group (entries 16 and 17), both activity stituent. This finding represents an improvement to
and enantioselectivity decreased considerably when the previous successfully pseudodipeptide ligands 3.
ortho-substituted aryl ketones were used (entries 19 In contrast to previous successful thioamides, enantio-
and 20). On the other hand, enantioselectivities are selectivity is hardly affected by the presence of elec-
not affected by the steric bulk of the alkyl substituent tron-withdrawing or electron-donating groups, there-
(entries 1 and 2 vs. 21–24). In line with previous re- fore, a range of para- and meta-substituted aryl alkyl
sults using thioamide ligands 2 the reduction of alkyl ketones were efficiently reduced. We have therefore
alkyl ketones proceeds with low conversions and demonstrated that the introduction of a furanoside
enantioselectivities (entry 25).
amino sugar moiety into the ligand design is advanta-
In summary, the modular ligand design (position of geous and it efficiently transfers the chiral informa-
the thioamide group, configuration at C-3 of the fura- tion to the products (ees ranging from 95% to 99% in
noside backbone and the substituents/configurations the reduction of a range of para- and meta-substituted
of the thioamide moieties) has been shown to be aryl alkyl ketones). These results, which are among
highly successful, both in finding highly selective li- the best that have been reported for this process,
gands for almost each substrate, and identifying three open up a new class of readily available ligands for
general ligands L7a, L7d and L7h with good perfor- the highly enantioselective ATH.
mance over the entire range of substrates (ees up to
99%). It should be pointed out that these catalysts
are also very tolerant to the electronic nature of the
Experimental Section
aryl ring and to the steric bulk of the alkyl group. In-
terestingly, when these latter results are compared
with the enantioselectivities obtained with their corre-
sponding non-sugar-based thioamide ligands 2,[14] we
can conclude that introducing a sugar amino alcohol
General Considerations
All reactions were carried out using standard Schlenk tech-
niques under an argon atmosphere. Solvents were purified
and dried by standard procedures. Sugar amino alcohols 4–7
Adv. Synth. Catal. 2012, 354, 415 – 427
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
421

Mercedes Coll et al.
FULL PAPERS
were prepared as previously described.[12] 1H and
13C{1H} NMR spectra were recorded using a 400 MHz spec-
trometer. Chemical shifts are relative to that of SiMe4 (1H
NH), 5.89 (d, 1H, H-1, 3J1,2 =3.6 Hz), 6.86 (m, 1H, NH);
13C NMR (CDCl3): d=21.9 (CH3, i-Bu), 22.8 (CH3, i-Bu),
24.7 (CH2, i-Bu), 26.0 (CH3), 26.8 (CH3), 28.3 (CH3, t-Bu),
37.0 (C-5), 40.5 (CH, i-Bu), 53.1 (CH), 75.6 (C-3), 79.8 (C-
4), 80.3 (C, t-Bu), 84.7 (C-2), 104.8 (C-1), 111.5 (CMe2),
155.8 (CO), 175.0 (CO); anal. calcd. (%) for C19H34N2O7: C
56.70, H 8.51, N 6.96; found: C 56.69, H 8.53, N 6.94.
1
and 13C) as internal standard. H and 13C assignments were
1
made on the basis of H-1H gCOSY and 1H-13C gHSQC.
1
Typical Procedure for the Preparation of
Pseudodipeptide Ligands L1–L4a–i
L1e: Yield: 306 mg (76%); H NMR (CDCl3): d=0.92 (s,
9H, CH3, t-Bu), 1.24 (s, 3H, CH3), 1.38 (s, 9H, CH3, t-Bu),
1.40 (s, 3H, CH3), 3.21 (m, 1H, H-5), 3.69 (m, 1H, H-5’),
To a cooled solution (À158C) of the desired N-Boc-protect-
ed amino acid (1 mmol) in THF (2 mL), N-methylmorpho-
line (NMM, 1.15 mmol, 126 mL) and isobutyl chloroformate
(1.15 mmol, 150 mL) were slowly added. After 45 min, a so-
lution of the desired amino alcohol (1 mmol, 189.2 mg), pre-
viously azeotropically dried with toluene, in THF (2 mL)
was added and the resulting mixture was stirred at room
temperature for 2 h. The crude mixture was purified by flash
chromatography to produce the corresponding ligands as
white solids.
3
3.82 (m, 1H, CH), 3.94 (d, 1H, H-3, J3,4 =2.0 Hz), 4.02 (m,
1H, H-4), 4.51 (d, 1H, H-2, 3J2,1 =3.6 Hz), 5.30 (m, 1H,
NH), 5.84 (d, 1H, H-1, 3J1,2 =3.6 Hz), 7.03 (m, 1H, NH);
13C NMR (CDCl3): d=26.0 (CH3), 26.7 (CH3, t-Bu), 26.8
(CH3), 28.3 (CH3, t-Bu), 34.5 (C, t-Bu), 37.1 (C-5), 62.2
(CH), 73.7 (C-3), 79.7 (C-4), 80.1 (C, t-Bu), 84.8 (C-2), 104.7
(C-1), 111.5 (CMe2), 155.9 (CO), 173.3 (CO); anal. calcd.
(%) for C19H34N2O7: C 56.70, H 8.51, N 6.96; found: C
56.67, H 8.52, N 6.95.
1
L1f: Yield: 249 mg (69%); H NMR (CDCl3): d=1.24 (s,
1
L1a: Yield: 315 mg (81%); H NMR (CDCl3): d=0.91 (d,
3H, CH3), 1.29 (d, 3H, CH3, 3JH,H =7.2 Hz), 1.38 (s, 9H,
CH3, t-Bu), 1.40 (s, 3H, CH3), 3.18 (m, 1H, H-5), 3.74 (m,
3
3
3H, CH3, i-Pr, JH,H =7.2 Hz), 0.94 (d, 3H, CH3, i-Pr, JH,H
=
7.2 Hz), 1.29 (s, 3H, CH3), 1.43 (s, 9H, CH3, t-Bu), 1.46 (s,
3H, CH3), 2.13 (m, 1H, CH, i-Pr), 3.24 (m, 1H, H-5), 3.81
3
1H, H-5’), 3.90 (d, 1H, H-3, J3,4 =2.4 Hz), 3.96 (m, 1H, H-
3
4), 4.09 (m, 1H, CH), 4.51 (d, 1H, H-2, J2,1 =3.6 Hz), 5.00
3
(m, 1H, H-5’), 3.87 (m, 1H, CH), 3.95 (d, 1H, H-3, J3,4
=
3
(m, 1H, NH), 5.84 (d, 1H, H-1, J1,2 =3.6 Hz), 6.91 (m, 1H,
3
2.4 Hz), 4.03 (m, 1H, H-4), 4.56 (d, 1H, H-2, J2,1 =3.6 Hz),
NH); 13C NMR (CDCl3): d=17.9 (CH3), 26.0 (CH3), 26.7
(CH3), 28.3 (CH3, t-Bu), 37.0 (C-5), 50.1 (CH), 73.7 (C-3),
79.8 (C-4), 80.2 (C, t-Bu), 84.7 (C-2), 104.8 (C-1), 111.5
(CMe2), 155.6 (CO), 175.0 (CO); anal. calcd. (%) for
C16H28N2O7: C 53.32, H 7.83, N 7.77; found: C 53.34, H 7.85,
N 7.74.
3
4.99 (m, 1H, NH), 5.89 (d, 1H, H-1, J1,2 =3.6 Hz), 6.72 (m,
1H, NH); 13C NMR (CDCl3): d=19.3 (CH3, i-Pr), 26.0
(CH3), 26.8 (CH3), 28.3 (CH3, t-Bu), 30.3 (CH, i-Pr), 37.1
(C-5), 60.2 (CH), 73.7 (C-3), 78.7 (C, t-Bu), 79.8 (C-4), 84.7
(C-2), 104.8 (C-1), 111.5 (CMe2), 151.2 (CO), 174.1 (CO);
anal. calcd. (%) for C18H32N2O7: C 55.65, H 8.30, N 7.21;
found: C 55.69, H 8.34, N 7.18.
1
L1g: Yield: 250 mg (75%); H NMR (CDCl3): d=1.28 (s,
1
3H, CH3), 1.42 (s, 9H, CH3, t-Bu), 1.44 (s, 3H, CH3), 3.27
L1b: Yield: 334 mg (79%); H NMR (CDCl3): d=1.26 (s,
(m, 1H, H-5), 3.75 (m, 3H, H-5’, CH2), 4.05 (d, 1H, H-3,
3H, CH3), 1.38 (s, 3H, CH3), 1.40 (s, 9H, CH3, t-Bu), 3.22
3
3J3,4 =2.4 Hz), 4.05 (m, 1H, H-4), 4.54 (d, 1H, H-2, J2,1
=
(m, 1H, H-5), 3.78 (m, 2H, H-5ꢃ and H-3), 3.92 (m, 1H, H-
3
3
3.6 Hz), 5.43 (m, 1H, NH), 5.88 (d, 1H, H-1, J1,2 =3.6 Hz),
7.07 (m, 1H, NH); 13C NMR (CDCl3): d=26.0 (CH3), 26.7
(CH3), 28.2 (CH3, t-Bu), 37.3 (C-5), 44.1 (CH2), 73.9 (C-3),
79.6 (C-4), 80.6 (C, t-Bu), 84.8 (C-2), 104.7 (C-1), 111.5
(CMe2), 156.2 (CO), 171.7 (CO); anal. calcd. (%) for
C15H26N2O7: C 52.01, H 7.57, N 8.09; found: C 52.06, H 7.56,
N 8.07.
4), 4.48 (d, 1H, H-2, J2,1 =3.6 Hz), 5.23 (m, 1H, CH), 5.70
3
(m, 1H, NH), 5.82 (d, 1H, H-1, J1,2 =3.6 Hz), 7.00 (m, 1H,
NH), 7.34 (m, 5H, CH=); 13C NMR (CDCl3): d=26.3
(CH3), 26.9 (CH3), 28.5 (CH3, t-Bu), 37.5 (C-5), 58.7 (CH),
74.0 (C-3), 79.8 (C-4), 80.8 (C, t-Bu), 84.9 (C-2), 104.9 (C-1),
111.7 (CMe2), 127.2 (CH=), 128.9 (CH=), 129.3 (CH=),
137.3 (C), 155.4 (CO), 172.9 (CO); anal. calcd (%) for
C21H30N2O7: C 59.70, H 7.16, N 6.63; found: C 59.74, H 7.18,
N 6.59.
1
L1h: Yield: 307 mg (79%); H NMR (CDCl3): d=0.90 (d,
3
3
3H, CH3, i-Pr, JH,H =7.2 Hz), 0.93 (d, 3H, CH3, i-Pr, JH,H
=
1
7.2 Hz), 1.28 (s, 3H, CH3), 1.41 (s, 9H, CH3, t-Bu), 1.44 (s,
3H, CH3), 2.03 (m, 1H, CH, i-Pr), 3.20 (m, 1H, H-5), 3.78
L1c: Yield: 375 mg (86%); H NMR (CDCl3): d=1.28 (s,
3H, CH3), 1.38 (s, 9H, CH3, t-Bu), 1.42 (s, 3H, CH3), 3.02
(m, 2H, CH2, Bn), 3.13 (m, 1H, H-5), 3.70 (m, 1H, H-5’),
3.95 (m, 2H, H-3 and H-4), 4.32 (m, 1H, CH), 4.55 (d, 1H,
H-2, 3J2,1 =3.6 Hz), 5.16 (m, 1H, NH), 5.82 (d, 1H, H-1,
3J1,2 =3.6 Hz), 6.69 (m, 1H, NH), 7.1–7.3 (m, 5H, CH=);
13C NMR (CDCl3): d=26.0 (CH3), 26.7 (CH3), 28.3 (CH3, t-
Bu), 37.2 (C-5), 38.3 (CH2), 55.9 (CH), 73.7 (C-3), 79.6 (C-
4), 80.6 (C, t-Bu), 84.8 (C-2), 104.8 (C-1), 111.5 (CMe2),
127.1 (CH=), 128.7 (CH=), 129.2 (CH=), 136.2 (C), 155.5
(CO), 173.6 (CO); anal. calcd. (%) for C22H32N2O7: C 60.54,
H 7.39, N 6.42; found: C 60.52, H 7.37, N 6.47.
3
(m, 1H, H-5’), 3.95 (m, 1H, CH), 3.98 (d, 1H, H-3, J3,4
=
3
2.4 Hz), 4.02 (m, 1H, H-4), 4.55 (d, 1H, H-2, J2,1 =4.0 Hz),
3
5.23 (m, 1H, NH), 5.87 (d, 1H, H-1, J1,2 =4.0 Hz), 7.21 (m,
1H, NH); 13C NMR (CDCl3): d=18.2 (CH3, i-Pr), 19.5
(CH3, i-Pr), 26.3 (CH3), 26.9 (CH3), 28.5 (CH3, t-Bu), 31.0
(CH, i-Pr), 37.4 (C-5), 60.0 (CH), 74.0 (C-3), 80.0 (C-4), 80.5
(C, t-Bu), 85.0 (C-2), 104.9 (C-1), 111.7 (CMe2), 156.2 (CO),
174.3 (CO); anal. calcd. (%) for C18H32N2O7: C 55.65, H
8.30, N 7.21; found: C 55.71, H 8.36, N 7.16.
1
L1i: Yield: 321 mg (76%); H NMR (CDCl3): d=1.25 (s,
L1d: Yield: 350 mg (87%); 1H NMR (CDCl3): d=0.92
(m, 6H, CH3, i-Bu), 1.29 (s, 3H, CH3), 1.42 (s, 9H, CH3, t-
Bu), 1.45 (s, 3H, CH3), 1.47 (m, 1H, CH2, i-Bu), 1.64 (m,
2H, CH and CH2, i-Bu), 3.22 (m, 1H, H-5), 3.78 (m, 1H, H-
3H, CH3), 1.40 (s, 9H, CH3, t-Bu), 1.42 (s, 3H, CH3), 3.43
(m, 1H, H-5), 3.66 (m, 1H, H-5’), 3.73 (m, 1H, H-3), 3.89
3
(m, 1H, H-4), 4.51 (d, 1H, H-2, J2,1 =3.6 Hz), 5.27 (m, 1H,
CH), 5.72 (m, 1H, NH), 5.76 (d, 1H, H-1, 3J1,2 =3.6 Hz),
6.89 (m, 1H, NH), 7.42 (m, 5H, CH=); 13C NMR (CDCl3):
d=26.4 (CH3), 27.1 (CH3), 28.6 (CH3, t-Bu), 37.8 (C-5), 58.1
3
5’), 3.94 (d, 1H, H-3, J3,4 =2.4 Hz), 4.01 (m, 1H, H-4), 4.05
3
(m, 1H, CH), 4.56 (d, 1H, H-2, J2,1 =3.6 Hz), 4.92 (m, 1H,
422
asc.wiley-vch.de
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 415 – 427

Modular Furanoside Pseudodipeptides and Thioamides, Readily Available Ligand Libraries
(CH), 74.4 (C-3), 79.9 (C-4), 80.3 (C, t-Bu), 84.4 (C-2), 104.3
13C NMR (CDCl3): d=17.8 (CH3, i-Pr), 19.3 (CH3, i-Pr),
(C-1), 112.1 (CMe2), 127.4 (CH=), 128.8 (CH=), 129.2 (CH= 26.1 (CH3), 26.6 (CH3), 28.3 (CH3, t-Bu), 30.5 (CH, i-Pr),
57.4 (C-3), 60.1 (CH and C-5), 77.2 (C-4), 80.0 (C, t-Bu),
84.6 (C-2), 104.4 (C-1), 112.0 (CMe2), 156.0 (CO), 172.7
(CO); anal. calcd. (%) for C18H32N2O7: C 55.65, H 8.30, N
7.21; found: C 55.69, H 8.33, N 7.19.
), 137.4 (C), 155.7 (CO), 172.7 (CO); anal. calcd. (%) for
C21H30N2O7: C 59.70, H 7.16, N 6.63; found: C 59.72, H 7.17,
N 6.61.
1
L2a: Yield: 330 mg (85%); H NMR (CDCl3): d=0.86 (d,
1
3
3
L4a: Yield: 334 mg (86%); H NMR (CDCl3): d=0.88 (d,
3H, CH3, i-Pr, JH,H =7.2 Hz), 0.91 (d, 3H, CH3, i-Pr, JH,H
=
3
3
3H, CH3, i-Pr, JH;H =7.2 Hz), 0.93 (d, 3H, CH3, i-Pr, JH,H
=
7.2 Hz), 1.30 (s, 3H, CH3), 1.39 (s, 9H, CH3, t-Bu), 1.52 (s,
3H, CH3), 2.08 (m, 1H, CH, i-Pr), 3.54 (m, 2H, H-5 and H-
5’), 3.68 (m, 1H, H-3), 3.87 (m, 1H, H-4), 3.93 (m, 1H, CH),
7.2 Hz), 1.31 (s, 3H, CH3), 1.40 (s, 9H, CH3, t-Bu), 1.49 (s,
2
3H, CH33), 2.11 (m, 1H, CH, i-Pr), 3.64 (dd, 1H, H-5, J5,5’
=
3
3
13.2 Hz, J5,4 =2.8 Hz), 3.74 (m, 1H, H-4), 3.81 (dd, 1H, H-5,
2J5,5’ =13.2 Hz, 3J5,4 =2.4 Hz), 3.93 (m, 1H, CH), 4.20 (m,
1H, H-3), 4.59 (dd, 1H, H-2, 3J2,1 =4.0 Hz, 3J2,3 =3.6 Hz),
4.53 (dd, 1H, H-2, J2,1 =4.0 Hz, J2,3 =3.6 Hz), 5.22 (m, 1H,
NH), 5.69 (d, 1H, H-1, 3J1,2 =4.0 Hz), 6.72 (m, 1H, NH);
13C NMR (CDCl3): d=17.8 (CH3, iPr), 19.4 (CH3, i-Pr), 26.4
(CH3), 26.6 (CH3), 28.4 (CH3, t-Bu), 30.8 (CH, iPr), 39.7 (C-
5), 60.2 (CH), 72.9 (C-3), 78.5 (C-4), 79.0 (C-2), 80.1 (C, t-
Bu), 103.8 (C-1), 112.9 (CMe2), 156.0 (CO), 172.9 (CO);
anal. calcd. (%) for C18H32N2O7: C 55.65, H 8.30, N 7.21;
found: C 55.70, H 8.35, N 7.20.
3
5.10 (m, 1H, NH), 5.84 (d, 1H, H-1, J1,2 =4.0 Hz), 6.59 (m,
1H, NH); 13C NMR (CDCl3): d=17.6 (CH3, i-Pr), 19.2
(CH3, i-Pr), 26.3 (CH3), 26.4 (CH3), 28.2 (CH3, t-Bu), 30.5
(CH, i-Pr), 51.3 (C-3), 59.8 (CH), 60.5 (C-5), 78.8 (C-2), 80.1
(C, t-Bu), 80.4 (C-4), 104.1 (C-1), 112.5 (CMe2), 155.8 (CO),
172.8 (CO); anal. calcd. (%) for C18H32N2O7: C 55.65, H
8.30, N 7.21; found: C 55.72, H 8.36, N 7.16.
1
L3a: Yield: 280 mg (72%); H NMR (CDCl3): d=0.93 (m,
6H, CH3, i-Pr), 1.29 (s, 3H, CH3), 1.42 (s, 9H, CH3, t-Bu),
1.50 (s, 3H, CH3), 2.06 (m, 1H, CH, i-Pr), 3.80 (m, 3H, H-5,
H-5’ and CH), 4.31 (m, 1H, H-4), 4.41 (m, 1H, H-3), 4.53
3
Typical Procedure for the Benzoylation of L1–L4a–i
(d, 1H, H-2, J2,1 =4.0 Hz), 5.16 (m, 1H, NH), 5.86 (d, 1H,
H-1, 3J1,2 =4.0 Hz), 7.42 (m, 1H, NH); 13C NMR (CDCl3):
d=18.4 (CH3, i-Pr), 19.5 (CH3, i-Pr), 26.4 (CH3), 26.8 (CH3),
28.5 (CH3, t-Bu), 30.4 (CH, i-Pr), 57.1 (C-3), 59.8 (CH), 60.6
(C-5), 78.0 (C-4), 80.5 (C, t-Bu), 84.7 (C-2), 104.5 (C-1),
112.2 (CMe2), 156.4 (CO), 173.0 (CO): anal. calcd. (%) for
C18H32N2O7: C 55.65, H 8.30, N 7.21; found: C 55.66, H 8.32,
N 7.22.
A solution of benzoyl chloride (1.1 mmol, 130 mL) in di-
chloromethane (0.4 mL) was slowly added to a cooled solu-
tion (08C) of the desired pseudodipeptide (1 mmol) in pyri-
dine (1 mL). The reaction mixture was stirred overnight.
Then ice was added and the mixture was extracted with di-
chloromethane (3ꢅ20 mL), the extract was dried over
MgSO4, evaporated to dryness and the residue purified by
flash chromatography (pentane/ethyl acetate: 2/1) to pro-
duce the corresponding benzoylated product as white solids.
N-(tert-Butoxycarbonyl)-l-valine-(5-amide-3-O-benzoyl-
1,2-O-isopropylidene-a-d-xylofuranose) (8a): Yield: 374 mg
1
L3b: Yield: 346 mg (82%); H NMR (CDCl3): d=1.24 (s,
3H, CH3), 1.40 (s, 9H, CH3, t-Bu), 1.47 (s, 3H, CH3), 3.05
(m, 1H, H-5), 4.08 (m, 2H, H-5ꢃ and H-3), 4.28 (m, 1H, H-
3
4), 4.57 (m, 1H, CH), 4.60 (d, 1H, H-2, J2,1 =3.6 Hz), 5.19
3
1
(m, 1H, NH), 5.88 (d, 1H, H-1, J1,2 =3.6 Hz), 7.34 (m, 5H,
(76%); H NMR (400 MHz, CDCl3): d=0.89 (d, 3H, CH3,
J=6.8 Hz), 0.95 (d, 3H, CH3, J=6.8 Hz), 1.33 (s, 3H, CH3),
CH=), 7.51 (m, 1H, NH); 13C NMR (CDCl3): d=26.4
(CH3), 26.9 (CH3), 28.5 (CH3, t-Bu), 57.8 (C-3), 59.2 (CH),
60.0 (C-5), 77.7 (C-4), 80.6 (C, t-Bu), 84.4 (C-2), 104.5 (C-1),
112.2 (CMe2), 127.3 (CH=), 128.7 (CH=), 129.2 (CH=),
137.6 (C), 155.6 (CO), 171.6 (CO); anal. calcd. (%) for
C21H30N2O7: C 59.70, H 7.16, N 6.63; found: C 59.76, H 7.19,
N 6.61.
1.44 (s, 9H, CH3), 1.53 (s, 3H, CH3), 2.16 (m, 1H, CH), 3.58
(t, 2H, H-5, H-5’, 3J5,5’-4 =6.4 Hz), 3.95 (t, 1H, CH-NH,
3
J
CH,NH =6.8 Hz), 4.43 (dt, 1H, H-4, 3J4-5,5’ =6.6 Hz, J4,3
=
2.8 Hz), 4.68 (d, 1H, H-2, 3J2,1 =3.6 Hz), 5.09 (d, 1H,
NHBoc, JNH,CH =9.2 Hz), 5.42 (d, 1H, H-3, 3J3,4 =2.8 Hz),
3
6.00 (d, 1H, H-1, J1,2 =3.6 Hz), 6.41 (b, 1H, NH), 7.44–8.15
L3d: Yield: 322 mg (80%); 1H NMR (CDCl3): d=0.93
(m, 6H, CH3, i-Bu), 1.30 (s, 3H, CH3), 1.42 (s, 9H, CH3, t-
Bu), 1.48 (s, 3H, CH3), 1.51 (m, 1H, CH2, i-Bu), 1.64 (m,
2H, CH and CH2, i-Bu), 3.76 (m, 2H, H-5 and CH), 3.80
(m, 1H, H-5’), 4.29 (m, 1H, H-4), 4.39 (m, 1H, H-3), 4.51
(m, 5H, CH=); 13C NMR (100 MHz, CDCl3): d=17.9
(CH3), 19.5 (CH3), 26.4 (CH3), 26.8 (CH3), 28.5 (CH3), 31.1
(CHMe2), 37.9 (C-5), 60.0 (CH), 77.0 (C-3), 78.2 (C-4), 83.8
(C-2), 104.9 (C-1), 112.6 (CMe2), 128.6–134.0 (CH=), 156.0
(CMe3), 165.7 (CO), 171.9 (CO).
3
(d, 1H, H-2, J2,1 =4.0 Hz), 5.11 (m, 1H, NH), 5.79 (d, 1H,
N-(tert-Butoxycarbonyl)-l-phenylglycine-(5-amide-3-O-
benzoyl-1,2-O-isopropylidene-a-d-xylofuranose) (8b): Yield:
H-1, 3J1,2 =4.0 Hz), 7.37 (m, 1H, NH); 13C NMR (CDCl3):
d=21.8 (CH3, i-Bu), 22.7 (CH3, i-Bu), 24.7 (CH2, i-Bu), 26.4
(CH3), 26.9 (CH3), 28.4 (CH3, t-Bu), 40.4 (CH, i-Bu), 57.0
(C-3), 59.7 (CH), 60.3 (C-5), 78.2 (C-4), 80.6 (C, t-Bu), 84.9
(C-2), 103.9 (C-1), 112.4 (CMe2), 156.2 (CO), 174.1 (CO);
anal. calcd. (%) for C19H34N2O7: C 56.70, H 8.51, N 6.96;
found: C 56.67, H 8.52, N 6.95.
1
337 mg (64%); H NMR (400 MHz, CDCl3): d=1.31 (s, 3H,
CH3), 1.40 (s, 9H, CH3), 1.51 (s, 3H, CH3), 3.44 (m, 1H, H-
5’), 3.63 (m, 1H, H-5), 4.37 (sp, 1H, H-4), 4.63 (d, 1H, H-2,
3
3J2,1 =4 Hz), 5.18 (a, 1H, CH-NH), 5.26 (d, 1H, H-3, J3,4
=
3
2.8 Hz), 5.92 (a, 1H, NHBoc), 5.95 (d, 1H, H-1, J1,2 =4 Hz),
6.42 (a, 1H, NH), 7.27–8.11 (m, 10H, CH=); 13C NMR
(100 MHz, CDCl3): d=26.4 (CH3), 26.8 (CH3), 28.4 (CH3),
38.4 (C-5), 58.7 (CH-NH), 76.9 (C-3), 78.1 (C-4), 83.6 (C-2),
104.8 (C-1), 112.5 (CMe2), 127.3–133.9 (CH=), 138.4 (CAr),
155.3 (CMe3) 165.6 (CO), 170.6 (CO).
1
L3h: Yield: 319 mg (82%); H NMR (CDCl3); d=0.90 (d,
3
3
3H, CH3, JH,H =7.2 Hz), 0.97 (d, 3H, CH3, JH,H =7.2 Hz),
1.29 (s, 3H, CH3), 1.43 (s, 9H, CH3, t-Bu), 1.49 (s, 3H, CH3),
2.11 (m, 1H, CH, i-Pr), 2.77 (m, 1H, H-5), 3.83 (d, 1H, H-3,
3J3,4 =1.2 Hz), 3.89 (m, 2H, H-5’ and H-4), 4.32 (m, 1H,
CH), 4.55 (d, 1H, H-2, 3J2,1 =3.6 Hz), 5.18 (m, 1H, NH),
5.88 (d, 1H, H-1, 3J1,2 =3.6 Hz), 7.52 (m, 1H, NH);
N-(tert-Butoxycarbonyl)-l-phenylalanine-(5-amide-3-O-
benzoyl-1,2-O-isopropylidene-a-d-xylofuranose) (8c): Yield:
1
260 mg (48%); H NMR (400 MHz, CDCl3): d=1.33 (s, 3H,
Adv. Synth. Catal. 2012, 354, 415 – 427
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
423

Mercedes Coll et al.
FULL PAPERS
CH3), 1.40 (s, 9H, CH3), 1.56 (s, 3H, CH3),3.04 (m, 2H, H-8,
N-(tert-Butoxycarbonyl)-d-valine-(5-amide-3-O-benzoyl-
1,2-O-isopropylidene-a-d-xylofuranose) (8h): Yield: 305 mg
(62%); H NMR (400 MHz, CDCl3): d=0.91 (d, 6H, CH3,
H-8’), 3.38 (m, 1H, H-5’), 3.59 (m, 1H, H-5), 4.24 (m, 1H,
3
1
H-4), 4.37 (a, 1H, CH-NH), 4.63 (d, 1H, H-2, J2,1 =4 Hz),
5.14 (m, 1H, H-3), 5.27 (a, 1H, NHBoc), 5.95 (d, 1H, H-1,
3J1,2 =3.6 Hz), 6.37 (a, 1H, NH), 7.20–8.11 (m, 10H, CH=);
13C NMR (100 MHz, CDCl3): d=26.3 (CH3), 26.8 (CH3),
28.4 (CH3), 37.6 (C-5), 39.0 (CH2), 56.2 (CH-NH), 76.8 (C-
3), 77.9 (C-4), 83.7 (C-2), 104.8 (C-1), 112.5 (CMe2), 127.1–
133.9 (CH=), 136.8 (CAr), 155.6 (CMe3) 165.7 (CO), 171.7
(CO).
J=6.8 Hz), 1.30 (s, 3H, CH3), 1.41 (s, 9H, CH3), 1.49 (s, 3H,
CH3), 2.06 (m, 1H, CH), 3.53 (m, 1H, H-5’), 3.66 (m, 1H,
H-5), 3.96 (t, 1H, CH-NH, JCH,NH =7.8 Hz), 4.59 (sp, 1H, H-
3
3
4), 4.65 (d, 1H, H-2, J2,1 =4 Hz), 5.43 (d, 1H, H-3, J3,4
=
2.4 Hz), 5.46 (d, 1H, NHBoc, J=8.4 Hz), 5.96 (d, 1H, H-1,
3J1,2 =4 Hz), 6.81 (a, 1H, NH), 7.40–8.09 (m, 5H, CH=);
13C NMR (100 MHz, CDCl3): d=18.1 (CH3), 19.3 (CH3),
26.3 (CH3), 26.7 (CH3), 28.4 (CH3), 31.1 (CHMe2), 38.0 (C-
5), 60.2 (CH), 76.9 (C-3), 77.9 (C-4), 83.7 (C-2), 104.8 (C-1),
112.5 (CMe2), 128.4–133.8 (CH=), 156.2 (CMe3), 165.6
(CO), 170.4 (CO).
N-(tert-Butoxycarbonyl)-l-leucine-(5-amide-3-O-benzoyl-
1,2-O-isopropylidene-a-d-xylofuranose) (8d): Yield: 213 mg
1
(42%); H NMR (400 MHz, CDCl3): d=0.94 (dd, 6H, CH3,
J=8 Hz, J=4 Hz), 1.34 (s, 3H,CH3), 1.45 (s, 9H, CH3), 1.55
(s, 3H, CH3), 1.66 (m, 3H, CH2, CH), 3.59 (t, 2H, H-5, H-5’,
N-(tert-Butoxycarbonyl)-d-phenylglycine-(5-amide-3-O-
benzoyl-1,2-O-isopropylidene-a-d-xylofuranose) (8i): Yield:
337 mg (64%); 1H NMR (400 MHz, CDCl3): d=1.31 (s,
3H,CH3), 1.40 (s, 9H, CH3), 1.48 (s, 3H, CH3), 3.45 (m, 1H,
3
3J=6 Hz), 4.13 (a, 1H, CH-NH), 4.32 (dt, 1H, H-4, J4-5,5’
=
3
3
6.5 Hz, J4,3 =3 Hz), 4.69 (d, 1H, H-2, J2,1 =3.6 Hz), 4.84 (a,
1H, NHBoc), 5.42 (d, 1H, H-3, J3,4 =2.8 Hz), 6.01 (d, 1H,
3
3
3
H-1, J1,2 =3.6 Hz), 6.48 (t, 1H, NH, J=6 Hz), 7.45–8.12 (m,
H-5’), 3.64 (m, 1H, H-5), 4.36 (dt, 1H, H-4, J4-5,5’ =6.5 Hz,
5H, CH=); 13C NMR (100 MHz, CDCl3): d=22.1 (CH3),
23.2 (CH3), 25.0 (CH2), 26.4 (CH3), 26.8 (CH3), 28.5 (CH3),
38.2 (C-5), 41.6 (CHMe2), 56.8 (CH-NH), 77.4 (C-3), 78.2
(C-4), 83.8 (C-2), 104.9 (C-1), 112.6 (CMe2), 128.7–133.9
(CH=), 150.4 (CMe3), 165.5 (CO), 172.9 (CO).
3J4,3 =2.8 Hz), 4.65 (d, 1H, H-2, 3J2,1 =4 Hz), 5.16 (a, 1H,
CH-NH), 5.39 (d, 1H, H-3, 3J3,4 =3.2 Hz), 5.88 (d, 1H,
3
NHBoc, J=7.2 Hz), 5.94 (d, 1H, H-1, J1,2 =3.2 Hz), 6.42 (t,
1H, NH, J=5.6 Hz), 7.27–8.10 (m, 10H, CH=); 13C NMR
(100 MHz, CDCl3): d=26.4 (CH3), 26.8 (CH3), 28.4 (CH3),
38.1 (C-5), 58.6 (CH-NH), 76.9 (C-3), 77.8 (C-4), 83.6 (C-2),
104.8 (C-1), 112.5 (CMe2), 127.3–133.9 (CH=), 138.3 (CAr),
155.3 (CMe3) 165.8 (CO), 170.2 (CO).
N-(tert-Butoxycarbonyl)-l-tert-leucine-(5-amide-3-O-ben-
zoyl-1,2-O-isopropylidene-a-d-xylofuranose) (8e): Yield:
1
400 mg (79%); H NMR (400 MHz, CDCl3): d=0.98 (s, 9H,
CH3), 1.30 (s, 3H,CH3), 1.41 (s, 9H, CH3), 1.51 (s, 3H,
CH3), 3.51 (m, 1H, H-5’), 3.62 (m, 1H, H-5), 3.91 (d, 1H,
CH-NH, J=9.6 Hz), 4.43 (m, 1H, H-4), 4.66 (d, 1H, H-2,
3J2,1 =4 Hz), 5.40 (d, 1H, H-3, 3J3,4 =2.4 Hz), 5.45 (m, 1H,
N-(tert-Butoxycarbonyl)-l-valine-(5-amide-3-O-benzoyl-
1,2-O-isopropylidene-a-d-ribofuranose) (9a): Yield: 374 mg
(76%); H NMR (400 MHz, CDCl3): d=0.89 (d, 3H, CH3,
J=8 Hz), 0.95 (d, 3H, CH3, J=4 Hz), 1.33 (s, 3H, CH3),
1.45 (s, 9H, CH3), 1.56 (s, 3H, CH3), 2.15 (m, 1H, CH), 3.52
1
3
NHBoc), 5.98 (d, 1H, H-1, J1,2 =4 Hz), 6.46 (m, 1H, NH),
7.41–8.16 (m, 5H, CH=); 13C NMR (100 MHz, CDCl3): d=
26.4 (CH3), 26.7 (CH3), 26.8 (CH3), 28.4 (CH3), 37.8 (C-5),
62.5 (CH-NH), 77.0 (C-3), 78.1 (C-4), 83.7 (C-2), 104.8 (C-
1), 112.5 (CMe2), 128.4–134.7 (CH=), 156.0 (CMe3), 165.7
(CO), 169.9 (CMe3), 171.4 (CO).
(m, 1H, H-5’), 3.76 (m, 1H, H-5), 3.93 (t, 1H, CH-NH,
3
J
CH,NH =6 Hz), 4.36 (sp, 1H, H-4), 4.71 (dd, 1H, H-3, J3,2
=
3
3
8 Hz , J3,4 =4 Hz), 4.94 (t, 1H, H-2, J2-1,3 =6 Hz), 5.00 (a,
1H, NHBoc), 5.85 (d, 1H, H-1, 3J1,2 =4 Hz), 6.26 (a, 1H,
NH), 7.43–8.09 (m, 5H, CH=); 13C NMR (100 MHz,
CDCl3): d=17.5 (CH3), 19.5 (CH3), 26.7 (CH3), 28.5 (CH3),
31.0 (CHMe2), 39.7 (C-5), 60.1 (CH), 73.7 (C-3), 76.4 (C-4),
77.7 (C-2), 104.3 (C-1), 113.4 (CMe2), 128.6–133.7 (CH=),
149.8 (CMe3), 166.1 (CO), 172.0 (CO).
N-(tert-Butoxycarbonyl)-l-alanine-(5-amide-3-O-benzoyl-
1,2-O-isopropylidene-a-d-xylofuranose) (8f): Yield: 293 mg
(63%); 1H NMR (400 MHz, CDCl3): d=1.31 (s, 3H,CH3),
1.34 (d, 3H, CH3, J=7.2 Hz), 1.43 (s, 9H, CH3), 1.52 (s, 3H,
CH3), 3.59 (m, 2H, H-5, H-5’), 4.19 (a, 1H, CH-NH), 4.44
N-(tert-Butoxycarbonyl)-l-valine-(3-amide-5-O-benzoyl-
3
3
(dt, 1H, H-4, J4-5,5’ =6.4 Hz, J4,3 =2.6 Hz), 4.67 (d, 1H, H-2,
1,2-O-isopropylidene-a-d-xylofuranose)
(10a):
Yield:
3J2,1 =3.6 Hz), 5.20 (a, 1H, NHBoc), 5.42 (d, 1H, H-3, J3,4
=
251 mg (51%); H NMR (400 MHz, CDCl3): d=0.86 (d, 3H,
CH3, J=4 Hz), 0.95 (d, 3H, CH3, J=8 Hz), 1.33 (s, 3H,
CH3), 1.45 (s, 9H, CH3), 1.55 (s, 3H, CH3), 2.21 (m, 1H,
CH), 3.86 (t, 1H, CH-NH, JCH,NH =8 Hz), 4.49 (m, 1H, H-3),
3
1
3
2.4 Hz), 5.99 (d, 1H, H-1, J1,2 =4 Hz), 6.74 (t, 1H, NH, J=
5.6 Hz), 7.42–8.11 (m, 5H, CH=); 13C NMR (100 MHz,
CDCl3): d=18.6 (CH3), 26.3 (CH3), 26.8 (CH3), 28.4 (CH3),
38.0 (C-5), 50.3 (CH), 76.9 (C-3), 78.1 (C-4), 83.7 (C-2),
104.9 (C-1), 112.5 (CMe2), 128.5–133.9 (CH=), 155.7
(CMe3), 165.7 (CO), 171.4 (CO).
3
4.52 (d, 1H, H-2, J2,1 =4 Hz), 4.60 (m, 1H, H-4), 4.66 (dd,
2H, H-5, H-5’, 2J5,5’ =8 Hz , 3J5,5-4 =4 Hz), 4.86 (a, 1H,
3
NHBoc), 5.90 (d, 1H, H-1, J1,2 =4 Hz), 6.41 (d, 1H, NH,
N-(tert-Butoxycarbonyl)-l-glycine-(5-amide-3-O-benzoyl-
1,2-O-isopropylidene-a-d-xylofuranose) (8g): Yield: 198 mg
(44%); 1H NMR (400 MHz, CDCl3): d=1.32 (s, 3H,CH3),
1.45 (s, 9H, CH3), 1.53 (s, 3H, CH3), 3.59 (m, 2H, H-5, H-
J=8 Hz), 7.44–8.11 (m, 5H, CH=); 13C NMR (100 MHz,
CDCl3): d=17.8 (CH3), 19.6 (CH3), 26.3 (CH3), 26.7 (CH3),
28.4 (CH3), 29.8 (CHMe2), 55.7 (C-5), 59.6 (CH), 62.0 (C-3),
76.1 (C-4), 84.6 (C-2), 104.7 (C-1), 112.5 (CMe2), 128.6–
133.4 (CH=), 146.9 (CMe3), 166.2 (CO), 171.7 (CO).
3
5’), 3.78 (m, 2H, CH2-NH), 4.43 (dt, 1H, H-4, J4-5,5’ =6.4 Hz,
3
3J4,3 =3.2 Hz), 4.68 (d, 1H, H-2, J2,1 =3.6 Hz), 5.16 (t, 1H,
N-(tert-Butoxycarbonyl)-l-phenylglycine-(3-amide-5-O-
3
NHBoc, J=5.6 Hz), 5.43 (d, 1H, H-3, J3,4 =2.8 Hz), 5.99 (d,
benzoyl-1,2-O-isopropylidene-a-d-xylofuranose)
Yield: 342 mg (65%); H NMR (400 MHz, CDCl3): d=1.27
(10b):
3
1
1H, H-1, J1,2 =3.6 Hz), 6.52 (a, 1H, NH), 7.43–8.02 (m, 5H,
CH=); 13C NMR (100 MHz, CDCl3): d=26.1 (CH3), 26.6
(CH3), 28.3 (CH3), 37.7 (C-5), 44.2 (CH2-NH), 76.8 (C-3),
77.9 (C-4), 83.6 (C-2), 104.5 (C-1), 112.4 (CMe2), 128.0–
133.8 (CH=), 165.5 (CO), 169.6 (CO).
(s, 3H,CH3), 1.41 (s, 9H, CH3), 1.52 (s, 3H, CH3), 4.39 (s,
3
1H, H-2), 4.53 (d, 1H, H-3, J3,4 =6 Hz), 4.58 (m, 1H, H-4),
2
3
4.63 (dd, 2H, H-5, H-5’, J5,5’ =8.8 Hz, J5,5’-4 =3.2 Hz), 5.19
(a, 1H, CH-NH), 5.71 (a, 1H, NHBoc), 5.77 (s, 1H, H-1),
424
asc.wiley-vch.de
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 415 – 427

Modular Furanoside Pseudodipeptides and Thioamides, Readily Available Ligand Libraries
3
6.66 (a, 1H, NH), 7.29–8.12 (m, 10H, CH=); 13C NMR
(100 MHz, CDCl3): d=26.3 (CH3), 26.7 (CH3), 28.4 (CH3),
56.2 (C-5), 59.2 (CH-NH), 62.0 (C-3), 76.2 (C-4), 84.4 (C-2),
104.6 (C-1), 112.5 (CMe2), 127.3–133.7 (CH=), 137.5 (CAr),
155.6 (CMe3) 166.3 (CO), 170.7 (CO).
1H, CH-NH), 4.63 (sp, 1H, H-4), 4.70 (d, 1H, H-2, J2,1 =
3
4 Hz), 5.26 (a, 1H, NHBoc), 5.42 (d, 1H, H-3, J3,4 =2.8 Hz),
6.01 (d, 1H, H-1, J1,2 =4 Hz), 7.45–8.04 (m, 5H, CH=), 8.25
3
(m, 1H, NH); 13C NMR (100 MHz, CDCl3): d=17.9 (CH3),
19.8 (CH3), 26.4 (CH3), 26.8 (CH3), 28.5 (CH3), 33.5
(CHMe2), 43.8 (C-5), 55.7 (CH), 76.4 (C-4), 77.2 (C-3), 83.7
(C-2), 104.9 (C-1), 112.7 (CMe2), 128.8–134.2 (CH=), 155.8
(CMe3), 165.8 (CO), 205.2 (CS); anal. calcd. (%) for
C25H36N2O7S: C 59.03, H 7.13, N 5.51, S 6.30; found: C
59.00, H 7.08, N 5.49, S 6.28.
N-(tert-Butoxycarbonyl)-l-leucine-(3-amide-5-O-benzoyl-
1,2-O-isopropylidene-a-d-xylofuranose)
(10d):
Yield:
1
288 mg (57%); H NMR (400 MHz, CDCl3): d=0.86 (d, 3H,
CH3, J=4 Hz), 0.95 (d, 3H, CH3, J=8 Hz), 1.33 (s, 3H,
CH3), 1.45 (s, 9H, CH3), 1.55 (s, 3H, CH3), 1.66 (m, 3H,
CH2, CH), 3.86 (t, 1H, CH-NH, JCH,NH =8 Hz), 4.49 (m, 1H,
1
L5b: Yield: 287 mg (66%); H NMR (400 MHz, CDCl3):
d=1.32 (s, 3H, CH3), 1.42 (s, 9H, CH3), 1.51 (s, 3H, CH3),
3
H-3), 4.52 (d, 1H, H-2, J2,1 =4 Hz), 4.60 (m, 1H, H-4), 4.66
2
3
(dd, 2H, H-5, H-5’, J5,5’ =8 Hz , J5,5’-4 =4 Hz), 4.86 (a, 1H,
3.83 (m, 1H, H-5’), 4.11 (m, 1H, H-5), 4.59 (m, 1H, H-4),
3
3
4.66 (d, 1H, H-2, 3J2,1 =4 Hz), 5.31 (d, 1H, H-3, J3,4
=
=
NHBoc), 5.90 (d, 1H, H-1, J1,2 =4 Hz), 6.41 (d, 1H, NH,
J=8 Hz), 7.44–8.11 (m, 5H, CH=); 13C NMR (100 MHz,
CDCl3): d=22.1 (CH3), 23.2 (CH3), 26.3 (CH3), 27.2 (CH3),
28.4 (CH3), 32.8 (CHMe2), 55.7 (C-5), 59.6 (CH), 62.0 (C-3),
76.1 (C-4), 84.6 (C-2), 104.7 (C-1), 112.5 (CMe2), 128.6–
133.4 (CH=), 146.9 (CMe3), 166.2 (CO), 171.7 (CO).
3
2.4 Hz), 5.47 (a, 1H, CH-NH), 5.97 (d, 1H, H-1, J1,2
3.6 Hz), 6.16 (d, 1H, NHBoc, J=6.4 Hz), 7.27–8.12 (m,
10H, CH=), 8.41 (a, 1H, NH); 13C NMR (100 MHz, CDCl3):
d=26.4 (CH3), 26.8 (CH3), 28.4 (CH3), 44.2 (C-5), 64.0 (CH-
NH), 76.4 (C-4), 77.1 (C-3), 83.6 (C-2), 104.8 (C-1), 112.7
(CMe2), 127.1–133.9 (CH=), 139.5 (CAr), 154.9 (CMe3)
165.7 (CO), 202.9 (CS); anal. calcd. (%) for C28H34N2O7S: C
61.97, H 6.32, N 5.16, S 5.91; found: C 61.92, H 6.30, N 5.18,
S 5.88.
N-(tert-Butoxycarbonyl)-d-valine-(3-amide-5-O-benzoyl-
1,2-O-isopropylidene-a-d-xylofuranose)
290 mg (59%); H NMR (400 MHz, CDCl3): d=0.88 (d, 6H,
(10h):
Yield:
1
CH3, J=6.8 Hz), 1.30 (s, 3H, CH3), 1.44 (s, 9H, CH3), 1.53
1
(s, 3H, CH3), 2.03 (m, 1H, CH), 3.88 (t, 1H, CH-NH,
L5c: Yield: 361 mg (81%); H NMR (400 MHz, CDCl3):
3
J
CH,NH =8 Hz), 4.42 (m, 1H, H-3), 4.50 (d, 1H, H-2, J2,1
=
=
d=1.34 (s, 3H,CH3), 1.42 (s, 9H, CH3), 1.57 (s, 3H, CH3),
3.10 (m, 1H, H-8’), 3.20 (m, 1H, H-8), 3.67 (m, 1H, H-5’),
4.00 (m, 1H, H-5), 4.31 (m, 1H, H-4), 4.56 (a, 1H, CH-NH),
4.64 (d, 1H, H-2, J2,1 =4 Hz), 5.01 (m, 1H, H-3), 5.43 (a,
1H, NHBoc), 5.94 (d, 1H, H-1, J1,2 =4 Hz), 7.23–8.09 (m,
2
4 Hz), 4.60 (m, 1H, H-4), 4.68 (dd, 2H, H-5, H-5’, J5,5’
9.4 Hz , 3J5,5’-4 =3.4 Hz), 5.27 (d, 1H, NHBoc, J=7.6 Hz),
5.93 (d, 1H, H-1, 3J1,2 =3.6 Hz), 6.79 (d, 1H, NH, J=
8.4 Hz), 7.41–8.12 (m, 5H, CH=); 13C NMR (100 MHz,
CDCl3): d=17.8 (CH3), 19.3 (CH3), 26.1 (CH3), 26.5 (CH3),
28.3 (CH3), 30.6 (CHMe2), 55.6 (C-5), 60.4 (CH), 62.1 (C-3),
75.9 (C-4), 84.5 (C-2), 104.6 (C-1), 112.2 (CMe2), 128.4–
133.4 (CH=), 156.2 (CMe3), 166.1 (CO), 172.1 (CO).
3
3
10H, CH=), 7.80 (a, 1H, NH); 13C NMR (100 MHz, CDCl3):
d=26.4 (CH3), 26.9 (CH3), 28.5 (CH3), 42.4 (CH2), 43.3 (C-
5), 60.6 (CH-NH), 76.3 (C-4), 77.4 (C-3), 83.8 (C-2), 104.8
(C-1), 112.8 (CMe2), 127.3–134.1 (CH=), 136.8 (CAr), 155.2
(CMe3) 165.9 (CO), 204.2 (CS); anal. calcd. (%) for
C29H36N2O7S: C 62.57, H 6.52, N 5.03, S 5.76; found: C
62.54, H 6.49, N 4.98, S 5.71.
N-(tert-Butoxycarbonyl)-l-valine-(3-amide-5-O-benzoyl-
1,2-O-isopropylidene-a-d-ribofuranose) (11a): Yield: 399 mg
1
(81%); H NMR (400 MHz, CDCl3): d=0.95 (d, 3H, CH3,
J=8 Hz), 1.00 (d, 3H, CH3, J=4 Hz), 1.38 (s, 3H, CH3),
1.47 (s, 9H, CH3), 1.59 (s, 3H, CH3), 2.17 (m, 1H, CH), 3.99
(a, 1H, CH-NH), 4.09 (m, 1H, H-4), 4.3 (dd, 1H, H-5’,
L5d: Yield: 96 mg (23%); 1H NMR (400 MHz, CDCl3):
d=0.94 (dd, 6H, CH3, J=6.2 Hz, J=1.8 Hz), 1.33 (s,
3H,CH3), 1.44 (s, 9H, CH3), 1.54 (s, 3H, CH3), 1.58–1.74 (m,
3H, CH2, CH), 3.93 (m, 1H, H-5’), 4.06 (m, 1H, H-5), 4.39
(m, 1H, CH-NH), 4.62 (sp, 1H, H-4), 4.70 (d, 1H, H-2,
3J2,1 =4 Hz), 5.13 (d, 1H, NHBoc, J=7.6 Hz), 5.42 (d, 1H,
H-3, J3,4 =2.8 Hz), 6.01 (d, 1H, H-1, J1,2 =4 Hz), 7.45–8.04
(m, 5H, CH=), 8.36 (a, 1H, NH); 13C NMR (100 MHz,
CDCl3): d=22.1 (CH3), 23.1 (CH3), 25.1 (CH2), 26.4 (CH3),
26.8 (CH3), 28.5 (CH3), 44.0 (C-5), 44.8 (CHMe2), 59.6 (CH-
NH), 76.5 (C-4), 77.2 (C-3), 83.8 (C-2), 104.9 (C-1), 112.7
(CMe2), 128.3–134.0 (CH=), 155.7 (CMe3), 165.7 (CO),
206.3 (CS); anal. calcd. (%) for C26H38N2O7S: C 59.75, H
7.33, N 5.36, S 6.14; found: C 59.77, H 7.29, N 5.34, S 6.11.
3
2J5,5’ =12 Hz, J5,5’-4 =4 Hz), 4.46 (m, 1H, H-3), 4.65 (t, 1H,
3
2
3
H-2, J2-1,3 =4 Hz), 4.74 (dd, 1H, H-5, J5,5’ =12 Hz, J5,5’-4
=
3
4 Hz), 5.09 (a, 1H, NHBoc), 5.91 (d, 1H, H-1, J1,2 =4 Hz),
6.36 (d, 1H, NH, J=12 Hz), 7.44–8.12 (m, 5H, CH=);
13C NMR (100 MHz, CDCl3): d=17.8 (CH3), 19.6 (CH3),
26.5 (CH3), 26.8 (CH3), 28.5 (CH3), 31.0 (CHMe2), 52.0 (C-
3), 59.9 (CH), 63.6 (C-5), 78.5 (C-4), 78.9 (C-2), 104.7 (C-1),
117.7 (CMe2), 128.5–133.2 (CH=), 149.8 (CMe3), 166.4
(CO), 171.9 (CO).
3
3
Typical Procedure for the Preparation of Thioamide
Ligands L5–L8a–i
1
L5f: Yield: 299 mg (78%); H NMR (400 MHz, CDCl3):
d=1.33 (s, 3H, CH3), 1.42 (s, 3H, CH3), 1.44 (s, 9H, CH3),
1.54 (s, 3H, CH3), 3.95 (m, 1H, H-5’), 4.05 (m, 1H, H-5),
To a cooled solution of the desired benzoylated product
(1 mmol) in THF (4 mL) Lawessonꢃs reagent (0.8 mmol,
317 mg) was added. The reaction was stirred overnight at
608C. Then, the reaction mixture was evaporated and chro-
matographed (pentane/ethyl acetate: 3/1) to produce the
corresponding thioamides as white solids.
4.43 (m, 1H, CH-NH), 4.61 (sp, 1H, H-4), 4.70 (d, 1H, H-2,
3
3J2,1 =4 Hz), 5.15 (a, 1H, NHBoc), 5.43 (d, 1H, H-3, J3,4
=
3
4 Hz), 6.01 (d, 1H, H-1, J1,2 =4 Hz), 7.45–8.03 (m, 5H, CH=
), 8.28 (a, 1H, NH); 13C NMR (100 MHz, CDCl3): d=21.9
(CH3), 26.4 (CH3), 26.9 (CH3), 28.5 (CH3), 44.0 (C-5), 52.5
(CH), 76.5 (C-3), 77.4 (C-4), 83.8 (C-2), 104.9 (C-1), 112.7
(CMe2), 128.8–134.0 (CH=), 157.7 (CMe3), 165.8 (CO),
206.2 (CS); anal. calcd. (%) for C23H32N2O7S: C 57.48, H
6.71, N 5.83, S 6.67; found: C 57.44, H 6.70, N 5.81, S 6.64.
1
L5a: Yield: 232 mg (57%); H NMR (400 MHz, CDCl3):
2
3
d=0.93 (dd, 6H, CH3, J5,5’ =10.6 Hz, J5,5’-4 =6.8 Hz), 1.33 (s,
3H, CH3), 1.44 (s, 9H, CH3), 1.53 (s, 3H, CH3), 2.28 (m,
1H, CH), 3.97 (m, 1H, H-5’), 4.02 (m, 1H, H-5), 4.08 (m,
Adv. Synth. Catal. 2012, 354, 415 – 427
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
425

Mercedes Coll et al.
FULL PAPERS
1
L5g: Yield: 295 mg (79%); H NMR (400 MHz, CDCl3):
d=1.32 (s, 3H, CH3), 1.45 (s, 9H, CH3), 1.52 (s, 3H, CH3),
3.95 (m, 1H, H-5’), 4.09 (m, 1H, H-5), 4.15 (d, 2H, H-7, H-
26.7 (CH3), 28.4 (CH3), 32.0 (CHMe2), 61.3 (C-5), 61.7 (C-
3), 68.3 (CH), 75.7 (C-4), 83.7 (C-2), 104.6 (C-1), 112.7
(CMe2), 128.6–134.3 (CH=), 156.1 (CMe3), 166.1 (CO),
205.3 (CS); anal. calcd. (%) for C25H36N2O7S: C 59.03, H
7.13, N 5.51, S 6.30; found: C 58.99, H 7.11, N 5.45, S 6.26.
2
3
7’, J7,7’ =7.2 Hz), 4.62 (sp, 1H, H-4), 4.69 (d, 1H, H-2, J2,1
=
3
4 Hz), 5.31 (a, 1H, NHBoc), 5.44 (d, 1H, H-3, J3,4 =3.2 Hz),
5.99 (d, 1H, H-1, 3J1,2 =3.6 Hz), 7.43–8.01 (m, 5H, CH=),
8.55 (a, 1H, NH); 13C NMR (100 MHz, CDCl3): d=26.4
(CH3), 26.8 (CH3), 28.4 (CH3), 43.8 (C-5), 52.3 (CH2-NH),
76.5 (C-4), 77.2 (C-3), 83.7 (C-2), 104.9 (C-1), 112.6 (CMe2),
128.7–133.9 (CH=), 165.6 (CO), 200.8 (CS); anal. calcd. (%)
for C22H30N2O7S: C 56.64, H 6.48, N 6.00, S 6.87; found: C
56.60, H 6.45, N 5.99, S 6.84.
1
L7b: Yield: 103 mg (19%); H NMR (400 MHz, CDCl3):
d=1.29 (s, 3H, CH3), 1.44 (s, 9H, CH3), 1.54 (s, 3H, CH3),
3
4.51 (d, 1H, H-2, 3J2,1 =3.2 Hz), 4.62 (d, 1H, H-3, J3,4
=
=
2
5.2 Hz), 4.68 (m, 1H, H-4), 5.20 (dd, 1H, H-5, H-5’, J5,5’
3
8.2 Hz, J5,5’-4 =3.4 Hz), 5.51 (d, 1H, CH-NH), 5.69 (a, 1H,
NHBoc), 5.75 (d, 1H, H-1, 3J1,2 =3.6 Hz), 7.25–8.11 (m,
10H, CH=), 8.45 (a, 1H, NH); 13C NMR (100 MHz, CDCl3):
d=26.4 (CH3), 26.7 (CH3), 28.4 (CH3), 61.6 (C-5), 61.7 (C-
3), 65.8 (CH), 75.5 (C-4), 83.5 (C-2), 104.6 (C-1), 112.8
(CMe2), 127.0–133.8 (CH=), 138.5 (CAr), 155.3 (CMe3)
166.2 (CO), 203.2 (CS); anal. calcd. (%) for C28H34N2O7S: C
61.97, H 6.32, N 5.16, S 5.91; found: C 61.94, H 6.30, N 5.11,
S 5.89.
1
L5h: Yield: 260 mg (64%); H NMR (400 MHz, CDCl3):
d=0.93 (d, 6H, CH3, J=6 Hz), 1.31 (s, 3H, CH3), 1.43 (s,
9H, CH3), 1.49 (s, 3H, CH3), 2.19 (m, 1H, CH), 3.84 (m,
1H, H-5’),4.09 (t, 1H, CH-NH, JCH,NH =7.6 Hz), 4.17 (m,
1H, H-5), 4.65 (sp, 1H, H-4), 4.67 (d, 1H, H-2, J2,1 =4 Hz),
5.32 (a, 1H, NHBoc), 5.42 (d, 1H, H-3, J3,4 =2.4 Hz), 5.96
3
3
L7d: Yield: 67 mg (16%); 1H NMR (400 MHz, CDCl3):
d=0.96 (dd, 6H, CH3, J=6.2 Hz, J=1.8 Hz), 1.35 (s,
3H,CH3), 1.42 (s, 9H, CH3), 1.51 (s, 3H, CH3), 1.6–1.8 (m,
3H, CH2, CH), 4.06 (t, 1H, CH-NH, JCH,NH =8 Hz), 4.61 (m,
3
(d, 1H, H-1, J1,2 =3.6 Hz), 7.44–8.01 (m, 5H, CH=), 8.48 (a,
1H, NH); 13C NMR (100 MHz, CDCl3): d=18.3 (CH3), 19.6
(CH3), 26.5 (CH3), 26.8 (CH3), 28.5 (CH3), 33.6 (CHMe2),
44.0 (C-5), 66.7 (CH), 76.3 (C-4), 76.9 (C-3), 83.7 (C-2),
104.8 (C-1), 112.6 (CMe2), 128.8–133.9 (CH=), 156.1
(CMe3), 165.7 (CO), 205.1 (CS); anal. calcd. (%) for
C25H36N2O7S: C 59.03, H 7.13, N 5.51, S 6.30; found: C
59.02, H 7.12, N 5.50, S 6.28.
1H, H-3), 4.65 (m, 2H, H-2 and H-4), 5.01 (d, 1H, NHBoc,
3
J=8 Hz), 5.26 (dd, 2H, H-5, H-5’, 2J5,5’ =8 Hz , J5,5’-4
=
4 Hz), 5.92 (d, 1H, H-1, 3J1,2 =4 Hz), 7.44–8.06 (m, 5H,
CH=), 8.42 (a, 1H, NH); 13C NMR (100 MHz, CDCl3): d=
22.1 (CH3), 23.1 (CH3), 25.1 (CH2), 26.4 (CH3), 26.8 (CH3),
32.0 (CHMe2), 61.2 (C-5), 61.9 (C-3), 68.6 (CH), 75.9 (C-4),
83.3 (C-2), 104.1 (C-1), 112.2 (CMe2), 128.6–134.3 (CH=),
156.1 (CMe3), 166.3 (CO), 205.6 (CS); anal. calcd. (%) for
C26H38N2O7S: C 59.75, H 7.33, N 5.36, S 6.14; found: C
59.74, H 7.30 N 5.34, S 6.12.
1
L5i: Yield: 321 mg (74%); H NMR (400 MHz, CDCl3):
d=1.32 (s, 3H, CH3), 1.43 (s, 9H, CH3), 1.47 (s, 3H, CH3),
3.87 (t, 1H, H-5’, J=7 Hz), 3.98 (t, 1H, H-5, J=5.8 Hz),
4.54 (m, 1H, H-4), 4.68 (d, 1H, H-2, J2,1 =3.6 Hz), 5.40 (d,
1H, H-3, J3,4 =2.4 Hz), 5.47 (a, 1H, CH-NH), 5.95 (d, 1H,
3
3
3
H-1, J1,2 =3.6 Hz), 6.12 (a, 1H, NHBoc), 7.27–8.10 (m, 10H,
L7h: Yield: 85 mg (21%); 1H NMR (400 MHz, CDCl3):
d=0.83 (d, 3H, CH3, J=6.8 Hz), 0.91 (d, 3H, CH3, J=
6.4 Hz), 1.32 (s, 3H, CH3), 1.44 (s, 9H, CH3), 1.56 (s, 3H,
CH=), 8.37 (a, 1H, NH); 13C NMR (100 MHz, CDCl3): d=
26.4 (CH3), 26.8 (CH3), 28.4 (CH3), 44.1 (C-5), 63.9 (CH-
NH), 76.3 (C-4), 76.9 (C-3), 83.6 (C-2), 104.8 (C-1), 112.7
(CMe2), 127.0–134.0 (CH=), 139.4 (CAr), 155.1 (CMe3)
165.8 (CO), 202.9 (CS); anal. calcd. (%) for C28H34N2O7S: C
61.97, H 6.32, N 5.16, S 5.91; found: C 61.95, H 6.30, N 5.15,
S 5.89.
CH3), 2.87 (m, 1H, CH), 3.48 (t, 1H, CH-NH, JCH,NH
=
5 Hz), 3.67 (t, 1H, NHBoc, J=5 Hz), 4.51 (m, 1H, H-3),
3
4.59 (d, 1H, H-2, J2,1 =3.6 Hz), 4.69 (m, 1H, H-4), 5.26 (dd,
2
3
2H, H-5, H-5’, J5,5’ =8.2 Hz, J5,5’-4 =3.8 Hz), 5.94 (d, 1H, H-
3
1, J1,2 =3.6 Hz), 7.44–8.14 (m, 5H, CH=), 8.54 (a, 1H, NH);
L6a: Yield: 93 mg (23%); 1H NMR (400 MHz, CDCl3):
d=0.92 (d, 3H, CH3, J=8 Hz), 0.95 (d, 3H, CH3, J=4 Hz),
1.34 (s, 3H, CH3), 1.46 (s, 9H, CH3), 1.56 (s, 3H, CH3), 2.33
(m, 1H, CH), 3.98 (m, 1H, H-5’), 4.17 (m, 1H, H-5), 4.20 (a,
1H, CH-NH), 4.52 (sp, 1H, H-4), 4.73 (dd, 1H, H-3, J3,2
anal. calcd. (%) for C25H36N2O7S: C 59.03, H 7.13, N 5.51, S
6.30; found: C 59.00, H 7.09, N 5.47, S 6.26.
1
L8a: Yield: 154 mg (38%); H NMR (400 MHz, CDCl3):
d=0.95 (dd, 6H, CH3, J=10.6 Hz, J=6.6 Hz), 1.36 (s, 3H,
CH3), 1.44 (s, 9H, CH3), 1.59 (s, 3H, CH3), 2.29 (m, 1H,
CH), 4.11 (t, 1H, CH-NH, JCH,NH =7.8 Hz), 4.23 (m, 1H, H-
3
=
3
3
10 Hz , J3,4 =6 Hz), 4.98 (t, 1H, H-2, J2-1,3 =4 Hz), 5.18 (a,
1H, NHBoc), 5.87 (d, 1H, H-1, J1,2 =4 Hz), 7.45–8.09 (m,
3
2
3
4), 4.34 (dd, 1H, H-5’, J5,5’ =12.6 Hz, J5,5’-4 =5.8 Hz), 4.76 (t,
1H, H-2, 3J2-1,3 =1 Hz), 4.78 (dd, 1H, H-5, 2J5,5’ =5.4 Hz ,
3J5,5’-4 =2 Hz), 5.20 (m, 1H, H-3), 5.28 (a, 1H, NHBoc), 5.93
(d, 1H, H-1, 3J1,2 =4 Hz), 7.41–8.08 (m, 5H, CH=);
13C NMR (100 MHz, CDCl3): d=17.8 (CH3), 19.7 (CH3),
26.3 (CH3), 26.6 (CH3), 28.3 (CH3), 33.2 (CHMe2), 56.5 (C-
3), 63.7 (C-5), 67.1 (CH), 78.1 (C-4), 78.3 (C-2), 104.6 (C-1),
113.1 (CMe2), 128.1–133.0 (CH=), 155.6 (CMe3), 166.2
(CO), 205.7 (CS); anal. calcd. (%) for C25H36N2O7S: C
59.03, H 7.13, N 5.51, S 6.30; found: C 58.99, H 7.08, N 5.47,
S 6.24.
5H, CH=), 8.11 (a, 1H, NH); 13C NMR (100 MHz, CDCl3):
d=17.6 (CH3), 20.0 (CH3), 26.7 (CH3), 28.5 (CH3), 33.2
(CHMe2), 45.8 (C-5), 67.4 (CH), 74.0 (C-3), 75.5 (C-4), 77.6
(C-2), 104.5 (C-1), 113.6 (CMe2), 128.6–133.7 (CH=), 155.8
(CMe3), 166.0 (CO), 205.3 (CS); anal. calcd. (%) for
C25H36N2O7S: C 59.03, H 7.13, N 5.51, S 6.30; found: C
59.00, H 7.11, N 5.48, S 6.27.
L7a: Yield: 49 mg (12%); 1H NMR (400 MHz, CDCl3):
d=0.79 (d, 3H, CH3, J=8 Hz), 0.93 (d, 3H, CH3, J=4 Hz),
1.34 (s, 3H, CH3), 1.44 (s, 9H, CH3), 1.57 (s, 3H, CH3), 2.44
(m, 1H, CH), 4.09 (t, 1H, CH-NH, JCH,NH =8 Hz), 4.57 (m,
3
1H, H-3), 4.62 (d, 1H, H-2, J2,1 =4 Hz), 4.68 (m, 1H, H-4),
5.02 (d, 1H, NHBoc, J=8 Hz), 5.25 (dd, 2H, H-5, H-5’,
2J5,5’ =8 Hz, 3J5,5’À4 =4 Hz), 5.88 (d, 1H, H-1, 3J1,2 =4 Hz),
7.44–8.06 (m, 5H, CH=), 8.40 (a, 1H, NH); 13C NMR
(100 MHz, CDCl3): d=17.5 (CH3), 19.3 (CH3), 26.3 (CH3),
Typical Procedure for the ATH of Ketones
The desired ligand (0.0055 mmol), catalyst precursor {[RuCl2
AHCNUTTGERG(NNNU p-cymene)2]2 or [RhCl2Cp*2]2} (0.0025 mmol), and LiCl
426
asc.wiley-vch.de
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 415 – 427

Modular Furanoside Pseudodipeptides and Thioamides, Readily Available Ligand Libraries
(4.2 mg, 0.1 mmol) were treated under vacuum for 10 min.
Under argon, substrate (1 mmol), propan-2-ol (2 mL) and
THF (2.5 mmol) were sequentially added. The reaction was
initiated by adding i-PrONa (0.1M, 0.5 mL, 0.05 mmol) to
the solution. After completion of the reaction the solution
was filtered through a plug of silica and eluted with Et2O,
and the solvents were evaporated. The products were ana-
lyzed by GC (CP Chirasil DEX CB).[7a,b,d]
[6] See, for example: a) S. J. Nordin, P. Roth, T. Tarnai,
D. A. Alonso, P. Brandt, P. G. Andersson, Chem. Eur. J.
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Tarnai, P. G. Andersson, M. Thommen, U. Pittelkow, J.
Org. Chem. 2000, 65, 3116; c) D. A. Alonso, D. Guijar-
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Pastor, P. Vꢆstilꢆ, H. Adolfsson, Chem. Commun. 2002,
2046; j) A. B. Zaitsev, H. Adolfsson, Org. Lett. 2006, 8,
5129.
Acknowledgements
We would like to thank the Swedish Research Council, the
Knut and Alice Wallenberg foundation, the Spanish Govern-
ment for providing grants CTQ2010-15835 and 2008PGIR/07
to O. Pꢀmies and 2008PGIR/08 to M. Diꢁguez, the Catalan
Government for grant 2009SGR116, and the ICREA Foun-
dation for providing M. Diꢁguez and O. Pꢀmies with finan-
cial support through the ICREA Academia awards.
[7] a) I. M. Pastor, P. Vꢆstilꢆ, H. Adolfsson, Chem. Eur. J.
2003, 9, 4031; b) A. Bøgevig, I. M. Pastor, H. Adolfs-
son, Chem. Eur. J. 2004, 10, 294; c) P. Vꢆstilꢆ, J. Wet-
tergren, H. Adolfsson, Chem. Commun. 2005, 4039;
d) J. Wettergren, A. Bøgevig, M. Portier, H. Adolfsson,
Adv. Synth. Catal. 2006, 348, 1277; e) P. Vꢆstilꢆ, A. B.
Zaitsev, J. Wettergren, T. Privalov, H. Adolfsson,
Chem. Eur. J. 2006, 12, 3218; f) J. Wettergren, A. B.
Zaitsev, H. Adolfsson, Adv. Synth. Catal. 2007, 349,
2556; g) J. Wettergren, E. Buitrago, P. Ryberg, H.
Adolfsson, Chem. Eur. J. 2009, 15, 5709.
[8] a) K. Ahlford, J. Ekstrçm, A. B. Zaitsev, P. Ryberg, L.
Eriksson, H. Adolfsson, Chem. Eur. J. 2009, 15, 11197;
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hedron Lett. 2009, 50, 6321.
[9] a) M. Diꢁguez, O. Pꢀmies, C. Claver, Chem. Rev. 2004,
104, 3189; b) M. Diꢁguez, O. Pꢀmies, A. Ruiz, Y. Dꢂaz,
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89% ee for S5, 94% ee for S6, 92% ee for S7, 97% ee
for S9 and 97% for S10. There are no data reported for
substrate S8. See refs.[6j,8]
Adv. Synth. Catal. 2012, 354, 415 – 427
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