Formamides derived from N-methyl amino acids serve as new chiral organocatalysts in the enantioselective reduction of aromatic ketimines with trichlorosilane

Article abstract of DOI:10.1016/j.tet.2005.08.117

Asymmetric reduction of N-aryl ketimines 1a-k, 43, and 45 with trichlorosilane can be catalyzed by new N-methyl l-amino acid-derived Lewis-basic organocatalysts, such as the valine-derived bisamide 3d (10 mol%), in toluene at room temperature with high enantioselectivity (≤92% ee). The structure-reactivity investigation shows that the product configuration is controlled by the nature of the side chain of the catalyst scaffold (e.g., i-Pr vs Me, as in 3d and 6e), so that catalysts of the same absolute configuration may induce the formation of the opposite enantiomers of the product. Arene-arene interactions between the catalyst and the incoming imine appear to be the prerequisite for asymmetric induction. This metal-free, organocatalytic protocol is competitive with the traditional, metal-catalyzed methodology.

Full text of DOI:10.1016/j.tet.2005.08.117

Tetrahedron 62 (2006) 264–284
Formamides derived from N-methyl amino acids serve as new
chiral organocatalysts in the enantioselective reduction of
aromatic ketimines with trichlorosilane
*
ˇ
Andrei V. Malkov, Sigitas Stoncius, Kenneth N. MacDougall, Andrea Mariani,
*
´
ˇ
Grant D. McGeoch and Pavel Kocovsky
Department of Chemistry, WestChem University of Glasgow, Glasgow G12 8QQ, UK
Received 1 July 2005; revised 8 August 2005; accepted 31 August 2005
Available online 10 October 2005
Dedicated to Professor Peter Pauson on the occasion of his 80th birthday
Abstract—Asymmetric reduction of N-aryl ketimines 1a–k, 43, and 45 with trichlorosilane can be catalyzed by new N-methyl L-amino acid-
derived Lewis-basic organocatalysts, such as the valine-derived bisamide 3d (10 mol%), in toluene at room temperature with high
enantioselectivity (%92% ee). The structure–reactivity investigation shows that the product configuration is controlled by the nature of the
side chain of the catalyst scaffold (e.g., i-Pr vs Me, as in 3d and 6e), so that catalysts of the same absolute configuration may induce the
formation of the opposite enantiomers of the product. Arene–arene interactions between the catalyst and the incoming imine appear to be the
prerequisite for asymmetric induction. This metal-free, organocatalytic protocol is competitive with the traditional, metal-catalyzed
methodology.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Generally, development of any new catalytic protocol
includes a delicate balancing of various factors, such as
catalyst structure and loading, solvent, temperature, etc.
Often, even minor changes in any of these characteristics
can produce a dramatic effect on the stereochemical
outcome of the reaction.1,6 Among the approaches aiming
at the enhancement of enantioselectivity through structural
variations, the chiral relay effect7 is now gaining recognition
as a powerful tool. The philosophy of this approach is based
on the behavior of a conformationally flexible group,
positioned in such a way that it can effectively convey the
chiral information from the scaffold to the reaction center.7
While asymmetric reduction of ketones (both stoichiometric
and catalytic) is now well developed,1 ketimines seem to be
a Cinderella, with only a limited portfolio of acceptably
efficient protocols reported to date.1–3 The currently most
successful methods are based on transition metal-catalyzed
high-pressure hydrogenation,1,2 hydrosilylation,1,3 and
transfer hydrogenation.2j,4 However, this traditional
approach to imine reduction (Scheme 1) is tainted by the
problems associated with metal leaching and catalyst
regeneration, so that development of an organocatalytic5
alternative appears to be very attractive.
As part of another project, focused on the enantioselective,
transition metal-catalyzed reactions,8 we have recently
developed new N-methylamino acid-derived amido-
phoshine ligands and demonstrated that the conformational
bias, imposed by the tertiary amide group, can lead to high
enantioselectivity in the Cu(I)-catalyzed conjugate addition
of Et2Zn to a,b-enones.9 Interestingly, our ligands derived
from N-methyl valine proved to be superior to those
prepared from proline, showing that the rigid cyclic
framework of proline may not always be an advantage.9
Herein, we demonstrate that these principles can be
extended to the realm of organocatalysis and report on a
Scheme 1. Asymmetric reduction of ketimines. For R1 and R2, see Tables 1
and 2.
Keywords: Organocatalysis; Asymmetric reduction; Imines; Hydrosilyla-
tion; Lewis bases; Enantiopure amines.
*
Corresponding authors. Tel.: C44 141 330 5943/+44 330 4199;
fax: C44 141 330 4888; e-mail: amalkov@chem.gla.ac.uk;
pavelk@chem.gla.ac.uk
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.117

A. V. Malkov et al. / Tetrahedron 62 (2006) 264–284
265
Scheme 2. Amino acid-derived organocatalysts.
powerful, organocatalytic reduction of ketimines with
trichlorosilane to produce chiral amines.10
Since Cl3SiH can be activated by Lewis bases, such as R3N,
DMF, and MeCN, etc., to effect hydrosilylation of imines,11,12
we set out to design a suitable chiral Lewis-basic catalyst that
could be viewed as a chiral analogue of DMF with one of the
methyl groups replaced by a chiral moiety (Scheme 2).12–14
2. Results and discussion
2.1. Catalyst design and synthesis
The strategy of designing chiral analogues of DMF relied on
the use of amino acids as the chiral scaffold, with the
a-amino group converted into the N-methyl formamide
moiety. It was also intended to convert the amino acid
carboxyl into another amide group, with either aromatic or
aliphatic substituent adjacent to the nitrogen. In our
preliminary communication,10 we have reported on form-
amides 3–5, derived from valine and the series is now
extended to other amino acid scaffolds, namely 6a–f, 7, and
8, supplemented by 10 and 11 and by dipeptides 12a–c.
While this initial work was in progress, Matsumura reported
on the synthesis of the N-formyl proline derivatives 9a,b
(vide infra).14
The synthesis of valine-derived formamides commenced
with N-methylation of the BOC-protected L-valine 13 with
MeI in the presence of NaH15 (Scheme 3), which afforded
the BOC-protected N-methyl valine16 14 (98%). The latter
Scheme 3. Catalyst synthesis.

266
A. V. Malkov et al. / Tetrahedron 62 (2006) 264–284
aniline, reflecting the reduced nucleophilicity of the
nitrogen. Therefore, pivalyl chloride was employed here
to generate the mixed anhydride,17 which proved to react
efficiently. However, this reaction led to the simultaneous
loss of the BOC group, so that the free amine 17 was
obtained instead of the expected BOC derivative. BOC-
deprotection (with TFA) of each of the amides 15a–d, 15f,g,
and 16a,b was followed by formylation with a mixed
anhydride, generated in situ from formic acid and acetic
anhydride, to produce the desired N-methyl formamides
3a–d, 3f,g, and 4a,b. The remaining member of this family,
formamide 3e, was obtained by formylation of amine 17.
Trifluoroacetamide 10 was obtained from the BOC-
protected amide 15a via deprotection with trifluoroacetic
acid followed by acylation with trifluoroacetic anhydride.
Finally, 15d was converted into the urea derivative 11 via
deprotection followed by treatment with phenylisocyanate.
Scheme 4. Catalyst synthesis.
The same strategy was employed for the synthesis of the
remaining amino acid-derived amides and proved to work
successfully with the BOC-protected phenylglycine,
phenylalanine, alanine, and leucine (18c–f) as starting
materials, to produce formamides 6c–f in four steps
(Scheme 4). However, when applied to the BOC-protected
cyclohexylglycine and t-leucine (18a,b), it failed in the first
step, as the N-methylation turned out to be sluggish.
Attempted alkylation of both 18a,b using (MeO)2SO2 and
NaH18 and the variant utilizing Nosyl- instead of BOC-
protected substrate for N-alkylation with MeI and Et3N in
MeCN19 were equally unsuccessful. Therefore, an alterna-
tive route had to be sought.
In an alternative approach20 to N-methylation, the BOC-
protected 18a,b were first converted into the respective
oxazolidinones 21a,b (Scheme 5). Treatment of the latter
intermediates with Et3SiH and CF3CO2H in chloroform
effected both the desired cleavage of the C–O bond and the
loss of the BOC group to produce the N-methyl amino acids
22a,b. Subsequent N-formylation under standard conditions
afforded the N-methyl formamides 23a,b,21 which were
then reacted with 3,5-dimethyl aniline using the carbodi-
imide method. The resulting amides 6a,b, however, turned
out to be racemic, as a result of racemization in the last
Scheme 5. Catalyst synthesis.
derivative was then converted into a series of secondary and
tertiary amides 15 and 16, employing the mixed anhydride
method (or, as in the case of 16b, the carbodiimide method).
The mixed anhydride was generated in situ from 14 and
methyl chloroformate and then reacted with the respective
amine to produce 15a–d, 15f,g, and 16a. Only in one case
this protocol failed, namely for 3,5-bis-(trifluoromethyl)-
Scheme 6. Catalyst synthesis.

A. V. Malkov et al. / Tetrahedron 62 (2006) 264–284
267
Scheme 7. Catalyst synthesis.
step.22 Since the mixed anhydride method proved equally
fruitless, a further modification of this approach was sought.
The new alternative employed the Cbz protecting group to
prevent the loss of N-protection in the reduction step
(Scheme 6).23 Thus, the Cbz-protected amino acids 24a,b
were converted into the respective oxazolidinones 25a,b in
the same way as their BOC counterparts. However, the
desired C–O bond cleavage to give the expected N-methyl
derivatives 26a,b turned out to be sluggish (room
temperature, 1 week) and rather low-yielding. Subsequent
reaction of 26a with 3,5-dimethyl aniline, using the
carbodiimide method, afforded 27a in moderate yield
(64%), whereas 27b was isolated as an inseparable mixture
with 25b in low yield. The final reductive deprotection of
27a,b, followed by formylation, proceeded uneventfully,
affording 6a,b in good yields.
Scheme 8. Catalyst synthesis.
The synthesis of 7 (Scheme 7), starting with the BOC-
protected a-methyl phenylglycine 29, utilized the oxa-
zolidinone-type methylation again and proved to be
uneventful, except for the low yielding amide formation
step (32/7), which obviously stems from the steric
hindrance in this a,a-disubstituted amino acid derivative.
The synthesis of the histidine-derived candidate catalyst 8
(Scheme 8) commenced with N-methylation of the
imidazole nitrogen in the BOC-protected histidine (33/
34) using the MeI/NaH method,24 followed by amidation
under the standard carbodiimide conditions. The resulting
amide 3525 was then deprotected and formylated to produce
8 in good overall yield. The valine-derived formamide 5 was
synthesized in the same manner from the BOC-protected
valine (S)-13 (Scheme 8).
Scheme 9. Amino acid-derived orgnocatalysts.
2.2. Asymmetric reduction of ketimines with Cl3SiH
catalyzed by chiral formamides
Finally, dipeptides 12a–c were synthesized from the BOC-
protected N-methyl valine (S)-14, which served as the
building block for the N-terminus, and amides (S)-40a–c,
obtained in two steps from the respective BOC-protected
amino acids (S)-13 and (S)-18c,d (Scheme 9).26 The peptide
bond was constructed using the carbodiimide method and
the resulting products 41a–c were deprotected to afford
42a–c. Subsequent formylation gave rise to the desired
formamides (S,S)-12a–c.
Reduction of imines 1a–k (Scheme 1), catalyzed by
formamides 3–5 (10 mol%), has been reported in our
preliminary communication10 and the salient features,
required for further discussion, are highlighted in Table 1.
Herein, we present an orchestration of our earlier efforts by
extending the set of catalysts (6–8 and 10–12) and substrates
and by reporting the temperature and solvent effects.
Reduction of ketimine 1a (derived from acetophenone and

268
A. V. Malkov et al. / Tetrahedron 62 (2006) 264–284
Table 1. Reduction of ketimines 1a–j with trichlorosilane, catalyzed by (S)-3a and (S)-9a,ba
Entry
Imine
R1, R2
Catalyst
Solvent
Yield (%)b
2, % eec (config)d
1
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1e
1f
Ph, Ph
Ph, Ph
Ph, Ph
Ph, Ph
Ph, Ph
Ph, Ph
4-MeOC6H4, Ph
4-CF3C6H4, Ph
2-Naphth, Ph
c-C6H11, Ph
c-C6H11, Ph
Ph, 4-MeOC6H4
Ph, 2-MeOC6H4
Ph, c-C6H11
Ph, n-Bu
3a
3a
3a
3a
9a
9b
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
CH2Cl2
CHCl3
CHCl3
MeCN
CH2Cl2
CH2Cl2
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
CHCl3
CHCl3
CHCl3
68
79
49
65
91
52
57
43
60
80
53
96
36
50
60
46
79 (S)
86 (S)
92 (S)
30 (S)
55 (R)f
66 (R)f
80 (S)
87 (S)
87 (S)
37 (S)
59 (S)
85 (S)
22 (S)
!5
2
3e
4
5
6
7
8
9
10
11e
12
13
14
15
16
1g
1h
1i
!5
8
1j
Ph, CH2Ph
a The reaction was carried out at 0.5 mmol scale with 1.5 equiv of Cl3SiH and 10 mol% of the catalyst at room temperature for 16 h.
b Isolated yield.
c Determined by chiral HPLC or GC.
d Established from the optical rotation (measured in CHCl3) by comparison with the literature data (see the Section 4) and/or by HPLC/GC via comparison with
authentic samples.
e The reaction was carried out at K20 8C.
Ref. 14a.
f
aniline) with Cl3SiH in the presence of the L-valine-derived
catalyst (S)-3a (10 mol%), was carried out in CH2Cl2 at
room temperature, and afforded the corresponding amine
(S)-2a in good yield and with 79% ee (Table 1, entry 1).
Changing the solvent to chloroform had a beneficial effect,
as both the yield and enantioselectivity had improved (entry
2). Further increase in enantioselectivity (to 92% ee) was
attained by lowering the reaction temperature to K20 8C,
though at the expense of the reaction rate (entry 3). The use
of acetonitrile as solvent led to a dramatic reduction of
enantioselectivity (entry 4).27
way as 1a (entry 9) but the cyclohexyl analogue 1e
exhibited a significantly reduced enantioselectivity,
although in this case the overall result was affected by
rather fast, non-catalytic background reaction (entry 10).
Here, decreasing the temperature resulted in the increase of
enantioselectivity by 22% (entry 11), presumably by
suppressing the competing, non-catalytic process.
Variation of the imine N-substituent (R2) had a more
dramatic effect. Thus, while p-methoxy imine 1f gave high
conversion and enantioselectivity (entry 12), reduction of its
o-isomer 1g was much less efficient (entry 13), indicating
the influence of the steric effect. By contrast, imines 1h–j,
derived from non-aromatic amines, afforded practically
racemic products (entries 14–16), demonstrating the crucial
role of the N-aryl moiety of the ketimine for asymmetric
induction.30
While our initial work was in progress, Matsumura reported
on the same reduction catalyzed by the L-proline-derived
formamides (S)-9a,b (10–20 mol%) with %66% ee (entries
5 and 6);14a however, he obtained the opposite enantiomer
of the product! The latter results are intriguing and suggest
that the enantiodifferentiation mechanisms for valine- and
proline-derived catalysts are dramatically different, which
warranted a thorough study of the structural effects of both
the catalyst and the substrate.
The role of the amide functionality in the catalyst, in
particular its contribution to aromatic interactions, was
elucidated with the aid of amides 3–5.31 Catalyst 3b with a
donor group was found to be slightly less efficient with
imine 1a, compared to 3a (Table 2, entry 1; compare with
Table 1, entry 2). Additional methoxy substituent (3c) led to
a further decrease in selectivity (entries 2–4). 3,5-
Dimethylphenylamide 3d generally gave higher yields and
slightly better selectivity than the parent phenylamide 3a
(entries 5–11). By contrast, a significantly reduced efficacy
was observed for the electron-poor 3,5-bis(trifluoromethyl)-
and 3,5-dichloroanalogues 3e and 3f (entries 20–22). No
reaction was observed with n-butyl amide 3g (Table 2, entry
23), confirming the importance of the aromatic system in
this position. Tertiary amide 4a, lacking the NH group,
proved to be a sluggish catalyst (entry 24), which may
suggest that a hydrogen bonding between the NH group of
the catalyst and the imine nitrogen plays a role in the
transition state. As expected, diethylamide 4b proved inert
(entry 25). Furthermore, removing the N-Me group from the
formamide part, as in catalyst 5, proved to be detrimental to
Recently, we have shown that arene-arene interactions have
a strong impact on the reactivity and enantioselectivity in
organocatalysis,28 which prompted us to probe the extent of
non-covalent interactions involved in this reduction of
imines. The solvent effect observed (entries 1–3) is
consistent with the involvement of hydrophobic, presum-
ably arene–arene interactions of the catalyst and the
substrate29 but further evidence was required.
In order to shed light on the origin of the asymmetric
induction and, in the same time, to probe the scope of this
reduction, the aromatic system in the ketimine 1 and in the
catalyst 3 was varied. The electronic effect on the
conversion and enantioselectivity turned out to be marginal,
as demonstrated by comparison of the electron-rich and
electron-poor imines 1b and 1c (entries 7 and 8, and further
entries in Table 2). 2-Naphthyl-imine 1d reacted in the same

A. V. Malkov et al. / Tetrahedron 62 (2006) 264–284
269
Table 2. Reduction of ketimines 1a–k with trichlorosilane, catalyzed by (S)-3a–g, 4a,b, and 5a
Entry
Imine
Catalyst
Solvent
Temperature
(8C)
Yield
(%)b
2, % eec
(config)d
1
2
3
4
5
6
7
8
1a
1a
1c
1f
1a
1a
1b
1c
1c
1f
Ph, Ph
Ph, Ph
4-CF3C6H4, Ph
Ph, 4-MeOC6H4
Ph, Ph
(S)-3b
(S)-3c
(S)-3c
(S)-3c
(S)-3d
(S)-3d
(S)-3d
(S)-3d
(S)-3d
(S)-3d
(S)-3d
(S)-3d
(S)-3d
(S)-3d
(S)-3d
(S)-3d
(S)-3d
(S)-3d
(S)-3d
(S)-3e
(S)-3e
(S)-3f
(S)-3g
(S)-4a
(S)-4b
(S)-5
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
Tol
Tol
Tol
Tol
Tol
Tol
Tol
Tol
Ambient
Ambient
Ambient
Ambient
Ambient
K20
Ambient
Ambient
K20
Ambient
K20
Ambient
K20
Ambient
Ambient
K20
Ambient
K20
Ambient
Ambient
Ambient
Ambient
Ambient
Ambient
Ambient
Ambient
62
81
94
82
70
94
62
88
95
79
85
81
54
86
86
80
85
46
90
88
92
35
0
85 (S)
82 (S)
77 (S)
79 (S)
89 (S)
92 (S)
87 (S)
87 (S)
89 (S)
86 (S)
90 (S)
92 (S)
92 (S)
85 (S)
89 (S)
89 (S)
91 (S)
93 (S)
92 (S)e
53 (S)
69 (S)
56 (S)
—
Ph, Ph
4-MeOC6H4, Ph
4-CF3C6H4, Ph
4-CF3C6H4, Ph
Ph, 4-MeOC6H4
Ph, 4-MeOC6H4
Ph, Ph
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
1f
1a
1a
1b
1c
1c
1f
Ph, Ph
4-MeOC6H4, Ph
4-CF3C6H4, Ph
4-CF3C6H4, Ph
Ph, 4-MeOC6H4
Ph, 4-MeOC6H4
2-MeC6H4, Ph
Ph, Ph
4-CF3C6H4, Ph
Ph, Ph
Ph, Ph
1f
1k
1a
1c
1a
1a
1a
1a
1c
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
Ph, Ph
Ph, Ph
4-CF3C6H4, Ph
23
0
84
7 (S)
—
35 (S)
a The reaction was carried out at 0.5 mmol scale with 1.5 equiv of Cl3SiH and 10 mol% of the catalyst for 16 h.
b Isolated yield.
c Determined by chiral HPLC or GC.
d Established from the optical rotation (measured in CHCl3) by comparison with the literature data (see the Section 4) and/or by HPLC/GC via comparison with
authentic samples.
e Configuration of 2k is assumed to be (S) in analogy with the rest of the series.
enantioselectivity (entry 26; compare with entry 3), showing
the importance of the N-Me for the chiral relay.9
with MeCN proved its inferiority, clearly indicating that the
reaction requires nonpolar solvents. However, neither
CH2Cl2 nor CHCl3 are environmentally friendly, so that
other non-polar solvents were probed as the next stage and
toluene was found to be the solvent-of-choice: in this
solvent, the enantioselectivity attained with catalyst 3d at
All the experiments discussed to this point were run in
chlorinated solvents, namely CH2Cl2 and CHCl3, of which
the latter gave somewhat better results. A few experiments
Table 3. Reduction of ketimines 1a,c,f with trichlorosilane, catalyzed by 6a–f, 7–11, and 12a–ca
Entry
Imine
R1, R2
Catalyst
Solvent
Yield (%)b
2, % eec (config)d
1
2
3
4
5
6
7
8
1c
1f
1c
1f
1a
1c
1f
1c
1f
1c
1c
1f
1c
1f
1a
1c
1c
1f
1f
1f
4-CF3C6H4, Ph
Ph, 4-MeOC6H4
4-CF3C6H4, Ph
Ph, 4-MeOC6H4
Ph, Ph
4-CF3C6H4, Ph
Ph, 4-MeOC6H4
4-CF3C6H4, Ph
Ph, 4-MeOC6H4
4-CF3C6H4, Ph
4-CF3C6H4, Ph
Ph, 4-MeOC6H4
4-CF3C6H4, Ph
Ph, 4-MeOC6H4
Ph, Ph
(R)-6a
(R)-6a
(S)-6b
(S)-6b
(R)-6c
(R)-6c
(R)-6c
(S)-6d
(S)-6d
(S)-6e
(S)-6f
(S)-7
(S)-7
(S)-8
(S)-10
(S)-11
12a
Tol
Tol
Tol
Tol
Tol
Tol
Tol
Tol
Tol
Tol
Tol
Tol
Tol
Tol
CH2Cl2
Tol
Tol
Tol
Tol
Tol
74
95
84
95
84
70
76
85
84
92
89
89
80
0
!10
70
84
91
78
87
89 (R)e
82 (R)e
82 (S)
83 (S)
0
0
0
26 (S)
49 (S)
38 (R)
10 (S)
47 (S)
42 (S)
—
9
10
11
12
13
14
15
16
17
18
19
20
0
0
4-CF3C6H4, Ph
4-CF3C6H4, Ph
Ph, 4-MeOC6H4
Ph, 4-MeOC6H4
Ph, 4-MeOC6H4
17 (R)
10 (R)
7 (S)
0
12a
12b
12c
a The reaction was carried out at 0.5 mmol scale with 1.5 equiv of Cl3SiH and 10 mol% of the catalyst at room temperature, 16 h.
b Isolated yield.
c Determined by chiral HPLC or GC.
d Established from the optical rotation (measured in CHCl3) by comparison with the literature data (see the Section 4) and/or by HPLC/GC via comparison with
authentic samples.
e Note the (R) configuration of the catalyst.

270
A. V. Malkov et al. / Tetrahedron 62 (2006) 264–284
alanine-, and leucine-derived catalysts 6d–f (entries 8–11).
Interestingly, the alanine-derived catalyst 6e induced the
preferential formation of the opposite enantiomer of the
product, though with moderate enantioselectivity (38% ee;
entry 10), suggesting that competing transition states play a
role in this series. In contrast to the phenylglycine-derived
catalyst 6c, which gave racemic products, its methylated
analogue 7 resumed a moderate level of enantioselectivity
(entries 12–13). In contrast to the rest of the series, the
histidine derivative 8 failed to catalyze the reaction (entry
14), suggesting an interference by the imidazole moiety.
The valine-derivative 10, having the formamide moiety
replaced by the much less Lewis-basic trifluoroacetamide
group, proved equally inefficient (entry 15), demonstrating
the crucial role of the formamide group (compare with
Table 1, entry 1). The urea derivative 11 did catalyze the
reaction but afforded a racemic product (Table 3, entry 16)
and the dipeptides 12a–c behaved similarly, exhibiting very
low enantioselectivity, if any (entries 17–20).
Scheme 10. Asymmetric reduction of of ketimines.
Table 4. Reduction of ketimines 43 and 45 with trichlorosilane, catalyzed
by (S)-3da
Entry
Imine
Temperature
(8C)
Yield (%)b
% eec (config)d
1
2
3
4
43
43
45
45
Ambient
K20
Ambient
K20
59
64
68
69
74 (S)
81 (S)
30 (R)e
59 (R)e,f
From the efficiency standpoint, 3,5-dimethylphenylamide
3d is clearly the champion catalyst. Therefore, it was this
derivative that was employed to briefly probe the scope of
this methodology (Scheme 10). With the chalcone-derived
imine 43, the reduction proceeded well, though with rather
reduced enantioselectivity (Table 4, entries 1 and 2). Imine
45, whose reduction produced the phenylglycine derivative
46, exhibited good reactivity but rather low enantio-
selectivity (entry 3). Lowering the temperature resulted in
an increase of the asymmetric induction (to 59% ee) but at
the expense of the reaction rate (entry 4).
a The reaction was carried out at 0.5 mmol scale with 1.5 equiv of Cl3SiH
and 10 mol% of the catalyst in toluene for 16 h.
b Isolated yield.
c Determined by chiral HPLC or GC.
d Established from the optical rotation (measured in CHCl3) by comparison
with the literature data (see the Section 4) and/or by HPLC/GC via
comparison with authentic samples.
e Note the change of substituent priorities in the CIP nomenclature.
f
The reaction was run for 24 h.
room temperature (Table 2, entry 12) matched the result
obtained for CHCl3 at K20 8C (Table 1, entry 3) but with
much higher yield. Marginal increase in the enantio-
selectivity was observed for 1f in toluene at K20 8C
(Table 2, entries 17 and 18), whereas 1a and 1c showed no
further improvement at low temperature (Table 2, entries
12, 13, 15, and 16).
2.3. Mechanistic considerations
Our experiments indicate that for the activation of
trichlorosilane, the catalyst is required to posses two
amide groups, one of the formamide type, the other as
anilide, both of which can be assumed to be available for
coordination as donors (Fig. 1). In the 13C NMR spectrum of
a 1:1 mixture of 3d and HSiCl3, shifts of w0.1 and 0.2 ppm
were observed for the corresponding signals of the
formamide and anilide carbonyls relative to free 3d.
Furthermore, the methyl groups at the aromatic ring became
non-equivalent,32 suggesting a weak coordination (possibly
bidentate) that restricts the rotation about the N–Ar bond.
Variation of the side chain of the amino acid scaffold was
investigated next (6–8, 10–12; Table 3). The cyclohexyl
analogue 6a exhibited similar enantioselectivity (Table 3,
entries 1 and 2) as its isopropyl counterpart derived from
valine (Table 2, entries 15 and 17). The t-butyl derivative 6b
showed only a marginally reduced efficiency (Table 3,
entries 3 and 4), whereas the application of the phenyl-
glycine-derived catalyst 6c gave rise, surprisingly, to
racemic products (Table 3, entries 5–7). Modest to low
enantioselectivity was also observed for the phenylalanine-,
In the series of catalysts 3a–f, the Lewis basicity of the
Figure 1. Key features of the catalyst and the substrate.

A. V. Malkov et al. / Tetrahedron 62 (2006) 264–284
271
formamide moiety remained constant while the substituents
in the arylamide part were designed to affect its donor
properties. Apparently, catalyst 3f, having electron with-
drawing groups at the aromatic ring, is less efficient in
coordination, which may account for the decreased
enantioselectivity in this instance (Table 2, entry 22). 3,5-
Dimethylanilide 3d appears to represent the right balance of
the electronic and steric properties, giving rise to the highest
reactivity and enantioselectivity (Fig. 1).
vs 15). With a non-aromatic group at this position, such as
cyclohexyl (1e), the reaction does occur but with a lower
degree of asymmetric induction (Table 1, entries 10 and 11),
owing partly to the competing, uncatalyzed background
reaction. When the conjugation is extended, as in the
vinylogue 43, the reaction reverts to high enantioselectivity
(Table 4, entries 1 and 2), demonstrating the beneficial
effect of conjugation. Regarding the R2 group, its aromatic
character (1a–f) is crucial for attaining high asymmetric
induction (Table 1, entries 1–12); the absence of conju-
gation, as in 1h–j, does not prevent the reaction but results
in the formation of a practically racemic product in good
yield (Table 1, entries 14–16). Examination of the phenyl
and methoxyphenyl derivatives (1a,f,g) revealed that steric
congestion close to the nitrogen (as in the o-methoxy
derivative 1g) should be avoided, for it results in a dramatic
decrease in the reaction rate and enantioselectivity (Table 1,
entry 13). On the other hand, 1a and 1f gave comparable
result (e.g., Table 1, entries 2 and 12). The good
enantioselectivity attained with the p-methoxy derivative
1f is particularly important, since this electron-rich N-Aryl
group can be removed by oxidative methods,35 which
extends the scope of this methodology to the realm of
primary amines.
While the secondary anilides 3a–f were identified as
efficient catalysts, the tertiary anilide 4a proved inert,
suggesting that the N–H group plays an important role
(Fig. 1), either through hydrogen bonding or by allowing
greater flexibility of the amide group (vide infra).
Furthermore, the reaction does require an N-Ar group to
be part of the catalyst (as in 3a–f, 6a–f, 7, and 9) since the
N-Bu derivative 3g fails to catalyze the reaction. This
behavior can be best rationalized by the arene-arene
interactions between the catalyst and the imine, as an
important factor contributing to the facial discrimination of
the incoming imine.
The tertiary formamide group (as in 3a–f, 6a–f, 7, 9, and
12a–c) is a prerequisite for the catalytic activity (Fig. 1).
Here, the carbonyl must be sufficiently Lewis basic (note
that 10 is ineffective) and, simultaneously, the group must
be sufficiently small (i.e., formamide); note that the bulkier
amides, such as the benzamide congener of 6c, the
acetamide counterpart of 9a,14a the BOC derivative 15a,
and the urea analogue 11 are ineffective. The role of the
N-Me group in the formamide moiety is important for the
enantioselectivity, though not crucial for the reaction to
occur, as can be seen from the comparison of 3c with 5
(Table 2, compare entries 3, 4, and 26). It can be
hypothesized that the N-methyl is responsible for assuming
the right conformation of the formamide group that conveys
the chiral information from the chiral center.33
Another notable feature of this reduction is the linear
relationship between the enantiomeric purity of the catalyst
and the product, observed for 3d as the representative
catalyst, suggesting that no more than one molecule of the
catalyst is involved in the enantiodifferentiating process.
3. Conclusions
The structural features and their implications to the reaction
mechanism of this hydrosilylation of ketimines can be
summarized, with reference to Fig. 1, as follows: (1) the
N-methyl formamide moiety of the catalyst is crucial for the
enantioselectivity, presumably by controlling the spatial
orientation of the formamide group and relaying the chiral
information from the chiral center. (2) The anilide part of
the catalyst and the N-aryl substituent of the substrate imine
(R2) are crucial for the enantiodifferentiating process,
suggesting arene–arene interactions. (3) The anilide moiety
of the catalyst must constitute a secondary amide, with an
NH group. This effect is not clear at present, since it can
either be rationalized by a hydrogen bonding to the substrate
or attributed to the increased flexibility of the secondary (vs
tertiary) amide; docking of the substrate imine by the
CONH-R group may also be possible, in light of the recent
model calculation of the rather strong attractive interaction
between the formamide and benzene molecules.36 (4) The
reagent, Cl3SiH, is apparently activated by the formamide
moiety of the catalyst, in consonance with other investiga-
tions.11b,13 The anilide carbonyl is also capable of
coordinating the silicon, as evidenced by the NMR, so
that it can be conjectured to take part in the enantio-
differentiation, but more experiments will be required to
address this issue. (5) The nature of the amino acid side
chain determines the configuration of the resulting product,
apparently by controlling the conformation of the transition
state; the valine-derived (S)-3d and the proline-derived
The side chain of the amino acid scaffold exhibits the most
intriguing effect (Fig. 1). Thus, the i-Pr group of the valine
derived catalysts 3a–f, c-Hex of 6a, t-Bu of 6b, and PhCH2
of 6d (Table 1, entries 1–3; Table 2, entries 1–23; Table 3,
entries 1–4, 8, and 9) all induce the formation of the amine
of the same configuration (the latter analogue with a rather
decreased level of selectivity). The alanine derivative with
the Me substituent (6e) induces formation of the opposite
enantiomer with modest enantioselectivity (Table 2, entry
10) and this trend is further increased with the proline-
derived formamides 9a,b14a (Table 1, entries 5 and 6). The
phenylglycine derivative 6c gives a racemic product
(Table 2, entries 5–7), which places this catalyst at the
borderline. Apparently, the side chain is responsible for
inducing subtle conformational changes34 of the catalyst,
which play a key role in determining the sense of
enantiodifferentiation in the transition state.
The structural requirements for the ketimine 1 are as follows
(Fig. 1): the R1 group should preferably be aromatic, as in
1a–d, to attain high conversion and enantioselectivity
(Table 1, entries 1–9); both electron-donating and
electron-withdrawing groups are well tolerated, as in 1b,c
(compare Table 1, entry 7 vs 8; Table 2, entries 7 vs 8 and 14

272
A. V. Malkov et al. / Tetrahedron 62 (2006) 264–284
(S)-9b14a represent the extremes, favoring the formation of
(S)-2a (%92% ee) and (R)-2a (%66% ee), respectively.
CH2Cl2. The filtrate was evaporated in vacuo and the
product was crystallized from petroleum ether at 5 8C to
give pure 1c (0.67 g, 48%): mp 74–77 8C; 1H NMR
(400 MHz, CDCl3) d 2.17 (s, 3H), 6.71 (d, JZ8.0 Hz,
2H), 7.03 (t, JZ8.0 Hz, 1H), 7.30 (t, JZ8.0 Hz, 2H), 7.61
(d, JZ8.2 Hz, 2H), 7.99 (d, JZ8.2 Hz, 2H); 13C NMR d
17.80 (CH3), 119.57 (CH), 124.04 (CH), 125.72 (CH),
127.92 (CH), 129.44 (CH), 132.31 (CF3), 143.02 (C),
151.51 (C), 164.69 (C); IR (NaCl) n 1643 cmK1; MS m/z
(%) 263 (MC, 61), 248 (100), 244 (7), 152 (4), 181 (16), 77
(71); HRMS (EI): 263.0922 (C15H12N2F3 requires
263.0921).
In conclusion, we have designed new amino acid-derived
organocatalysts 3 and 6, which effect hydrosilylation of
N-aryl ketimines 1a–k, 43, and 45 with Cl3SiH to afford
secondary amines 2a–k, 44, and 46, respectively. The
observed enantioselectivity (%93% ee) of this metal-free
protocol matches the level of the transition metal-catalyzed
methods,2 with the L-valine-derived formamide 3d being the
champion catalyst and toluene the solvent of choice. Arene–
arene interactions between the anilide moiety of the catalyst
and N-aryl substituent of the substrate ketimine appear to
be the key factor contributing to the enantiodifferentiation
process.
4.2. Protocol A: general procedure for the catalytic
hydrosilylation of imines 1a–k, 43, and 45
Trichlorosilane (77 mL, 0.77 mmol) was added dropwise
to a stirred solution of the imine 1a–k (0.51 mmol) and
the catalyst (0.051 mmol) in anhydrous CH2Cl2 (or CHCl3
or MeCN; see Tables 1 and 2) at 0 8C (or at K20 8C), and
the mixture was allowed to stir overnight at room
temperature (or at K20 8C) under an argon atmosphere.
The reaction was quenched with a saturated solution of
NaHCO3 (10 mL) and the product was extracted with ethyl
acetate (100 mL). The extract was washed with brine and
dried over anhydrous MgSO4 and the solvent was
evaporated. Purification using column chromatography on
silica gel with a petroleum ether–ethyl acetate mixture
(24/1) afforded the product as an oil. The yields and ee are
given in Tables 1–4.
4. Experimental
4.1. General methods
Melting points were determined on a Kofler block and are
uncorrected. Optical rotations were recorded in CHCl3 at
25 8C unless otherwise indicated, with an error of %G0.1.
The [a]D values are given in 10K1 deg cm3 gK1. The NMR
spectra were recorded in CDCl3, 1H at 400 MHz and 13C at
100.6 MHz with chloroform-d1 (d 7.26, 1H; d 77.0, 13C) as
internal standard unless otherwise indicated. Various
2D-techniques and DEPT experiments were used to
establish the structures and to assign the signals. The IR
spectra were recorded for CHCl3 solutions unless otherwise
indicated. The mass spectra (EI and/or CI) were measured
on a dual sector mass spectrometer using direct inlet and the
lowest temperature enabling evaporation. All reactions were
performed under an atmosphere of dry, oxygen-free argon in
oven-dried glassware, twice evacuated and filled with inert
gas. Solvents and solutions were transferred by syringe-
septum and cannula techniques. All solvents for the
reactions were of reagent grade and were dried and distilled
immediately before use (dichloromethane from calcium
hydride). Petroleum ether refers to the fraction boiling in the
range of 60–80 8C. Yields are given for isolated products
showing one spot on a TLC plate and no impurities
detectable in the NMR spectrum. The identity of the
products prepared by different methods was checked by
comparison of their NMR, IR, and MS data and by the TLC
behavior. The chiral GC and HPLC methods were calibrated
with the corresponding racemic mixtures. The imines
1a,2j,37 1b,2j 1d,2j 1e,2j,3c 1f,38 1g,38 1h,39 1i,37 1j,2j 1k,3c
and 43,40 and 4514a are known compounds and were
prepared according to the procedure shown for 1c, the only
new member of this series. Amines 2a,41,42 2b,2j,37 2c,42
2d,41,42 2e,3c 2f,42 2g,43 2h,44 2i,37 2j,2j,37 2k,3c,14a 44,40,45
and 4646 are all know compounds and their absolute
configuration was established in reference to the literature
data.
4.2.1. Compound (S)-(C)-2a. [a]D C16.8 (c 0.5, MeOH);
1H NMR (400 MHz, CDCl3) d 1.41 (d, JZ7.1 Hz, 3H), 3.94
(br s, 1H), 4.41 (q, JZ6.7 Hz, 1H), 6.44 (d, JZ8.6 Hz, 2H),
6.57 (t, JZ7.3 Hz, 1H), 7.01 (t, JZ7.5 Hz, 2H), 7.13 (t, JZ
6.8 Hz, 1H), 7.27 (t, JZ7.3 Hz, 2H), 7.30 (d, JZ7.3 Hz,
2H) in agreement with the literature data;42 chiral HPLC
(Chiralcel OD-H, hexane/2-propanol 15:1C0.1% NEt3,
0.5 mL/min) showed 92% ee (tSZ15.1 min, tRZ
17.7 min).47
4.2.2. Compound (S)-(C)-2b. [a]D C4.45 (c 0.5, MeOH);
1H NMR (400 MHz, CDCl3) d 1.38 (d, JZ7.2 Hz, 3H), 3.68
(s, 3H), 3.90 (br s, 1H), 4.35 (q, JZ6.6 Hz, 1H), 6.41 (d, JZ
8.5 Hz, 2H), 6.55 (t, JZ7.31 Hz, 1H), 6.77 (d, JZ7.2 Hz,
2H), 6.97 (t, JZ6.5 Hz, 2H), 7.14 (d, JZ7.2 Hz, 2H) in
agreement with the literature data;2j,37 chiral HPLC
(Chiralcel OD-H, hexane/2-propanol 15:1C0.1% NEt3
0.5 mL/min) showed 80% ee (tSZ19.3 min, tRZ
22.7 min).47
4.2.3. Compound (S)-(C)-2c. [a]D C20.0 (c 0.5, CHCl3);
1H NMR (400 MHz, CDCl3) d 1.46 (d, JZ7.1 Hz, 3H), 3.97
(br s, 1H), 4.46 (q, JZ6.7 Hz, 1H), 6.38 (d, JZ7.6 Hz, 2H),
6.59 (t, JZ7.4 Hz, 1H), 7.02 (t, JZ7.3 Hz, 2H), 7.41 (d, JZ
8.2 Hz, 2H), 7.51 (d, JZ8.2 Hz, 2H) in agreement with the
literature data;42 chiral GC (Supelco b-DEX 120 column,
oven: 125 8C for 2 min, then 1 8C/min to 200 8C, 10 min at
that temperature) showed ee of 89% (tSZ42.8 min, tRZ
43.2 min).
4.1.1. Imine 1c. A mixture of NaHCO3 (2.2 g, 26 mmol),
aniline (0.48 mL, 5.3 mmol), p-trifluoromethylaceto-
phenone (1.0 g, 5.3 mmol), and activated molecular sieves
(4 g, 4 A) in anhydrous toluene (5 mL) was heated at 80 8C
for 12 h under an argon atmosphere. The mixture was
filtered through celite and the celite was washed with
˚
4.2.4. Compound (S)-(C)-2d. [a]D C16.2 (c 1.0, MeOH);
1H NMR (400 MHz, CDCl3) d 1.49 (d, JZ7.1 Hz, 3H), 4.03

A. V. Malkov et al. / Tetrahedron 62 (2006) 264–284
273
(br s, 1H), 4.54 (q, JZ6.7 Hz, 1H), 6.45 (d, JZ8.0 Hz, 2H),
6.56 (t, JZ7.5 Hz, 1H), 6.98 (t, JZ7.6 Hz, 2H), 7.30 (t, JZ
7.8 Hz, 2H), 7.36 (d, JZ7.2 Hz, 2H), 7.69 (d, JZ7.8 Hz,
2H), 7.70 (s, 1H) in agreement with the literature data;41,42
chiral HPLC (Chiralcel OD-H, hexane/2-propanol 15:1C
0.1% NEt3, 0.5 mL/min) showed 88% ee (tSZ18.7 min,
tRZ21.2 min).47
reflux with acetyl chloride (3 equiv), triethylamine (3 equiv)
and DMAP (cat.) in CHCl3 for 30 min. Aqueous work up
followed by purification using column chromatography on
silica gel with a petroleum ether–ethyl acetate mixture (2/1)
afforded the acetamide derivative as an oil: 1H NMR
(400 MHz, CDCl3) d 1.43 (d, JZ6.7 Hz, 3H), 1.69 (s, 3H),
2.48 (s, 3H), 6.27 (q, JZ6.8 Hz, 1H), 6.57 (d, JZ8.0 Hz,
1H), 6.82 (t, JZ7.6 Hz, 1H), 6.84–7.23 (m, 7H); chiral
HPLC (Whelk-O1, hexane/2-propanol 91:9, 1.0 mL/min)
showed 92% ee (tmajorZ12.7 min, tminorZ14.5 min). The
absolute configuration of the prevailing enantiomer is
assumed to be (S) in analogy with the rest of the series
but has not been rigorously proven.
4.2.5. Compound (S)-(C)-2e. [a]D C6.1 (c 1.0, CHCl3);
1H NMR (400 MHz, CDCl3) d 0.91–1.80 (m, 11H), 1.05
(d, JZ6.7 Hz, 3H), 3.2 (q, JZ8.0 Hz, 1H), 3.38 (br s, 1H),
6.49 (d, JZ8.0 Hz, 2H), 6.55 (t, JZ8.0 Hz, 1H), 7.07
(t, JZ10.0 Hz, 2H) in agreement with the literature
data;3c chiral HPLC (Chiralcel OD-H, hexane/2-propa-
nol 99:1, 0.75 mL/min) showed 37% ee (tRZ8.2 min,
tSZ8.7 min).
4.2.12. Compound (S)-(K)-44. [a]D K17.4 (c 1.0, CHCl3)
[lit.45 gives C4.4 (c 1.0, CHCl3) for the (R)-enantiomer];
1H NMR (400 MHz, CDCl3) d 1.32 (d, JZ6.6 Hz, 3H),
3.63 (br s, 1H), 4.05 (m, 1H), 6.13 (dd, JZ5.8, 16.0 Hz,
1H), 6.50 (d, JZ16.0 Hz, 1H), 6.56–7.28 (m, 10H) in
agreement with the literature data;40,45 For the ee
determination, amine 44 was converted into the acetyl
derivative by heating at reflux with acetyl chloride
(3 equiv), triethylamine (3 equiv) and DMAP (cat.) in
CHCl3 for 30 min. Aqueous work up followed by
purification using column chromatography on silica gel
with a petroleum ether–ethyl acetate mixture (2/1) afforded
4.2.6. Compound (S)-(C)-2f. [a]D C2.5 (c 1.0, MeOH);
1H NMR (400 MHz, CDCl3) d 1.40 (d, JZ7.0 Hz, 3H), 3.60
(s, 3H), 4.32 (q, JZ6.4 Hz, 1H), 6.37 (d, JZ8.1 Hz, 2H),
6.61 (d, JZ7.6 Hz, 2H), 7.15 (t, JZ7.4 Hz, 1H), 7.22 (t, JZ
7.4 Hz, 2H), 7.28 (d, JZ7.6 Hz, 2H) in agreement with the
literature data;42 chiral HPLC (Chiralcel OD-H, hexane/
2-propanol 99:1, 0.75 mL/min) showed 85% ee (tRZ
15.5 min, tSZ18.6 min).
4.2.7. Compound (S)-(C)-2g. [a]D C9.2 (c 0.5, CHCl3);
1H NMR (400 MHz, CDCl3) d 1.44 (d, JZ7.1 Hz, 3H), 3.80
(s, 3H), 4.38 (q, JZ6.8 Hz, 1H), 4.54 (br s, 1H), 6.25 (d, JZ
8.0 Hz, 1H), 6.52 (t, JZ6.9 Hz, 1H), 6.61 (t, JZ7.2 Hz,
1H), 6.69 (d, JZ7.1 Hz, 1H), 7.12 (t, JZ7.5 Hz, 1H), 7.24
(t, JZ7.2 Hz, 2H), 7.33 (d, JZ7.2 Hz, 2H) in agreement
with the literature data;43 chiral HPLC (Chiralcel OD-H,
hexane/2-propanol 99:1, 0.75 mL/min) showed 22% ee
(tSZ7.1 min, tRZ8.1 min).47
1
the acetamide derivative as an oil: H NMR (400 MHz,
CDCl3) d 1.16 (d, JZ6.5 Hz, 3H), 1.72 (s, 3H), 5.55 (q, JZ
6.7 Hz, 1H), 6.04 (dd, JZ5.8, 15.9 Hz, 1H), 6.40 (d, JZ
15.9 Hz, 1H) 7.03–7.34 (m, 10H); chiral HPLC (Chiralcel
OD-H, hexane/2-propanol 85:15, 1.0 mL/min) showed 74%
ee (tSZ17.5 min, tRZ36.8 min).
4.2.13. Compound (R)-(K)-46. [a]D K20.2 (c 1.0, CHCl3),
K13.2 (c 1.0, THF) [lit.46b gives C68.3 (c 0.32, THF) for
the (S)-enantiomer]; 1H NMR (400 MHz, CDCl3) d 3.66 (s,
3H), 4.87 (br s, 1H), 5.01 (d, JZ5.6 Hz, 1H), 6.47 (d, JZ
8.4 Hz, 2H), 6.62 (t, JZ6.8 Hz, 1H), 7.05 (t, JZ7.6 Hz,
2H), 7.24–7.31 (m, 3H), 7.43 (d, JZ7.6 Hz, 2H) in
agreement with the literature data;46 chiral HPLC (Chiralcel
OD-H, hexane/2-propanol 99:1, 1 mL/min) showed 30% ee
(tSZ19.5 min, tRZ23.1 min).
4.2.8. Compound (G)-2h. NMR (400 MHz, CDCl3) d
0.91–2.29 (m, 11H), 1.34 (d, JZ6.8 Hz, 3H), 3.93 (q, JZ
6.8 Hz, 1H), 7.16–7.29 (m, 5H) in agreement with the
literature data.44 The racemic nature was confirmed by
running the NMR spectrum in the presence of mandelic acid
(2 equiv).
4.2.9. Compound (G)-2i. NMR (400 MHz, CDCl3) d
0.79 (t, JZ7.3 Hz, 3H), 1.19 (m, 2H), 1.32 (d, JZ7.2 Hz,
3H), 1.36 (m, 2H), 2.40 (m, 2H), 3.73 (q, JZ6.6 Hz,
1H), 7.1–7.3 (arom, 5H) in agreement with the literature
data.37 The racemic nature was confirmed by running
the NMR spectrum in the presence of mandelic acid
(2 equiv).
4.3. Protocol B: general procedure for the synthesis of
formamides 3a–g, 4a,b, 5, and 6c–e
The BOC derivative 15a–d, 15f,g, 16a,b, 20c–e, and 37
(1.03 mmol) was dissolved in trifluoroacetic acid (2.0 mL)
at room temperature. After 1 h the reaction mixture was
evaporated in vacuo, the residue (the free amine) was
dissolved in formic acid (1.5 mL) and the resulting solution
was cooled to 0 8C. Acetic anhydride (0.68 mL, 7.21 mmol)
was added dropwise and the mixture was allowed to stir at
room temperature overnight. The volatiles were then
removed by reduced pressure. Purification using column
chromatography on silica gel with a petroleum ether–ethyl
acetate mixture (2/1) afforded the 3a–d, 3f,g, 4a,b, 5, and
6c–e; the yields are give below. Formylation of amine 17
(1.03 mmol) in the same fashion (skipping the deprotection
step) furnished 3e.
4.2.10. Compound 2j. 1H NMR (400 MHz, CDCl3) d 1.30
(d, JZ7.1 Hz, 3H), 2.13 (br s, 1H), 3.53 (m, 2H), 3.73 (q,
JZ5.5 Hz, 1H), 7.1–7.3 (arom, 10H) in agreement with the
literature data.2j,37 The almost racemic nature was con-
firmed by running the NMR spectrum in the presence of
mandelic acid (2 equiv).
4.2.11. Compound 2k. 1H NMR (400 MHz, CDCl3) d 1.41
(d, JZ6.6 Hz, 3H), 2.36 (s, 3H), 3.93 (br s, 1H), 4.60 (q, JZ
6.6 Hz, 1H), 6.36 (d, JZ8.6 Hz, 2H), 6.50 (t, JZ7.3 Hz,
1H), 6.94–7.46 (m, 6H).3c For the ee determination, amine
2k was converted into the acetyl derivative by heating at

274
A. V. Malkov et al. / Tetrahedron 62 (2006) 264–284
4.4. Protocol C: general procedure for the synthesis of
dipeptide formamides (S,S)-12a–c via N-BOC
deprotection
triturated with a petroleum ether–ether mixture (1/1) and
filtered to afford the pure product (R)-23a,(S)-23b, and
(S)-32, respectively; see below for the characteristics.
Trifluoroacetic acid (3 mL) was added dropwise to a
solution of (S,S)-41a–c (0.60 mmol) in dichloromethane
(3 mL) at 0 8C and the reaction mixture was stirred at 0 8C
for 1 h. The solvent was then removed under reduced
pressure and the residue was co-evaporated with toluene
(3!5 mL) to afford a TFA salt of the deprotected amide
42a–c as a colorless solid, which was used in the following
step without further purification. The crude amide 42a–c
was dissolved in formic acid (1.7 mL) and the resulting
solution was cooled to 0 8C. Acetic anhydride (0.86 mL,
9.1 mmol) was added dropwise and the reaction mixture
was allowed to stir at room temperature overnight, and then
evaporated to dryness. The traces of acids were removed by
co-evaporation with toluene (3!5 mL) and the residue was
purified by column chromatography on silica gel to afford
(S,S)-12a–c; the yields and chromatography details are give
below.
4.7. Protocol F: general procedure for the synthesis of
formamides (G)-6a,b and (S)-7 via amidation
Triethylamine (0.1 mL, 0.75 mmol) was added dropwise to
a cooled (0 8C) suspension of (R)-23a, (S)-23b, and (S)-32,
respectively (0.50 mmol), in dry dichloromethane (5 mL).
After the suspension had dissolved, 3,5-dimethylaniline
(0.075 mL, 0.6 mmol) was added, followed by 1-hydroxy-
benzotriazole hydrate (HOBt; 117 mg, ca. 0.65 mmol) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydro-
chloride (EDCI; 125 mg, 0.65 mmol). The mixture was
stirred at 0 8C for 1 h, and then at room temperature for 20 h.
The mixture was then diluted with ethyl acetate (25 mL) and
washed successively with water (10 mL), cold 0.5 M HCl
(2!10 mL), saturated NaHCO3 (2!10 mL), and brine
(10 mL) and dried over MgSO4, filtered and evaporated.
The residue was purified by column chromatography on
silica gel to afford (G)-6a,b and (S)-7, respectively.
4.5. Protocol D: general procedure for the synthesis of
6a,b via N-Cbz deprotection
4.8. Protocol G: general procedure for the synthesis of
N-methyl Boc-protected amino acids (S)-14, (R)-19c,
(S)-19d, and (S)-19e
Pd/C (10%, 334 mg) was added to a solution of (R)-27a and
(S)-27b, respectively (0.81 mmol) in a mixture of methanol
(23.4 mL) and formic acid (1.1 mL) and the mixture was
stirred at room temperature for 2 h, then filtered through a
Celite pad. The pad was washed with methanol, the
combined filtrate was evaporated to dryness, and
co-evaporated with toluene (3!10 mL) to afford a formate
salt of the deprotected amine (R)-28a and (S)-28b,
respectively, as a colorless solid. The latter solid was
dissolved in formic acid (2.7 mL) and the resulting solution
was cooled to 0 8C. Acetic anhydride (1.3 mL, 13.8 mmol)
was added dropwise and the reaction mixture was allowed
to stir at room temperature overnight, and then evaporated
to dryness. The traces of acids were removed by
co-evaporation with toluene (3!5 mL) and the remaining
yellowish oil was purified by column chromatography on
silica gel to afford (R)-6a and (S)-6b; the yields and
chromatography details are give below.
Sodium hydride (60% dispersion in mineral oil; 3.0 g,
138 mmol) was added in small portions to a stirred solution
of the respective BOC-protected amino acid (S)-13, (R)-18c,
(S)-18d, and (S)-18e (13.8 mmol) and methyl iodide (19.6 g,
138 mmol) in anhydrous THF (60 mL) at 0 8C. The mixture
was allowed to stir at room temperature for 24 h under an
argon atmosphere, the reaction was then quenched with
water (15 mL), ethyl acetate (10 mL) was added and the
mixture was evaporated in vacuo. The concentrate was
diluted with water (300 mL) and washed with ethyl acetate
(150 mL). The aqueous solution was acidified to pH 3.5
with a solution of 5% citric acid and extracted with ethyl
acetate (200 mL). The extract was washed with brine, dried
over anhydrous MgSO4, and evaporated in vacuo to give the
14 and 19c–d, respectively; the yields are given below.
4.6. Protocol E: general procedure for the synthesis of
N-methyl-formamides 23a,b and (S)-32 via reduction of
oxazolidinones
4.9. Protocol H: general procedure for the synthesis of
amides 15a–d, 15f,g, 16a, 20c–e, and 37
Methyl chloroformate (0.55 mL, 7.15 mmol) was added
dropwise to a stirred solution of (S)-14 (1.40 g, 6.05 mmol)
and triethylamine (1.0 mL, 7.15 mmol) in anhydrous THF
(30 mL) at 0 8C under an argon atmosphere and the mixture
was stirred at that temperature for 2 h. The precipitate was
removed by suction filtration and the filtrate was added
dropwise to a solution of the corresponding amine
(8.5 mmol) and triethylamine (1.0 mL, 7.15 mmol) in
anhydrous THF (30 mL) at 0 8C. The mixture was allowed
to stir at room temperature overnight under an argon
atmosphere and the solvent was then removed under
reduced pressure. The residue was purified using column
chromatography on silica gel with a petroleum ether–ethyl
acetate mixture (4/1) to afford 15a–d, 15f,g, 16a, 20c–e, and
37; the yields are given below.
Triethylsilane (0.5 mL, 3.1 mmol) and trifluoroacetic acid
(5 mL) were added dropwise to a stirred solution of (R)-21a,
(S)-21b, and (S)-30, respectively (1.00 mmol), in dry
chloroform (5 mL) and the mixture was stirred overnight
at room temperature. The mixture was then evaporated to
dryness and co-evaporated with toluene (3!10 mL) to
afford crude 22a,b and 31, respectively, as a colorless salt
(containing two TFA molecules) in quantitative yield,
which was used in the following step without further
purification. The latter salt was dissolved in formic acid
(3 mL) and the resulting solution was cooled to 0 8C. Acetic
anhydride (1.5 mL, 15.9 mmol) was added dropwise and the
mixture was allowed to stir at room temperature overnight,
and then evaporated to dryness and co-evaporated with
toluene (3!5 mL). The semi-solid crude product was

A. V. Malkov et al. / Tetrahedron 62 (2006) 264–284
275
4.10. Protocol I: general procedure for the synthesis of
the N-BOC protected amides (S)-39a–c
4.13. Protocol L: general procedure for the synthesis of
N-BOC protected dipeptides (S,S)-41a–c
Trifluoroacetic acid (5 mL) was added dropwise to a cooled
(0 8C) solution of (S)-39a–c, respectively (1.00 mmol), in
dichloromethane (5 mL) and the reaction mixture was
stirred at 0 8C for 1 h. The solvent was removed under
reduced pressure and the residue was co-evaporated with
toluene (3!5 mL) to afford a TFA salt of the deprotected
amide (S)-40a–c as a colorless solid, which was used in the
following step without further purification. Triethylamine
(0.42 mL, 3 mmol) was added dropwise to a suspension of
(S)-40a–c TFA in dichloromethane (15 mL) at 0 8C. A
solution of (S)-14 (231 mg, 1 mmol) in dichloromethane
(5 mL) was added dropwise to the resulting clear solution,
followed by 1-hydroxy-benzotriazole hydrate (HOBt;
234 mg, ca. 1.3 mmol) and 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (EDCI; 249 mg,
1.3 mmol). The reaction mixture was stirred at 0 8C for
1 h, and then at room temperature for 20 h. The mixture was
then diluted with ethyl acetate (50 mL) and washed
successively with water (20 mL), cold 0.5 M HCl (2!
20 mL), saturated NaHCO3 (2!20 mL), brine (20 mL),
dried over MgSO4, filtered and evaporated. Purification by
column chromatography on silica gel furnished the
respective product (S,S)-41a–c.
Triethylamine (1.05 mL, 7.5 mmol) was added to a solution
of 13 and 18c,d, respectively (5.00 mmol) in dry dichloro-
methane (50 mL) at 0 8C. To the resulting clear solution
were consecutively added 3,5-dimethylaniline (0.75 mL,
6 mmol), 1-hydroxy-benzotriazole hydrate (HOBt; 1.17 g,
ca. 6.5 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcar-
bodiimide hydrochloride (EDCI; 1.25 g, 6.5 mmol). The
reaction mixture was stirred at 0 8C for 1 h and then at room
temperature for 20 h. The mixture was then diluted with
ethyl acetate (250 mL) and washed successively with
water (100 mL), cold 0.5 M HCl (2!100 mL), saturated
NaHCO3 (2!100 mL), and brine (100 mL), dried over
anhydrous MgSO4, filtered and evaporated to afford amide
(S)-39a–c.
4.11. Protocol J: general procedure for the synthesis of
the N-Cbz protected amides 27a,b
Triethylsilane (0.25 mL, 1.55 mmol) and trifluoroacetic
acid (2.5 mL) were added dropwise to a stirred solution of
(R)-25a and (S)-25b, respectively (0.50 mmol), in dry
chloroform (2.5 mL) and the reaction mixture was stirred
for one week at room temperature. The mixture was then
evaporated to dryness and co-evaporated with toluene (3!
5 mL) to afford crude acid 26a and 26b, respectively, as an
oily residue that was used in the following step without
further purification. The later acid was dissolved in dry
dichloromethane (5 mL) and the solution was cooled to
0 8C. Triethylamine (0.21 mL, 1.5 mmol) was added
dropwise, followed by an addition of 3,5-dimethylaniline
(0.075 mL, 0.6 mmol), 1-hydroxy-benzotriazole hydrate
(HOBt; 117 mg, ca. 0.65 mmol) and 1-(3-dimethylamino-
propyl)-3-ethylcarbodiimide hydrochloride (EDCI; 125 mg,
0.65 mmol). The reaction mixture was stirred at 0 8C for 1 h,
and then at room temperature for 20 h. The mixture was
then diluted with ethyl acetate (25 mL) and washed
successively with water (10 mL), cold 0.5 M HCl (2!
10 mL), saturated NaHCO3 (2!10 mL), brine (10 mL),
dried over MgSO4, filtered and evaporated. The residue was
purified by column chromatography on silica gel.
4.13.1. N-methylformamide (S)-(K)-3a. Obtained from
(S)-15a using protocol B (oil, 180 mg, 75%): [a]D K187.0
(c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) d 0.85 (d, JZ
6.6 Hz, 3H), 0.99 (d, JZ6.7 Hz, 3H), 2.40 (m, 1H), 2.92 (s,
3H), 4.41 (d, JZ10.3 Hz, 1H), 7.0 (t, JZ7.4 Hz, 1H), 7.22
(t, JZ7.8 Hz, 2H), 7.46 (d, JZ7.7 Hz, 2H), 8.09 (s, 1H),
8.50 (br s, 1H); 13C NMR d 17.59 (CH3), 17.78 (CH3), 18.49
(CH3), 24.47 (CH), 30.60 (CH3), 67.99 (CH), 118.95 (CH),
123.39 (CH), 127.92 (CH) 136.80 (C), (CHO), 166.31 (CO);
IR (Golden Gate) n 3274 (NH), 1650 (CO) cmK1; MS m/z
(%) 234 (M%C, 8), 142 (20), 114 (35), 85 (65), 47 (15);
HRMS (EI) 234.1368 (C13H18O2N2 requires 234.1367).
4.13.2. N-methylformamide (S)-(K)-3b. Obtained from
(S)-15b using protocol B (oil, 84 mg, 57%): [a]D K201.6 (c
1
1.0, CHCl3); H NMR (400 MHz, CDCl3) d 0.83 (d, JZ
6.6 Hz, 3H), 0.98 (d, JZ6.5 Hz, 3H), 2.40 (m, 1H), 2.90 (s,
3H), 3.7 (s, 3H), 4.3 (d, JZ11.2 Hz, 1H), 6.70 (d, JZ
6.8 Hz, 2H), 7.30 (d, JZ9.0 Hz, 2H), 7.90 (br s, 1H), 8.10
(s, 1H); 13C NMR d 18.94 (CH3), 19.96 (CH3), 25.65 (CH),
31.99 (CH3), 55.88 (CH3), 63.44 (CH), 114.51 (CH), 121.97
(CH), 131.16 (C), 156.87 (C), 164.34 (CHO), 167.3 (CO);
IR (Golden Gate) n 3274 (NH), 2834, 1648 (CO) cmK1; MS
m/z (%) 264 (M%C, 6), 249 (1), 192 (3), 162 (5), 142 (41),
114 (100), 83 (68), 47 (11); HRMS (EI) 264.1474,
(C14H20O3N2 requires 264.1474).
4.12. Protocol K: general procedure for the synthesis of
5-oxazolidinones 21a,b, 25a,b and 30
Camphorsulfonic acid (158 mg, 0.68 mmol) and para-
formaldehyde (2.252 g, 75 mmol) were added to a solution
of (R)-18a, (S)-18b, (R)-24a, (S)-24b, and (S)-29,
respectively (8.80 mmol) in toluene (112 mL) and the
mixture was heated under reflux for 1 h. The mixture was
then cooled and filtered, the filtrate was diluted with ether
(200 mL), and washed with 2.5% aqueous sodium
bicarbonate solution (4!50 mL). The combined aqueous
layers were extracted with ether (50 mL) and the combined
organic phase was dried over anhydrous MgSO4, filtered,
and evaporated. The oily residue was purified using column
chromatography on silica gel to furnish pure oxazolidinone
21a,b, 25a,b, and 30, respectively; the yield and chroma-
tography conditions are shown below.
4.13.3. N-methylformamide (S)-(K)-3c. Obtained from
(S)-15c using protocol B (oil, 131 mg, 26%): [a]D K137.5
(c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) d 0.94 (d, JZ
6.7 Hz, 3H), 1.04 (d, JZ6.8 Hz, 3H), 2.49 (m, 1H), 3.02 (s,
3H), 3.79 (s, 6H), 4.38 (d, JZ11.2 Hz, 1H), 6.25 (s, 1H),
6.78 (s, 2H), 8.04 (br s, 1H), 8.17 (s, 1H); 13C NMR d 18.89
(CH3), 19.95 (CH3), 25.57 (CH3), 32.04 (CH), 55.79 (CH3),
63.76 (CH), 97.5 (CH), 98.37 (CH), 139.73 (CH), 161.42
(C), 164.50 (CHO), 167.52 (CO); IR (NaCl) n 3293 (NH),

276
A. V. Malkov et al. / Tetrahedron 62 (2006) 264–284
1655 (CO) cmK1; MS m/z (%) 294 (M%C, 4), 280 (41), 220
(3), 192 (11), 153 (100), 100 (40), 55 (19); HRMS (EI)
294.1580 (C15H22O4N2 requires 294.1582).
3H), 3.20 (s, 3H), 4.54 (d, JZ10.9 Hz, 1H), 7.05 (t, JZ
7.6 Hz, 1H), 7.30 (t, JZ7.8 Hz, 2H), 7.33 (d, JZ7.7 Hz,
2H), 7.84 (s, 1H); 13C NMR d 18.50 (CH3), 18.77 (CH3),
27.29 (CH), 31.39 (CH3), 38.01 (CH3), 64.21 (CH), 128.11
(CH), 129.16 (CH), 130.65 (CH), 142.98 (C), 163.44
4.13.4. N-methylformamide (S)-(K)-3d. Obtained from
(S)-15d using protocol B (142 mg, 82%): mp 83–86 8C;
[a]D K19.2 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) d
0.84 (d, JZ6.6 Hz, 3H), 0.99 (d, JZ6.5 Hz, 3H), 2.20 (s,
6H), 2.39 (m, 1H), 2.95 (s, 3H), 4.35 (d, JZ11.2 Hz, 1H),
6.67 (s, 1H), 7.09 (d, JZ8.3 Hz, 2H), 8.07 (s, 1H), 8.18 (br
s, 1H); 13C NMR d 18.97 (CH3), 19.92 (CH3), 21.71 (CH3),
25.74 (CH), 31.96 (CH), 63.47 (CH), 118.21 (CH), 126.56
(CH), 137.92 (C), 139.13 (C), 164.35 (CHO), 167.61 (CO);
IR (Golden Gate) n 3284 (NH), 1650 (CO) cmK1; MS m/z
(%) 262 (M%C, 29), 160 (7), 142 (43), 114 (100), 86 (21), 83
(19), 42 (7); HRMS (EI) 262.1681 (C15H22O2N2 requires
262.1680).
(CHO), 169.77 (CO); IR (Golden Gate) n 1658 (CO) cmK1
;
MS m/z (%) 248 (M%C, 3), 142 (21), 114 (53), 83 (100), 77
(5), 47 (16); HRMS 248.1526 (C14H20O2N2 requires
248.1525).
4.13.9. N-methylformamide (S)-(K)-4b. Obtained from
(S)-16b using protocol B (oil, 75 mg, 83%): [a]D K11.6 (c
1
1.5, CHCl3); H NMR (400 MHz, CDCl3) d 0.77 (d, JZ
6.7 Hz, 3H), 0.85 (d, JZ6.8 Hz, 3H), 1.09 (m, 3H), 1.11 (m,
3H), 2.36 (m, 1H), 2.85 (s, 3H), 3.20 (m, 2H), 3.33 (m, 2H),
4.76 (d, JZ10.7 Hz, 1H), 8.02 (br s, 1H); 13C NMR d 13.23
(CH3), 15.51 (CH3), 18.51 (CH3), 19.87 (CH3), 26.77 (CH),
31.26 (CH3), 40.87 (CH2), 42.06 (CH2), 63.79 (CH), 163.23
(CHO), 168.43 (CO); MS m/z (%) 215 (M%C, 100), 187 (4),
142 (10), 114 (8), 81 (19); HRMS (EI): 215.1760
(C11H23O2N2 requires 215.1761).
4.13.5. N-methylformamide (S)-(K)-3e. Obtained (via
protocol B) from the free amine (S)-17 so that no BOC
deprotection was required prior to the formylation (189 mg,
1
95%): mp 152–154 8C; [a]D K81.5 (c 1.5, CH2Cl2); H
NMR (400 MHz, CDCl3) d 0.89 (d, JZ6.6 Hz, 3H), 1.03 (d,
JZ6.6 Hz, 3H), 2.45 (m, 1H), 2.96 (s, 3H), 4.34 (d, JZ
11.3 Hz, 1H), 7.52 (s, 1H), 7.95 (s, 2H), 8.10 (s, 1H), 8.90
(br s, 1H); 13C NMR d 19.06 (CH3), 19.85 (CH3), 26.02
(CH3), 32.29 (CH), 63.67 (CH), 69.41 (CH), 117.80 (CH),
119.94 (CH), 139.84 (C), 164.51 (CHO), 168.35 (CO); IR
(NaCl) n 3233 (NH), 1648 (CO) cmK1; MS m/z (%) 370
(M%C, 24), 351 (65), 299 (16), 256 (15), 228 (26), 188 (8);
HRMS 370.1118 (C15H16O2N2F6 requires 370.1116).
4.13.10. Formamide (S)-(C)-5. Obtained from (S)-37
using protocol B (191 mg, 60%): mp 151–153 8C; [a]D
C1.2 (c 1.0, MeOH); H NMR (400 MHz, CDCl3) d 0.96
1
(d, JZ6.8 Hz, 3H), 0.98 (d, JZ6.7 Hz, 3H), 2.12 (m, 1H),
3.69 (s, 6H), 6.50 (t, JZ7.8 Hz, 1H), 6.16 (s, 1H), 6.48 (d,
JZ8.6 Hz, 1H), 6.70 (s, 2H), 8.21 (s, 1H), 8.37 (br s, 1H);
13C NMR d 18.76 (CH3), 19.67 (CH3), 31.83 (CH), 55.72
(CH3), 58.44 (CH), 97.4 (CH), 98.58 (CH), 139.73 (CH),
161.36 (C), 161.74 (CHO), 169.79 (CO); IR (NaCl) n 3272
(NH), 1645 (CO) cmK1; MS (CI) m/z (%) 281 ([MH]%C
,
100), 263 (2), 192 (3); HRMS (CI) 281.1501 (C14H21O4N2
requires 281.1501).
4.13.6. N-methylformamide (S)-(K)-3f. Obtained from
(S)-15f using protocol B (oil, 35 mg 41%): [a]D K99.4 (c
0.5, CHCl3); H NMR (400 MHz, CDCl3) d 0.82 (d, JZ
1
6.7 Hz, 3H), 0.97 (d, JZ6.5 Hz, 3H), 2.39 (m, 1H), 2.96 (s,
3H), 4.37 (d, JZ11.2 Hz, 1H), 7.05 (s, 1H), 7.48 (s, 2H),
8.10 (s, 1H), 8.84 (br s, 1H); 13C NMR d 19.01 (CH3), 19.85
(CH3), 25.87 (CH), 32.25 (CH3), 63.74 (CH), 118.55 (CH),
118.66 (CH), 124.64 (CH), 135.53 (C), 140.06 (C), 164.52
(CHO), 168.01 (CO); MS m/z (%) 303 (M%C, 100), 269 (9),
216 (5), 142 (39), 114 (25), 81 (52); HRMS (EI): 303.0067
(C13H17O2N2Cl2 requires 303.0673).
4.13.11. N-methylformamide (G)-6a. Obtained from (R)-
23a as colorless solid (137 mg, 91%), using protocol F: mp
135–137 8C; [a]D 0.0 (c 1.0, CHCl3); H NMR (400 MHz,
1
CDCl3, a mixture of rotamers in ca. 5:1 ratio; the signals for
the minor rotamer are marked by *) d 0.8–1.06 (m, 2H),
1.13–1.38 (m, 3H), 1.55–1.87 (m, 5H), 2.11–2.21 (m, 1H),
2.28 (s, 6H), 2.96* (s, 0.5H) and 2.99 (s, 2.5H), 3.73* (d, JZ
10.8 Hz, 0.15H), 4.48 (d, JZ11.2 Hz, 0.85H), 6.74 (s) and
6.77* (s, 1H), 7.16 (s) and 7.21* (s, 2H), 8.12 (br s, 0.85H),
8.13 (s, 0.85H), 8.21* (br s, 0.15H), 8.4* (s, 0.15H); 13C
NMR (CDCl3/CD3OD) d 21.07 (CH3), 25.62 (CH2), 25.81
(CH2), 28.44 (CH2), 29.36 (CH2), 40.56 (CH3), 57.05 (CH),
117.71 (CH), 126.12 (CH), 137.18 (C), 138.43 (C), 161.72
(CHO), 169.45 (CO); IR (KBr) n 3262, 2928, 2854, 1654,
1570, 1203, 1084, 892, 847, 822 cmK1; MS (EI) m/z (%)
302 (M%C, 25), 182 (43), 154 (100), 121 (23), 95 (42), 83
(30), 72 (24); HRMS (EI) 302.1995 (C18H26O2N2 requires
302.1994).
4.13.7. N-methylformamide (S)-(K)-3g. Obtained from
(S)-15g using protocol B; purification using column
chromatography on silica gel with an ethyl acetate–
methanol mixture (9/1) afforded the product as an oil
(357 mg, 51%); [a]D K8.10 (c 1.5, CHCl3); 1H NMR
(400 MHz, CDCl3) d 0.91 (m, 9H), 1.32 (m, 2H), 1.49 (m,
2H), 2.41 (m, 1H), 3.00 (s, 3H), 3.21 (m, 2H), 4.24 (d, JZ
11.2 Hz, 1H), 6.14 (br s, 1H), 8.15 (s, 1H); 13C NMR d 14.00
(CH3), 18.87 (CH3), 19.86 (CH3), 20.21 (CH2), 25.68 (CH),
27.88 (CH3) 31.68 (CH2), 39.51 (CH2), 62.58 (CH), 164.41
(CHO), 169.38 (CO); IR (NaCl) n 3318 (NH), 1653 (CO),
1558 cmK1; MS m/z (%) 215 (M%C, 100), 201 (5), 132 (8),
114 (6), 79 (4); HRMS (EI): 215.1760 (C11H23O2N2
requires 215.1760).
4.13.12. N-methylformamide (R)-(C)-6a. Obtained from
(R)-27a (226 mg, 92%) as a colorless foam using protocol
D; purified by column chromatography on silica gel with a
hexane–ethyl acetate mixture (6/4, RfZ0.58/0.33): [a]D
C153.9 (c 1.0, CHCl3); all spectroscopic data were
identical with those recorded for (G)-6a.
4.13.8. N-methylformamide (S)-(K)-4a. Obtained from
(S)-16a using protocol B (oil, 20 mg, 37%): [a]D K104.0 (c
1
0.5, CHCl3); H NMR (400 MHz, CDCl3) d 0.61 (d, JZ
4.13.13. N-methylformamide (G)-6b. Obtained from
(S)-23b (173 mg, 1 mmol), using protocol F; purification
6.7 Hz, 3H), 0.86 (d, JZ6.5 Hz, 3H), 2.37 (m, 1H), 2.76 (s,

A. V. Malkov et al. / Tetrahedron 62 (2006) 264–284
277
by column chromatography on silica gel with a hexane–
ethyl acetate mixture (65/35, RfZ0.49/0.24) afforded (G)-
6b (201 mg, 73%) as a colorless solid: mp 98–100 8C; [a]D
(CH), 126.15 (CH), 137.50 (C), 138.01 (C), 163.87 (CHO),
168.04 (CO); IR (NaCl) n 3289 (NH), 1644 (CO) cmK1; MS
m/z (%) 234 (M%C, 33), 199 (5), 147 (6), 113 (31), 82 (100),
58 (37), 49 (39); HRMS (EI) 234.1371 (C13H18O2N2
requires 234.1368).
1
0.0 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3, a mixture
of rotamers in ca. 2:1 ratio; the signals for the minor rotamer
are marked by *) d 1.14* (s) and 1.15 (s, 9H), 2.28 (s, 6H),
3.07* (s, 1H) and 3.24 (s, 2H), 3.82* (s, 0.33H) and 4.79 (s,
0.66H), 6.76 (s, 1H), 7.16* (s) and 7.19 (s, 2H), 8.18 (s,
0.66H), 8.27* (s, 0.33H), 8.36 (br s) and 8.47* (br s, 1H);
13C NMR d 21.34 (CH3), 27.43* (CH3), 27.85 (CH3),
30.38* (CH3), 34.24 (CH3), 35.47 (C), 35.65* (C), 62.66*
(CH), 70.01 (CH), 117.76 (CH), 117.91* (CH), 126.18
(CH), 126.38* (CH), 137.37* (C), 137.53 (C), 138.64 (C),
138.68* (C), 164.54 (CHO), 165.31* (CHO), 166.44* (CO),
166.96 (CO); IR (KBr) n 3280, 2958, 2915, 2870, 1660,
1559, 1180, 1068, 844, 829 cmK1; MS (EI) m/z (%) 276
(M%C, 35), 156 (87), 128 (100), 121 (71), 100 (16), 60 (38);
HRMS (EI) 276.1837 (C16H24O2N2 requires 276. 1837).
4.13.18. N-methylformamide (S)-(K)-6f. Obtained from
(S)-20f using protocol B (oil, 1.13 g, 84%): [a]D K191.1 (c
1
1.0, CHCl3); H NMR (400 MHz, CDCl3) d 0.98 (d, JZ
6.6 Hz, 3H), 1.01 (d, JZ6.6 Hz, 3H), 1.59 (hept, JZ6.6 Hz,
1H), 1.72 (ddd, JZ14.0, 8.0, 6.0 Hz, 1H), 1.87–1.94 (m,
1H), 2.30 (s, 6H), 2.90 (s, 3H), 4.99 (t, JZ8.0 Hz, 1H), 6.76
(s, 1H), 7.16 (s, 2H), 8.03 (br s, 1H), 8.16 (s, 1H); 13C NMR
d 21.37 (CH3), 22.83 (CH3), 24.77 (CH), 31.28 (CH3), 35.61
(CH2), 54.07 (CH), 117.90 (CH), 126.31 (CH), 137.24 (C),
138.71 (C), 164.12 (CHO), 167.88 (CO); IR (NaCl) n 3299
(NH), 1681 (CO); MS m/z (%) 276 (M%C, 36), 220 (5), 176
(4), 156 (30), 128 (100), 86 (23), 58 (16); HRMS (EI)
276.1840 (C16H24O2N2 requires 276.1838).
4.13.14. N-methylformamide (S)-(K)-6b. Obtained from
mixture of (S)-25a and (S)-27b (206 mg) using protocol D;
purification by column chromatography on silica gel with a
hexane–ethyl acetate mixture (65/35, RfZ0.49/0.24)
afforded (S)-(K)-6b (79 mg, 15% overall from 25b) as a
clear oil: [a]D K108.7 (c 0.67, CHCl3); all spectroscopic
data were identical with those recorded for (G)-6b.
4.13.19. N-methylformamide (S)-(C)-7. Obtained from
(S)-32 (62 mg, 0.3 mmol), using protocol F; purification by
column chromatography on silica gel with a petroleum
ether–ethyl acetate mixture (7/3, RfZ0.2) afforded (S)-(C)-
7 (31 mg, 33%) as colorless solid: mp 125–126 8C; [a]D
C2.4 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3, a mixture
of rotamers in ca. 2:1 ratio; the signals for the minor rotamer
are marked by *) d 1.84* (s, 1H), 2.05 (s, 2H), 2.26* (s) and
2.29 (s, 6H), 2.94 (s, 2H), 3.11* (s, 1H), 6.72* (s, 0.33H),
6.8 (s, 0.66H), 7.09 (s) and 7.12* (s, 2H), 7.29–7.48 (m,
5.66H), 8.27 (s, 1H), 8.72 (br s, 0.33H); 13C NMR d 21.29
(CH3), 25.24 (CH3), 26.51* (CH3), 28.87 (CH3), 33.54*
(CH3), 68.65* (C), 69.63 (C), 117.62–130.26 (a set of
signals, CH), 136.48– 140.39 (a set of signals, C), 163.68
(CHO), 164.35* (CHO), 169.01 (CO), 169.57* (CO); IR
(KBr) n 3433, 2917, 1695, 1671, 1616, 1561, 1371,
848 cmK1; MS (EI) m/z (%) 310 (M%C, 14), 190 (57), 162
(100), 134 (79), 121 (45), 77 (10), 56 (41); HRMS (EI)
310.1680 (C19H22O2N2 requires 310.1681).
4.13.15. N-methylformamide (R)-(C)-6c. Obtained from
(R)-20c using protocol B (solid, 292 mg, 34%): mp 149–
150 8C; [a]D C8.9 (c 1.0, CHCl3); H NMR (400 MHz,
1
CDCl3) d 2.23 (s, 6H), 2.94 (s, 3H), 6.22 (s, 1H), 6.80 (s,
1H), 7.16 (s, 2H), 7.43–7.47 (m, 5H), 8.26 (s, 1H); 13C NMR
d 21.04 (CH3), 28.81 (CH3), 58.34 (CH), 117.00–128.87
(CH), 134.65–138.45 (C), 167.52 (CO), 168.35 (CHO); IR
(KBr) n 3275 (NH), 1653 (CO) cmK1; MS m/z (%) 296
(M%C, 24), 274 (5), 210 (1), 175 (33), 148 (100), 120 (50),
77 (14), 42 (24); HRMS (EI) 296.1525 (C18H20O2N2
requires 296.1524).
4.13.16. N-methylformamide (S)-(K)-6d. Obtained from
(S)-20d using protocol B (solid, 1.50 g, 78%): mp 81–85 8C;
[a]D K87.8 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3, a
1
4.13.20. N-(3,5-dimethyl-phenyl)-2-formylamino-3-(t-
methyl-1H-imidazol-4-yl)-propionamide (S)-(8).
mixture of rotamers in ca. 4:1 ratio; the signals for the minor
rotamer are marked by *) d 2.29 (s, 6H), 2.94* (s, 0.6H),
2.98 (s, 2.4H), 3.01* (dd, JZ14.4, 1.4 Hz, 0.2H), 3.12 (dd,
JZ14.4, 8.4 Hz, 0.8H), 3.43 (dd, JZ14.4, 7.6 Hz, 0.8H),
3.56* (dd, JZ14.8, 4.4 Hz, 0.2H), 5.25 (t, JZ8.0 Hz, 1H),
6.76 (s, 0.8H), 6.85* (s, 0.2H), 7.13 (s, 1.6H), 7.18* (s,
0.4H), 7.28–7.36 (m, 5H), 8.06 (br s, 0.8H), 8.08 (s, 0.8H),
8.37* (s, 0.2H), 8.66* (s, 0.2H); 13C NMR d 20.94 (CH3),
26.62 (CH3), 34.78 (CH2), 62.26 (CH), 115.15–126.52 (a set
of signals, CH), 128.29–138.54 (a set of signals, C), 159.42–
168.36 (a set of signals, CO); IR (KBr) n 3308 (NH), 1703
(CO) cmK1; MS m/z (%) 310 (M%C, 50), 251 (10), 190 (39),
162 (100), 134 (85), 91 (29), 42 (15); HRMS (EI) 310.1681
(C19H22O2N2 requires 310.1682).
A
solution of [1-(3,5-dimethyl-phenylcarbamoyl)-2-(1-
methyl-1H-imidazol-4-yl)-ethyl]-carbamic acid tert-butyl
ester (S)-(35) and trifluoroacetic acid (5 mL) in dichloro-
methane (5 mL) was stirred at room temperature for 1 h.
The solvent was evaporated in vacuo and the crude TFA salt
of 36 was dissolved in formic acid (5 mL). Acetic anhydride
(2.5 mL) was added and the solution was allowed to stir at
room temperature for 72 h. The mixture was then
evaporated to dryness and the crude product was purified
by chromatography on a column of silica gel (60 g) with a
CH2Cl2–MeOH mixture (5/1) to afford (S)-8 (100 mg, 59%)
as an orange solid: mp 92–94 8C (dec); [a]2D5 0.0 (c 1.0,
1
CHCl3); H NMR (400 MHz, CDCl3) d 2.21 (s, 6H), 2.94
(dd, JZ15.2, 7.2 Hz, 1H), 3.11 (dd, JZ15.2, 4.0 Hz, 1H),
3.59, (s, 3H), 4.77 (d, JZ4.0 Hz, 1H), 6.66 (s, 1H), 6.73 (s,
1H), 7.10 (s, 2H), 7.39 (s, 1H), 7.64 (br s, 1H), 8.24 (s, 1H),
9.83 (br s, 1H); 13C NMR (CDCl3) d 21.4, 29.7, 33.7, 52.48,
117.6, 118.3, 126.0, 138.6, 161.4, 168.82; IR (NaCl) n 3019,
2399, 1215 cmK1; MS (CI/ISO) 318.29 [MC NH4]
(C16H20N4O2 C NH4 requires 300.14C18.04Z318.18).
4.13.17. N-methylformamide (S)-(K)-6e. Obtained from
(S)-20e using protocol B (oil, 916 mg, 78%): [a]D K222.6
(c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) d 1.46 (d, JZ
7.2 Hz, 3H), 2.30 (s, 6H), 2.97 (s, 3H), 5.08 (q, JZ7.2 Hz,
1H), 6.76 (s, 1H), 7.01 (s, 2H), 8.16 (s, 1H); 13C NMR d
12.64 (CH3), 21.35 (CH3), 30.98 (CH3), 51.29 (CH), 117.83

278
A. V. Malkov et al. / Tetrahedron 62 (2006) 264–284
4.13.21. (S)-3-methyl-2-[methyl-(2,2,2-trifluoro-acetyl)-
amino]-N-phenyl-butyramide (S)-(K)-(10). The BOC
derivative (S)-8 (92 mg, 0.3 mmol) was dissolved in
trifluoroacetic acid (2 mL) at room temperature. After 1 h
the reaction was evaporated in vacuo, dissolved in CH2Cl2
(5.0 mL) and cooled to 0 8C. Trifluoroacetic anhydride
(130 mL, 0.9 mmol) was added dropwise and the mixture
was allowed to stir overnight at room temperature. The
reaction was then diluted in DCM, washed with brine and
dried over MgSO4. The solvent was then removed by
reduced pressure. Purification using column chromato-
graphy on silica gel with a petroleum ether–ethyl acetate
mixture (3/1) afforded the product 10 as oil (57 mg, 63%):
[a]D K20.4 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) d
0.81 (d, JZ6.7 Hz, 3H), 0.99 (d, JZ6.5 Hz, 3H), 2.38 (m,
1H), 3.03 (s, 3H), 4.97 (d, JZ11.2 Hz, 2H), 7.08 (t, JZ
7.5 Hz, 1H), 7.23 (t, JZ7.8 Hz, 2H), 7.41 (d, JZ7.6 Hz,
2H), 7.81 (br s, 1H); 13C NMR 18.44 (CH3), 19.77 (CH3),
27.29 (CH), 31.57 (CH3), 64.07 (CH), 120.51 (CH), 125.33
(CF3), 129.45 (CH), 130.31 (CH), 138.51 (C), 172.10 (CO);
IR (Golden Gate) n 3338 (NH), 1666 (CO) cmK1; MS m/z
302 (M%C, 3%), 182 (7), 118 (4), 83 (100), 47 (16); HRMS
302.1243 (C14H17O2N2F3 requires 302.1242).
(CH), 117.99* (CH), 125.98 (CH), 126.46* (CH), 137.03*
(C), 137.47 (C), 138.49 (C), 138.58* (C), 163.38* (CHO),
163.64 (CHO), 169.27* (CO), 170.01 (CO), 170.25* (CO),
170.32 (CO); IR (KBr) n 3301, 2965, 2932, 1651, 1619,
1558, 1073, 844 cmK1; MS (EI) m/z (%) 361 (M%C, 10),
142 (59), 121 (100), 114 (75), 86 (20), 72 (15); HRMS (EI)
361.2363 (C20H31O3N3 requires 361.2365).
4.13.24. Dipeptide (S,S)-(K)-12b. Obtained from (S,S)-
41b using protocol C (303 mg, 99%) as a colorless foam;
purified by column chromatography on silica gel with a
petroleum ether–ethyl acetate mixture (1/1, RfZ0.33): [a]D
K58.2 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3,
rotamers) d 0.82–0.9 (m), 0.99 (d, JZ6.4 Hz) and 1.02 (d,
JZ6.4 Hz, 6H), 2.23* (s) and 2.24 (s, 6H), 2.3–2.39 (m,
1H), 2.75 (s, 0.65H), 2.81 (s, 1.35H), 2.91 (s, 0.3H), 2.94 (s,
0.7H), 3.59* (d, JZ10.4 Hz, 0.3H), 4.45 (d, JZ11.2 Hz,
0.7H), 5.57–5.65 (m, 1H), 6.72 (s) and 6.74*(s, 1H),
7.03*(s) and 7.05 (s, 2H), 7.3–7.44 (m, 5H), 7.71*(br s) and
7.76 (br s, 1H), 8.06*(s) and 8.16 (s, 1H); 13C NMR (major
rotamer) d 18.53 (CH3), 19.93 (CH3), 21.23 (CH3), 25.52
(CH), 31.39 (CH3), 57.84 (CH), 61.65 (CH), 117.45 (CH),
126.10 (CH), 127.26 (CH), 128.70 (CH), 129.05 (CH),
136.82 (C), 137.35 (C), 138.47 (C), 163.60 (CHO), 167.48
(CO), 169.14 (CO); IR (KBr) n 3301, 2965, 2921, 1651,
1619, 1560, 1072, 845, 733, 697 cmK1; MS (EI) m/z (%)
395 (M%C, 7), 248 (28), 142 (100), 114 (90), 106 (44), 86
(26), 57 (11); HRMS (EI) 395.2210 (C23H29O3N3 requires
395.2209).
4.13.22. Urea derivative (S)-(K)-11. The BOC derivative
(S)-15d (504 mg, 1.5 mmol) was dissolved in trifluoroacetic
acid (2.0 mL) at room temperature. After 1 h the reaction
mixture was evaporated in vacuo, the residue was dissolved
in cold, dry Et2O (50 mL) and the reaction stirred at room
temperature, under argon, for 90 min. Phenylisocyanate
(0.22 mL, 20.9 mmol) was then added dropwise to the
solution and then allowed to stir over night at room
temperature. The solvent was then removed in vacuo.
Purification using column chromatography on silica gel
with a petroleum ether–ethyl acetate mixture (1/1) afforded
(S)-11 as a solid (292 mg, 55%): mp 131–133 8C; [a]D
K158.1 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) d 0.87
(d, JZ6.4 Hz, 2H), 0.98 (d, JZ6.4 Hz, 2H), 2.21 (s, 6H),
2.34 (m, 1H), 2.98 (s, 3H), 4.33 (d, JZ11.6 Hz, 1H), 6.66 (s,
1H), 7.01 (t, JZ7.4 Hz, 1H), 7.07 (s, 2H), 7.32 (t, JZ
5.6 Hz, 2H), 7.34 (d, JZ7.6 Hz, 2H), 8.15 (br s, 1H); 13C
NMR d 18.82 (CH3), 19.87 (CH3), 21.38 (CH3), 26.33 (CH),
117.52 (CH), 120.32 (CH), 121.26 (CH), 123.75 (CH),
124.41 (CH), 125.99 (CH), 129.04 (CH), 129.39 (CH),
137.74 (C), 138.60 (C), 138.74 (C), 156.91 (CO), 168.87
(CO); IR (KBr) n 3272 (NH), 1644 (CO); MS m/z (%) 353
(M%C, 10), 232 (33), 205 (19), 160 (5), 121 (48), 86 (100),
84 (18), 49 (17); HRMS (EI) 353.2106 (C21H27O2N3
requires 353.2103).
4.13.25. Dipeptide (S,S)-(K)-12c. Obtained from (S,S)-41c
using protocol C (278 mg, 99%) as a colorless foam;
purified by column chromatography on silica gel with a
petroleum ether–ethyl acetate mixture (1/1, RfZ0.33): [a]D
1
K137.5 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3, a
mixture of rotamers in ca. 3:1 ratio; the signals for the minor
rotamer are marked by *) d 0.77 (d, JZ6.4 Hz), 0.81 (d, JZ
6.8 Hz), 0.86 (d, JZ6.4 Hz) and 0.91 (d, JZ6.4 Hz, 6H),
2.21* (s) and 2.24 (s, 6H), 2.1–2.37 (m, 1H), 2.6 (s, 2.25H),
2.69* (s, 0.75H), 2.97 (dd, JZ14.1, 9.5 Hz, 0.75H), 3.06*
(dd, JZ13.8, 7.9 Hz, 0.25H), 3.18* (dd, JZ13.8, 6.6 Hz,
0.25H), 3.27 (dd, JZ14.1, 5.6 Hz, 0.75H), 3.44* (d, JZ
10.6 Hz, 0.25H), 4.37 (d, JZ11.2 Hz, 0.75H), 4.83–4.93
(m, 1H), 6.73 (s, 1H), 7.0 (br s, 0.75H), 7.05 (s, 2H), 7.18–
7.28 (m, 5H), 7.41* (br s, 0.25H), 7.85 (s, 0.75H), 8.12* (s,
0.25H), 8.24 (br s, 1H); 13C NMR d 18.31 (CH3), 18.56*
(CH3), 19.48 (CH3), 21.05* (CH3), 21.25* (CH3), 21.29
(CH3), 25.11 (CH), 26.48* (CH), 27.04* (CH3), 31.08
(CH3), 37.43 (CH2), 38.26* (CH2), 55.03 (CH), 61.35 (CH),
68.08* (CH), 117.56 (CH), 118.01* (CH), 126.13 (CH),
126.60* (CH), 126.83 (CH), 127.21* (CH), 128.49 (CH),
128.80* (CH), 129.09* (CH), 129.23 (CH), 136.04* (C),
136.74 (C), 136.82 (C), 137.30 (C), 138.59 (C), 138.68*
(C), 163.18* (CHO), 163.51 (CHO), 168.75 (CO), 169.20*
(CO), 169.55* (CO), 169.69 (CO); IR (KBr) n 3298, 2964,
2923, 1651, 1619, 1065, 842, 738, 699 cmK1; MS (EI) m/z
(%) 409 (M%C, 23), 142 (62), 121 (100), 114 (81), 86 (26),
55 (10); HRMS (EI) 409.2368 (C24H31O3N3 requires
409.2365).
4.13.23. Dipeptide (S,S)-(K)-12a. Obtained from (S,S)-41a
using protocol C (198 mg, 96%) as a colorless foam;
purified by column chromatography on silica gel with
hexane–ethyl acetate mixture (1/1, RfZ0.2): [a]D K167.2
1
(c 1.0, CHCl3); H NMR (400 MHz, CDCl3, rotamers) d
0.8–1.03 (m, 12H), 2.22* (s) and 2.25 (s, 6H), 2.09–2.46 (m,
2H), 2.91* (s, 0.9H), 3.04 (s, 2.1H), 3.5* (d, JZ10.8 Hz,
0.3H), 4.3–4.42 (m, 0.7H), 6.73 (s) and 6.75* (s, 1H), 6.95*
(d, JZ8.8 Hz, 0.7H), 7.1* (s) and 7.12 (s, 2H), 7.21* (br s,
0.3H), 8.15 (s), 8.21 (s) and 8.23* (s, 2H); 13C NMR d
18.19–22.62 (a set of signals, CH3), 25.54 (CH), 26.51*
(CH), 27.19* (CH), 30.44 (CH), 31.10* (CH3), 31.53 (CH3),
59.43 (CH), 59.52* (CH), 61.86 (CH), 68.01* (CH), 117.57
4.13.26. (S)-2-(tert-butoxycarbonyl-methyl-amino)-3-
methyl-butyric Acid (S)-14. Obtained from (S)-13 as an
oil (3.15 g, 13.6 mmol, 98%) using protocol G; this product

A. V. Malkov et al. / Tetrahedron 62 (2006) 264–284
279
was used in the following step without further purification:
1H NMR (400 MHz, CDCl3) d 0.93 (d, JZ6.7 Hz, 3H), 1.05
(d, JZ6.6 Hz, 3H), 1.49 (s, 9H), 2.39 (m, 1H), 2.90 (s, 3H),
4.01 (d, JZ10.4 Hz, 1H), in agreement with literature.16
(400 MHz, CDCl3) d 0.74 (d, JZ6.8 Hz, 3H), 0.89 (d, JZ
6.7 Hz, 3H), 1.13 (s, 9H), 2.34 (m, 1H), 2.79 (s, 3H), 3.25 (s,
3H), 4.23 (d, JZ10.8 Hz, 1H), 7.11 (t, JZ7.5 Hz, 1H), 7.33
(t, JZ7.7 Hz, 2H), 7.41 (d, JZ7.5 Hz, 2H).
4.13.27. Amide (S)-15a. Obtained from (S)-14, using
protocol H (oil, 803 mg, 43%); 1H NMR (400 MHz,
CDCl3) d 0.85 (d, JZ6.7 Hz, 3H), 0.97 (d, JZ6.4 Hz,
3H), 1.43 (s, 9H), 2.32 (m, 1H), 2.75 (s, 3H), 4.03 (d, JZ
10.2 Hz, 1H), 6.98 (t, JZ7.4 Hz, 1H), 7.22 (t, JZ7.8 Hz,
2H), 7.44 (d, JZ7.8 Hz, 2H), 8.19 (br s, 1H); 13C NMR d
18.99 (CH3), 20.30 (CH3), 26.24 (CH3), 28.76 (CH3), 30.94
(CH3), 66.70 (C), 81.10 (C), 120.06 (CH), 124.48 (CH),
129.37 (CH), 138.45 (C), 169.18 (CO); IR (Golden Gate) n
3311 (NH), 1658 (CO) cmK1; MS m/z (%) 306 (MC, 6%)
214 (7), 186 (14), 130 (71), 83 (100), 57 (39), 47 (17);
HRMS (EI): 306.1943 (C17H26O3N2 requires 306.1943).
4.13.34. Amide (S)-16b. N,N0-Dicyclohexylcarbodiimide
(248 mg, 1.2 mmol) was added in small portions to a stirred
solution of (S)-14 (232 mg, 1.0 mmol) in anhydrous CH2Cl2
(3 mL), followed by dropwise addition of a solution of
diethylamine (145 mL, 1.4 mmol) in anhydrous CH2Cl2
(0.5 mL). The mixture was allowed to stir at room
temperature overnight under an argon atmosphere. The
solvent was then removed under reduced pressure.
Purification using column chromatography on silica gel
with a petroleum ether–ethyl acetate mixture (24/1) afforded
(S)-16b as an oil (120 mg, 42%):1H NMR (400 MHz,
CDCl3) d 0.77 (d, JZ6.6 Hz, 3H), 0.81 (d, JZ6.8 Hz, 3H),
1.04 (m, 3H), 1.08 (m, 3H), 1.42 (s, 9H), 2.3 (m, 1H), 2.68
(s, 3H), 3.18 (m, 2H), 3.34 (m, 2H), 4.52 (d, JZ10.8 Hz,
1H); 13C NMR d 13.30 (CH3), 15.01 (CH3), 18.28 (CH3),
20.16 (CH3), 27.51 (CH), 28.70 (CH3), 29.55 (CH3), 40.72
(CH2), 41.57 (CH2), 61.37 (CH), 80.04 (C), 156.31 (CO),
169.71 (CO).
4.13.28. Amide (S)-15b. Obtained from (S)-14, using
protocol H (oil, 188 mg, 59%); 1H NMR (400 MHz,
CDCl3) d 0.81 (d, JZ6.6 Hz, 3H), 0.91 (d, JZ6.5 Hz,
3H), 1.37 (s, 9H), 2.27 (m, 1H), 2.77 (s, 3H), 3.66 (s, 3H),
4.07 (d, JZ10.9 Hz, 1H), 6.72 (d, JZ8.5 Hz, 2H), 7.32 (d,
JZ8.8 Hz, 2H), 8.33 (br s, 1H); 13C NMR d 17.65 (CH3),
18.79 (CH3), 25.17 (CH), 27.33 (CH3), 29.44 (CH3), 64.76
(CH), 79.46 (CH), 113.02 (CH), 120.47 (CH), 130.27
(CH3), 155.21 (C), 156.31 (C), 167.70 (C).
4.13.35. Amide (S)-17. Following a literature protocol,17 a
solution of pivalyl chloride (1.1 mL, 8.6 mmol) in
anhydrous THF (8 mL) was added dropwise to a stirred
solution of (S)-14 (2.0 g, 8.6 mmol) and triethylamine
(1.2 mL, 8.6 mmol) in anhydrous THF (16 mL) at
K15 8C. The solution was then warmed to 0 8C and allowed
to stir at this temperature for 5 min. The solution was then
cooled again to K15 8C and a solution of 3,5-bis(trifluoro-
methyl)-aniline (1.34 mL) in anhydrous THF (8 mL) was
added dropwise and the mixture was stirred at 0 8C for 1 h.
The mixture was then warmed to room temperature and
stirring was continued for 27 h under an argon atmosphere.
The solvent was then removed under reduced pressure, the
residue was diluted with water (20 mL) and then extracted
with ethyl acetate (20 mL). The extracts were washed with
brine, dried over MgSO4, and concentrated under reduced
pressure. Purification using column chromatography on
silica gel with a petroleum ether–ethyl acetate mixture (1/1)
afforded (S)-17 as an oil (185 mg, 7%); 1H NMR (400 MHz,
CDCl3) d 0.87 (d, JZ6.9 Hz, 3H), 0.99 (d, JZ7.0 Hz, 3H),
2.15 (m, 1H), 2.42 (s, 3H), 2.87 (d, JZ4.24 Hz, 1H), 7.50 (s,
1H), 8.05 (s, 2H), 9.69 (br s, 1H).
4.13.29. Amide (S)-15c. Obtained from (S)-14, using
protocol H (oil, 451 mg, 29%); 1H NMR (400 MHz,
CDCl3) d 0.82 (d, JZ6.8 Hz, 3H), 0.96 (d, JZ6.7 Hz,
3H), 1.39 (s, 9H), 2.95 (m, 1H), 2.75 (s, 3H), 3.70 (s, 6H),
4.00 (m, 1H), 6.15 (s, 1H), 6.68 (s, 2H), 8.18 (br s, 1H).
4.13.30. Amide (S)-15d. Obtained from (S)-14, using
protocol H; purification by column chromatography on
silica gel with a petroleum ether–ethyl acetate mixture
1
(24/1) afforded pure product as an oil (240 mg, 70%); H
NMR (400 MHz, CDCl3) d 0.77 (d, JZ6.5 Hz, 3H), 0.88 (d,
JZ6.5 Hz, 3H), 1.38 (s, 9H), 2.17 (s, 6H), 2.25 (m, 1H),
2.76 (s, 3H), 4.08 (d, JZ10.8 Hz, 1H), 6.62 (s, 1H), 7.07 (s,
2H), 8.24 (br s, 1H).
4.13.31. Amide (S)-15f. Obtained from (S)-14, using
protocol H; purification by column chromatography on
silica gel with a petroleum ether–ethyl acetate mixture (6/1)
1
afforded a pure product as an oil (105 mg, 28%); H NMR
4.13.36. Compound (R)-19c. Obtained from (R)-18c as an
oil (2.33 g, 78%) using protocol G; this product was used in
(400 MHz, CDCl3) d 0.86 (d, JZ6.8 Hz, 3H), 0.93 (d, JZ
6.4 Hz, 3H), 1.41 (s, 9H), 2.30 (m, 1H), 2.76 (s, 3H), 3.95 (d,
JZ10.8 Hz, 1H), 7.00 (s, 1H), 7.41 (s, 2H), 8.51 (br s, 1H).
1
the following step without further purification: H NMR
(400 MHz, CDCl3) d 1.42 (s, 9H), 2.62 (s, 3H), 7.21–7.45
(m, 5H).
4.13.32. Amide (S)-15g. Obtained from (S)-14, using
protocol H; purification by column chromatography on
silica gel with a petroleum ether–ethyl acetate mixture (3/1)
4.13.37. Compound (S)-19d. Obtained from (S)-18d as an
oil (2.38 g, 71%) using protocol G; this product was used in
1
afforded a pure product as an oil (928 mg, 61%); H NMR
1
the following step without further purification: H NMR
(400 MHz, CDCl3) d 0.80 (m, 9H), 1.29 (m, 2H), 1.39 (s,
9H), 2.20 (m, 1H), 2.73 (s, 3H), 3.17 (m, 2H), 3.90 (d, JZ
10.9 Hz, 1H), 6.04 (br s, 1H).
(400 MHz, CDCl3 a mixture of rotamers in ca. 1:1 ratio) d
1.23 (s, 4.5H), 1.33 (s, 4.5H), 2.52 (s, 1.5H), 2.59 (s, 1.5H),
2.90 (m, 1H), 3.11 (m, 1H), 4.44 (dd, JZ4.0, 10.4 Hz,
0.5H), 4.65 (dd, JZ5.2, 10.8 Hz, 0.5H), 7.01–7.21 (m, 5H).
4.13.33. Amide (S)-16a. Obtained from (S)-14, using
protocol H; purification by column chromatography on
silica gel with a petroleum ether–ethyl acetate mixture (3/1)
4.13.38. Compound (S)-19e. Obtained from (S)-18e as an
oil (4.90 g, 98%) using protocol G; this product was used in
1
afforded a pure product as an oil (72 mg, 22%); H NMR

280
A. V. Malkov et al. / Tetrahedron 62 (2006) 264–284
1
the following step without further purification: H NMR
(400 MHz, CDCl3) d 1.37 (d, JZ6.7 Hz, 3H), 1.40 (s, 9H),
2.89 (s, 3H), 4.19 (m, 1H).
chromatography on silica gel with a hexane–ethyl acetate
mixture (10/1, RfZ0.35) afforded the product as a colorless
solid (886 mg, 41%): mp 57–58 8C; [a]D C98.8 (c 1.0,
CHCl3); 1H NMR (400 MHz, CDCl3) d 1.08 (s, 9H), 1.49 (s,
9H), 4.04 (br s, 1H), 5.07 (d, JZ4.4 Hz, 1H), 5.69 (br s, 1H);
13C NMR d 26.4 (CH3), 28.15 (CH3), 36.67 (C), 63.87 (CH),
78.9 (CH2), 82.26 (C), 153.81 (CO), 171.71 (CO); IR (KBr)
n 2977, 2932, 2874, 1798, 1704, 1366, 1166, 1130,
1024 cmK1; MS (CI) m/z (%) 244 ([MH]%C, 14), 144
(30), 89 (100), 81 (38), 71 (40); HRMS (CI) 244.1550
(C12H22O4N ([MH] %C) requires 244.1549).
4.13.39. Compound (S)-19f. Obtained from (S)-18f as an
oil (2.60 g, 72%) using protocol G; this product was used in
1
the following step without further purification: H NMR
(400 MHz, CDCl3) d 0.87 (d, JZ6.8 Hz, 3H), 0.89 (d, JZ
6.8 Hz, 3H), 1.39 (s, 9H), 1.49 (m, 1H), 1.66 (m, 1H), 2.73
(s, 3H), 4.73 (m, 1H).
4.13.40. Amide (R)-20c. Obtained from (R)-19c, using
protocol H; purification by column chromatography on
silica gel with a petroleum ether–ethyl acetate mixture (1/1)
4.13.46. N-methylformamide (R)-(C)-23a. Obtained from
(R)-21a (166 mg, 83%) as a colorless solid using protocol E:
mp 95–97 8C; [a]D C1.8 (c 1.0, MeOH); 1H NMR
(400 MHz, CDCl3, a mixture of rotamers in ca. 2:1 ratio;
the signals for the minor rotamer are marked by *) d 0.85–
1.35 (m, 5H), 1.58–2.05 (m, 6H), 2.92 (s, 2H) and 3.02* (s,
1H), 3.72 (d, JZ10.4 Hz, 0.66H) and 4.69* (d, JZ10.4 Hz,
0.33H), 8.12 (s) and 8.15* (s, 1H), 9.8 (br s, 1H); 13C NMR
d 25.39, 25.46, 25.51, 25.96, 29.04 and 29.86 (CH2 and
C*H2), 27.82 (CH), 32.39* (CH), 35.5* (CH3), 36.05 (CH3),
59.85* (CH), 66.53 (CH), 164.36 (CHO), 164.53* (CHO),
173.08 (CO), 173.49* (CO); IR (KBr) n 3500–2200, 2939,
2858, 1748, 1666, 1235, 1069 cmK1; MS (CI) m/z (%) 200
1
afforded a pure product as an oil (2.01 g, 56%); H NMR
(400 MHz, CDCl3) d 1.42 (s, 9H), 2.22 (s, 6H), 2.72 (s, 3H),
5.88 (br s, 1H), 6.69 (s, 1H), 7.09 (s, 2H), 7.23–7.46 (m,
5H).
4.13.41. Amide (S)-20d. Obtained from (S)-19d, using
protocol H; purification by column chromatography on
silica gel with a petroleum ether–ethyl acetate mixture (1/1)
1
afforded a pure product as an oil (2.38 g, 94%); H NMR
(400 MHz, CDCl3) d 1.42 (s, 9H), 2.22 (s, 6H), 2.80 (s, 3H),
3.10 (dd, JZ14, 8.2 Hz, 1H), 3.38 (dd, JZ14, 6.8 Hz, 1H),
4.98–5.01 (m, 1H), 6.74 (s, 1H), 7.12 (s, 2H), 7.15–7.32 (m,
5H), 8.11 (br s, 1H).
([MH]%C
, 100), 154 (10); HRMS (CI) 200.1286
(C10H18O3N ([MH]%C) requires 200.1287).
4.13.42. Amide (S)-20e. Obtained from (S)-19e, using
protocol H; purification by column chromatography on
silica gel with a petroleum ether–ethyl acetate mixture (2/1)
4.13.47. N-methylformamide (S)-(K)-23b. Obtained from
(S)-21b (320 mg, 1.3 mmol) as a colorless solid (164 mg,
73%) using protocol E: mp 76–78 8C; [a]D K1.5 (c 1.0,
MeOH); 1H NMR (400 MHz, CDCl3, a mixture of rotamers
in ca. 2:1 ratio; the signals for the minor rotamer are marked
by *) d 1.11 (s) and 1.14* (s, 9H), 3.05 (s, 2H) and 3.16* (s,
1H), 3.86 (s, 0.66H) and 4.96* (s, 0.33H), 8.16* (s) and 8.17
(s, 1H), 7.85 (br s, 1H), in agreement with literature data;21
13C NMR d 27.72 (CH3), 28.14* (CH3), 31.11 (CH3), 34.5*
(C), 34.76 (C), 35.19* (CH3), 61.81* (CH), 69.57 (CH),
165.01 (CHO), 165.04* (CHO), 172.58 (CO), 173.52*
(CO).
1
afforded a pure product as an oil (1.54 g, 93%); H NMR
(400 MHz, CDCl3) d 1.32 (d, JZ7.2 Hz, 3H), 1.43 (s, 9H),
2.26 (s, 6H), 2.74 (s, 3H), 4.75 (br s, 1H), 6.67 (s, 1H), 7.07
(s, 2H), 8.12 (br s, 1H).
4.13.43. Amide (S)-20f. Obtained from (S)-19f, using
protocol H; purification by column chromatography on
silica gel with a petroleum ether–ethyl acetate mixture (2/1)
1
afforded a pure product as an oil (1.70 g, 75%); H NMR
(400 MHz, CDCl3) d 0.88 (d, JZ6.4 Hz, 3H), 0.91 (d, JZ
6.4 Hz, 3H), 1.43 (s, 9H), 1.46–1.54 (m, 1H), 1.56–1.64
(1H, m), 1.69–1.82 (m, 1H), 2.26 (s, 6H), 2.71 (s, 3H), 4.66
(br s, 1H), 6.67 (s, 1H), 7.06 (s, 2H), 8.05 (br s, 1H).
4.13.48. Oxazolidinone (R)-(K)-25a. Obtained from (R)-
24a (520 mg, 1.8 mmol) using protocol K; the reaction was
carried out for 3 h and an additional amount of
paraformaldehyde (1/4 of the initial quantity) was added
in two equal portions after 1 and 2 h. Purification using
column chromatography on silica gel with petroleum ether–
ethyl acetate mixture (9/1, RfZ0.26) afforded the product as
a colorless solid (345 mg, 64%): mp 77–79 8C; [a]D
4.13.44. Oxazolidinone (R)-(K)-21a. Obtained from (R)-
18a using protocol K; purification by chromatography on a
column of silica gel with a hexane–ethyl acetate mixture
(10/1, RfZ0.31) afforded the product (1.94 g, 87%) as a
colorless oil, which solidified on standing: mp 63–64 8C,
[a]D K114.7 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) d
1.02–1.4 (m, 5H), 1.49 (s, 9H), 1.59–1.8 (m, 5H), 1.96 (br s,
1H), 4.15 (br s, 1H), 5.07 (br s, 1H), 5.57 (br d, 1H); 13C
NMR d 25.77 (CH2), 25.93 (CH2), 27.87 (CH2), 28.21
(CH3), 41.06 (CH), 60.28 (CH), 78.76 (CH2), 82.02 (C),
152.97 (CO), 172.57 (CO); IR (KBr) n 2974, 2928, 2853,
1795, 1710, 1366, 1170, 1132, 1051 cmK1; MS (CI) m/z (%)
270 ([MH]%C, 51), 226 (14), 214 (11), 198 (10), 170 (100);
HRMS (CI) 270.1707 (C14H21O4N ([MH]%C) requires
270.1705).
1
K113.0 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) d
1.08–1.45 (m, 5H), 1.6–1.79 (m, 5H), 2.0 (br s, 1H), 4.21 (br
s, 1H), 5.12–5.24 (m, 3H), 5.61 (br d, 1H), 7.31–7.42 (m,
5H); 13C NMR d 25.73 (CH2), 25.85 (CH2), 25.91 (CH2),
27.85 (CH2), 28.63 (CH2), 40.75 (CH), 59.88 (CH), 68.03
(CH2), 78.56 (CH2), 128.32 (CH), 128.59 (CH), 128.67
(CH), 135.35 (C), 153.6 (CO), 171.73 (CO); IR (KBr) n
3068, 3033, 2933, 2852, 1791, 1691, 1503, 1049, 742,
698 cmK1; MS (CI) m/z (%) 303 (M%C, 13), 220 (25), 168
(14), 91 (100), 86 (22); HRMS (EI) 303.1470 (C17H21O4N
requires 303.1471).
4.13.45. Oxazolidinone (S)-(C)-21b. Obtained from (S)-
18b using protocol K; purification using column
4.13.49. Oxazolidinone (S)-(C)-25b. Obtained from (S)-
24b (413 mg, 1.6 mmol) using protocol K; the reaction was

A. V. Malkov et al. / Tetrahedron 62 (2006) 264–284
281
carried out for 7 h and an additional amount of
paraformaldehyde (4!the initial quantity) was added in
four equal portions after 2, 3, 5 and 6 h. Purification using
column chromatography on silica gel with petroleum ether–
ethyl acetate mixture (9/1, RfZ0.28) afforded the product as
a colorless solid (350 mg, 81%): mp 35–36 8C; [a]D C82.2
(c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) d 1.07 (s, 9H),
4.11 (br s, 1H), 5.11–5.23 (m, 3H), 5.7 (br s, 1H), 7.31–7.42
(m, 5H); 13C NMR d 26.35 (CH3), 36.72 (C), 63.65 (CH),
68.35 (CH2), 78.82 (CH2), 128.45 (CH), 128.64 (CH),
128.67 (CH), 135.19 (C), 154.71 (CO), 171.11 (CO); IR
(KBr) n 3068, 3032, 2974, 2962, 2936, 1788, 1709, 1504,
recrystallized from ethyl acetate–hexane to afford (S)-(C)
-32 (100 mg, 85%) as an off-white solid: mp 143–145 8C;
[a]D C42.9 (c 0.86, MeOH); H NMR (400 MHz, CDCl3/
1
CD3OD, a mixture of rotamers in ca. 5:1 ratio; the signals
for the minor rotamer are marked by *) d 1.85* (s) and 1.86
(s, 3H), 2.64* (s, 0.5H), 2.81 (s, 2.5H), 7.27–7.37 (m, 5H),
8.01 (s, 0.8H), 8.09* (s, 0.2H); 13C NMR d 19.99* (CH3),
25.03 (CH3), 29.02 (CH3), 32.99* (CH3), 65.22* (C), 68.5
(C), 126.67 (CH), 127.67 (CH), 128.29 (CH), 128.36 (CH),
128.81 (CH), 136.66* (C), 139.03 (C), 163.86* (CHO),
164.85 (CHO), 173.14* (CO), 173.57 (CO); IR (KBr) n
3500–2200, 1721, 1612, 1493, 1379, 1269, 1096, 766,
800 cmK1; MS (CI) m/z (%) 208 ([MH]%C, 100), 162 (13),
113 (8), 85 (12), 73 (18); HRMS (CI) 208.0975 (C11H14O3N
([MH]%C) requires 208.0974).
1040, 1025, 760, 702 cmK1; MS (CI) m/z (%) ([MH]%C
,
100), 234 (71), 91 (16); HRMS (CI) 278.1391 (C15H20O4N
([MH]%C) requires 278.1392).
4.13.50. Cbz-protected amide (R)-(C)-27a. Obtained
from (R)-25a via (R)-26a, using protocol J and purified by
column chromatography on silica gel with petroleum ether–
ethyl acetate mixture (9/1, RfZ0.28) to afford a pure
product as clear oil (130 mg, 64%): [a]D C58.8 (c 1.0,
CHCl3); 1H NMR (400 MHz, CDCl3, a mixture of rotamers
in ca. 4:1 ratio; the signals for the minor rotamer are marked
by *) d 0.87–1.03 (m, 2H), 1.12–1.38 (m, 3H), 1.66–1.87
(m, 5H), 2.05–2.14 (m, 1H), 2.28 (s, 6H), 2.94 (s, 3H), 4.11*
(d, JZ10.8 Hz, 0.2H), 4.25 (d, JZ11.2 Hz, 0.8H), 5.05–
5.22 (m, 2H), 6.74 (s, 1H), 6.85* (s, 0.4H), 7.05* (br s,
0.2H), 7.14 (s, 1.6H), 7.29–7.45 (m, 5H), 8.04 (br s, 0.8H);
13C NMR (major rotamer) d 21.31 (CH3), 25.54 (CH2),
25.56 (CH2), 26.3 (CH2), 28.84 (CH2), 30.07 (CH2), 30.32
(CH), 35.02 (CH3), 65.39 (CH), 67.67 (CH2), 117.43 (CH),
125.94 (CH), 127.61 (CH), 128.05 (CH), 128.5 (CH),
136.32 (C), 137.62 (C), 138.64 (C), 157.81 (CO), 168.21
(CO); IR (KBr) n 3331, 2927, 2852, 1672, 1617, 1560, 1449,
1146, 1121, 843, 796, 696 cmK1; MS (EI) m/z (%) 408
(M%C, 10), 288 (11), 260 (32), 216 (65), 91 (100); HRMS
(EI) 408.2415 (C25H32O3N2 requires 408.2413).
4.13.54. N-t-Me-N-a-Boc-histidine (S)-(C)-(34). Sodium
hydride (705 mg, 29.4 mmol) was placed in a two-neck
flask, flushed with Ar, washed 3!with petroleum ether, and
dried under vacuum. The dry NaH was then added slowly to
a suspension of N-a-Boc-histidine (S)-33 (2.5 g, 9.8 mmol)
in CH3CN at K15 8C and stirred for 30 min. Methyl iodide
(1.53 g, 10.7 mmol) was added and the reaction mixture was
then heated to K5 8C and allowed to stir overnight at this
temperature. The reaction was quenched with excess MeOH
and the solvent was removed on a rotary evaporator. The
resulting solid was then extracted with CHCl3 (3!50 mL),
the solvent was evaporated and the resulting solid was
purified by chromatography on a column of silica gel (50 g),
with a CH2Cl2–MeOH mixture (5/1), to give N-t-Me-N-a-
Boc-histidine (S)-(C)-34 as a pale yellow solid (1.64 g,
66%): mp 166–168 8C (dec); [a]2D5 C29.5 (c 1.0, CHCl3) in
accordance with the literature;24 1H NMR (400 MHz,
DMSO-d6) d 1.36 (s, 9H) 2.82 (d, JZ4.8 Hz, 2H) 3.56 (s,
3H) 3.91 (br s, 1H) 6.17 (d, JZ5.6 Hz, 1H), 6.77 (s, 1H)
7.49 (s, 1H); 13C NMR (DMSO-d6) d 11.5, 28.2, 32.9, 45.6,
54.9, 77.5, 117.8, 154.83.
4.13.51. Cbz-protected amide (S)-27b. Obtained from (S)-
25a (460 mg, 1.66 mmol) via (S)-26b, using protocol J;
purification by column chromatography on silica gel with
petroleum ether–ethyl acetate mixture (9/1, RfZ0.33)
afforded an inseparable mixture of (S)-25a and (S)-27b
(206 mg) in ca. 1:3 ratio as a colorless oil, which was used
for further transformations.
4.13.55.
[1-(3,5-Dimethyl-phenylcarbamoyl)-2-(1-
methyl-1H-imidazol-4-yl)-ethyl]-carbamic acid tert-
butyl ester (S)-(C)-(35). 3,5-Dimethylaniline, (472 mg,
3.9 mmol) was added to a solution of N-t-Me-N-a-Boc-
histidine (S)-34, (1.0 g, 3.9 mmol), in dry MeCN. The
solution was cooled to 0 8C and 1-(3-dimethylamino-
propyl)-3-ethylcarbodiimide hydrochloride (EDCI;
910 mg, 4.7 mmol) was added and the reaction mixture
was allowed to stir at room temperature for 48 h. The
mixture was then poured into saturated NaHCO3 solution
and extracted 3!with AcOEt. The organic layer was
washed with water and brine and dried over MgSO4. The
solvent was evaporated in vacuo and the crude product was
purified by chromatography on a column of silica gel (75 g)
with a CH2Cl2–MeOH mixture (5/1) to afford (S)-(C)-35 as
a pale orange solid (896 mg, 60%):25 [a]D25 C53 (c 1.0,
CHCl3); 1H NMR (400 MHz, CDCl3) d 1.38 (s, 9H) 2.20 (s,
6H) 2.91 (dd, JZ15.6, 6.4 Hz, 1H) 3.05 (d, JZ15.6 Hz,
2H), 3.64 (s, 3H), 4.46 (s, 1H), 6.23 (s, 1H), 6.65 (s, 1H),
6.67 (s, 1H), 7.19 (s, 2H), 7.37 (s, 1H); 13C NMR (CDCl3) d
21.4, 28.3, 30.7, 33.4, 50.4, 117.6, 118.6, 125.9, 137.2,
138.5.
4.13.52. Oxazolidinone (S)-(C)-30. Obtained from (S)-29
(485 mg, 1.6 mmol) using protocol K; the reaction was
carried out for 2 h. Purification using column chromato-
graphy on silica gel with petroleum ether–ethyl acetate
mixture (9/1, RfZ0.32) afforded the product as a colorless
solid (220 mg, 50%): mp 74–75 8C; [a]D C109.7 (c 1.0,
CHCl3); 1H NMR (400 MHz, CDCl3) d 1.26 (s, 9H), 2.01 (s,
3H), 5.45 (br s, 1H), 5.49 (d, JZ4.4 Hz, 1H), 7.29–7.4 (m,
5H); 13C NMR d 22.73 (CH3), 28.05 (CH3), 61.96 (C), 77.31
(CH2), 81.86 (C), 125.43 (CH), 128.28 (CH), 128.72 (CH),
138.89(C), 152.17(CO), 173.96(CO); IR(KBr) n 3065, 3031,
2981, 2941, 1791, 1709, 1499, 1045, 759, 698 cmK1; MS (EI)
m/z (%) 277 (M%C, 1), 146 (8), 132 (25), 91 (15), 57 (100);
HRMS (EI) 277.1313 (C15H19O4N requires 277.1314).
4.13.53. N-methylformamide (S)-(C)-32. Obtained from
(S)-30 (157 mg, 0.57 mmol) using protocol E and
4.13.56. Amide (S)-37. Obtained from (S)-13, using
protocol H; purification by column chromatography on

282
A. V. Malkov et al. / Tetrahedron 62 (2006) 264–284
silica gel with a petroleum ether–ethyl acetate mixture (1/1)
afforded a pure product as an oil (309 mg, 19%); H NMR
(400 MHz, CDCl3) d 0.84 (d, JZ6.8 Hz, 3H), 0.93 (d, JZ
6.8 Hz, 3H), 1.39 (s, 9H), 2.90 (m, 1H), 3.70 (s, 6H), 3.90 (t,
JZ6.4 Hz, 1H), 4.98 (br s, 1H), 6.16 (s, 1H), 6.69 (s, 2H),
7.78 (br s, 1H).
by *) d 0.86–0.98 (m, 12H), 1.47 (s, 9H), 2.11–2.38 (m, 2H),
2.28 (s, 6H), 2.81 (s, 3H), 3.97* (br s, 0.2H), 4.09 (d, JZ
11.2 Hz, 0.8H), 4.25–4.4 (m, 1H), 6.31* (br s, 0.2H), 6.74
(s, 1H), 6.77* (br s, 0.8H), 7.13 (s, 2H), 7.88* (br s, 0.2H),
8.01 (br s, 0.8H); 13C NMR (major rotamer) d 17.75 (CH3),
18.56 (CH3), 19.51 (CH3), 19.86 (CH3), 21.35 (CH3), 22.67
(CH), 25.92 (CH), 28.41 (CH3), 30.02 (CH3), 59.24 (CH),
64.82 (CH), 80.57 (C), 117.69 (CH), 126.14 (CH), 137.41
(C), 138.69 (C), 157.01 (CO), 169.16 (CO), 171.48 (CO); IR
(KBr) n 3297, 2964, 2931, 1690, 1650, 1618, 1559, 1157,
845 cmK1; MS (EI) m/z (%) 433 (M%C, 12), 186 (12), 158
(11), 130 (100), 121 (66), 86 (76), 57 (43); HRMS (EI)
433.2939 (C24H39O4N3 requires 433.2941).
1
4.13.57. Amide (S)-(K)-39a. Obtained from (S)-13 as an
off-white solid (1.522 g, 95%) using protocol I; this product
was used in the following step without further purification:
mp 136–137 8C, [a]D K39.6 (c 1.0, CHCl3); 1H NMR
(400 MHz, CDCl3) d 0.99 (d, JZ6.8 Hz, 3H), 1.02 (d, JZ
6.4 Hz, 3H), 1.45 (s, 9H), 2.24 (s, 6H), 4.03–4.06 (m, 1H),
5.25 (d, JZ8.8 Hz, 1H), 6.71 (s, 1H), 7.13 (s, 2H), 8.16 (br
s, 1H), in agreement with literature data;26 13C NMR d 18.15
(CH3), 19.36 (CH3), 21.28 (CH3), 28.29 (CH3), 30.74 (CH),
60.88 (CH), 80.18 (C), 117.63 (CH), 126.01 (CH), 137.34
(C), 138.54 (C), 156.26 (CO), 170.17 (CO); IR (KBr) n
3303, 2976, 2930, 1683, 1661, 1611, 1565, 1521, 1171,
845 cmK1; MS (EI) m/z (%) 320 (M%C, 27), 247 (15), 172
(12), 148 (13), 121 (100), 116 (68), 72 (88), 57 (65); HRMS
(EI) 320.2103 (C18H28O3N2 requires 320.2100).
4.13.61. Dipeptide (S,S)-(K)-41b. Obtained from (S)-39b
and (S)-14 using protocol L. Purification by column
chromatography on silica gel with a petroleum ether–ethyl
acetate mixture (8/2, RfZ0.33) afforded the product
(420 mg, 90%) as a colorless solid: mp 76–78 8C; [a]D
K53.6 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3,
rotamers) d 0.88 (d, JZ6.8 Hz) and 0.98 (d, JZ6.8 Hz,
6H), 1.45 (s) and 1.49* (s, 9H), 2.21* (s) and 2.23 (s, 6H),
2.2–2.39 (m, 1H), 2.67 (s, 2H), 2.81* (s, 1H), 4.03–4.27 (m,
1H), 5.77 (d, JZ7.6 Hz, 1H), 6.68* (s) and 6.71 (s, 1H),
7.02* (s) and 7.08 (s, 2H), 7.27–7.46 (m, 5H), 7.58 (br s) and
7.69* (br s, 1H), 8.37 (br s) and 8.52* (br s, 1H); 13C NMR
(major rotamer) d 18.47 (CH3), 19.8 (CH3), 21.23 (CH3),
25.88 (CH), 28.34 (CH3), 29.98 (CH3), 57.55 (CH), 64.29
(CH), 80.4 (C), 117.53 (CH), 126.06 (CH), 128.35 (CH),
128.85 (CH), 128.93 (CH), 137.41 (C), 138.31 (C), 138.48
(C), 156.89 (CO), 167.63 (CO), 170.47 (CO); IR (KBr) n
4.13.58. Amide (S)-(C)-39b. Obtained from (S)-18c
(401 mg, 1.6 mmol) using protocol I; recrystallization
from hexane–ethyl acetate furnished a pure product
(440 mg, 78%) as a colorless solid: mp 118–120 8C, [a]D
C33.0 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) d 1.43
(s, 9H), 2.25 (s, 6H), 5.30 (br s, 1H), 5.83 (br s, 1H), 6.73 (s,
1H), 7.06 (s, 2H), 7.31–7.44 (m, 5H); 13C NMR d 21.26
(CH3), 28.29 (CH3), 59.12 (CH), 80.38 (C), 117.66 (CH),
126.22 (CH), 127.24 (CH), 128.49 (CH), 129.07 (CH),
137.13 (C), 137.77 (C), 138.57 (C), 155.45 (CO), 168.34
(CO); IR (KBr) n 3331, 1686, 1662, 1616, 1559, 1525, 1169,
847, 699 cmK1; MS (EI) m/z (%) 354 (M%C, 9), 280 (21),
206 (27), 150 (100), 106 (82), 57 (56); HRMS (EI) 354.1945
(C21H26O3N2 requires 354.1943).
3311, 2968, 2930, 1690, 1650, 1562, 1154, 844, 695 cmK1
;
MS (EI) m/z (%) 467 (M%C, 3), 264 (12), 214 (16), 158 (22),
130 (91), 116 (69), 86 (100), 57 (50); HRMS (EI) 467.2787
(C27H37O4N3 requires 467.2784).
4.13.62. Dipeptide (S,S)-(K)-41c. Obtained from (S)-39c
and (S)-14 using protocol L. Purification by column
chromatography on silica gel with a petroleum ether–ethyl
acetate mixture (8/2, RfZ0.32) afforded the product
(420 mg, 92%) as a colorless solid: mp 65–67 8C; [a]D
K93.4 (c 0.89, CHCl3); 1H NMR (400 MHz, CDCl3,
rotamers) d 0.84 (d, JZ6.8 Hz) and 0.89 (d, JZ6.4 Hz, 6H),
1.46 (s, 9H), 2.27 (s, 6H), 2.2–2.3 (m, 1H), 2.64 (s, 3H), 3.0–
3.26 (m, 2H), 3.95* (br s, 0.3H), 4.05 (d, JZ10.8 Hz, 0.7H),
4.73 (dd, JZ14.8, 7.2 Hz, 1H), 6.39* (br s, 0.3H), 6.74 (s,
1H), 6.8 (br s, 0.7H), 7.0* (s) and 7.02 (s, 2H), 7.22–7.32 (m,
5H), 7.52* (br s, 0.3H), 7.85 (br s, 0.7H); 13C NMR (major
rotamer) d 18.44 (CH3), 19.78 (CH3), 21.29 (CH3), 26.12
(CH), 28.35 (CH3), 37.32 (CH2), 55.04 (CH), 64.81 (CH),
80.46 (C), 117.69 (CH), 126.17 (CH), 126.92 (CH), 128.71
(CH), 129.12 (CH), 136.64 (C), 137.21 (C), 138.61 (C),
156.73 (CO), 168.64 (CO), 171.41 (CO); IR (KBr) n 3304,
2969, 2930, 1695, 1650, 1561, 1155, 841, 699 cmK1; MS
(EI) m/z (%) 481 (M%C, 17), 186 (15), 130 (100), 121 (59),
86 (79), 57 (41); HRMS (EI) 481.2943 (C28H39O4N3
requires 481.2941).
4.13.59. Amide (S)-(K)-39c. Obtained from (S)-18d
(428 mg, 1.6 mmol) using protocol I; purification by column
chromatography on silica gel with a petroleum ether–ethyl
acetate mixture (9/1, RfZ0.17) afforded a pure product
(574 mg, 97%) as a colorless solid: mp 122–123 8C, [a]D
K22.5 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) d 1.42
(s, 9H), 2.26 (s, 6H), 3.14 (d, JZ7.2 Hz, 2H), 4.44 (br s,
1H), 5.13 (br s, 1H), 6.74 (s, 1H), 7.0 (s, 2H), 7.24–7.33 (m,
5H); 13C NMR d 21.27 (CH3), 28.24 (CH3), 38.49 (CH2),
56.60 (CH), 80.45 (C), 117.76 (CH), 126.17 (CH), 126.96
(CH), 128.73 (CH), 129.30 (CH), 136.65 (C), 137.07 (C),
138.53 (C), 155.75 (CO), 169.52 (CO); IR (KBr) n 3320,
2971, 2918, 1692, 1663, 1615, 1541, 1526, 1168, 836,
702 cmK1; MS (EI) m/z (%) 368 (M%C, 37), 294 (19), 251
(15), 164 (47), 160 (35), 121 (100), 120 (99), 91 (57), 57
(88); HRMS (EI) 368.2102 (C22H28O3N2 requires
368.2100).
4.13.60. Dipeptide (S,S)-(K)-41a. Obtained from (S)-39a
and (S)-14 using protocol L. Purification by column
chromatography on silica gel with a hexane–ethyl acetate
mixture (8/2, RfZ0.34) afforded the product (259 mg, 60%)
as a colorless solid: mp 90–91 8C; [a]D K132.3 (c 1.0,
CHCl3); 1H NMR (400 MHz, CDCl3, a mixture of rotamers
in ca. 4:1 ratio; the signals for the minor rotamer are marked
Acknowledgements
We thank the EPSRC for grant No. GR/S87294/01, the
University of Glasgow for a fellowship to K. N. McD, the

A. V. Malkov et al. / Tetrahedron 62 (2006) 264–284
283
ˇ
´
´
ˇ
´
ˇ
S.; Cısarova, I.; Sejbal, J.; Tislerova, I.; Smrcina, M.; Lloyd-
Jones, G. C.; Stephen, S. C.; Butts, C. P.; Murray, M.; Langer,
V. J. Am. Chem. Soc. 1999, 121, 7714. (d) Lloyd-Jones, G. C.;
University of Rome ‘La Sapienza’ for a fellowship to A. M.,
and Degussa for the gift of cyclohexylglycine.
ˇ
Stephen, S. C.; Murray, M.; Butts, C. P.; Vyskocil, S.;
ˇ
ˇ
Kocovsky, P. Chem. Eur. J. 2000, 6, 4348. (e) Fairlamb,
´
ˇ
I. J. S.; Lloyd-Jones, G. C.; Vyskocil, S.; Kocovsky, P. Chem.
ˇ
ˇ
´
References and notes
Eur. J. 2002, 8, 4443. (f) Gouriou, L.; Lloyd-Jones, G. C.;
ˇ
ˇ
ˇ
´
Vyskocil, S.; Kocovsky, P. J. Organomet. Chem. 2003, 687,
525. Pyridine and bipyridine-type ligands: (g) Malkov, A. V.;
Baxendale, I. R.; Bella, M.; Langer, V.; Fawcett, J.; Russell,
1. (a) Morrison, J. D. In Asymmetric synthesis, Vol. 2; Academic:
New York, 1983. (b) Noyori, R. Asymmetric catalysis in
organic synthesis; Wiley: New York, 1994. (c) Ojima, I.
Catalytic asymmetric synthesis, 2nd ed.; Wiley: New York,
2000. (d) James, B. R. Catal. Today 1997, 37, 209. (e)
Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069.
ˇ
´
D. R.; Mansfield, D. J.; Valko, M.; Kocovsky, P. Organome-
´
tallics 2001, 20, 673. (h) Malkov, A. V.; Bella, M.; Stara, I. G.;
ˇ
´
Kocovsky, P. Tetrahedron Lett. 2001, 42, 3045. (i) Malkov,
´
A. V.; Pernazza, D.; Bell, M.; Bella, M.; Massa, A.; Teply, F.;
ˇ
´
Meghani, P.; Kocovsky, P. J. Org. Chem. 2003, 68, 4727. For
2. For recent reports on catalytic hydrogenation (with Ti, Ir, Rh,
and Ru), see Refs. 1b–d and the following: (a) Xiao, D.;
Zhang, X. Angew. Chem., Int. Ed. 2001, 40, 3425. (b) Jiang,
X. B.; Minnaard, A. J.; Hessen, B.; Feringa, B. L.; Duchateau,
A. L. L.; Andrien, J. G. O.; Boogers, J. A. F.; de Vries, J. G.
Org. Lett. 2003, 5, 1503. (c) Cobley, C. J.; Henschke, J. P. Adv.
Synth. Catal. 2003, 345, 195. (d) Okuda, J.; Verch, S.; Stu¨rmer,
R.; Spaniol, T. S. J. Organomet. Chem. 2000, 605, 55. (e)
amino acid-based ligands, see Ref. 9 and the following: (j)
ˇ
´
Malkov, A. V.; Spoor, P.; Vinader, V.; Kocovsky, P.
Tetrahedron Lett. 2001, 42, 509. For an overview of our
ˇ
earlier work, see: (k) Kocovsky, P.; Malkov, A.; Vyskocil, S.;
ˇ
´
ˇ
Lloyd-Jones, G. C. Pure Appl. Chem. 1999, 71, 1425. (l)
ˇ
Kocovsky, P. J. Organomet. Chem. 2003, 687, 256.
´
ˇ
´
9. Malkov, A. V.; Hand, J. B.; Kocovsky, P. Chem. Commun.
´
Guiu, E.; Mun˜oz, B.; Castillon, S.; Claver, C. Adv. Synth.
2003, 1948.
10. For a preliminary account of this work, see: Malkov, A. V.;
ˇ
´
Mariani, A.; MacDougall, K. N.; Kocovsky, P. Org. Lett.
Catal. 2003, 345, 169. (f) Cobbley, C. J.; Foucher, E.;
Lecouve, J.-P.; Lennon, I. C.; Ramsden, J. A.; Thominot, G.
Tetrahedron: Asymmetry 2003, 14, 3431. (g) Chi, Y.; Zhou,
Y. G.; Zhang, X. J. Org. Chem. 2003, 68, 4120. (h) Bozeio,
2004, 6, 2253.
11. (a) Benkeser, R. A.; Snyder, D. J. Organomet. Chem. 1982,
225, 107. (b) Kobayashi, S.; Yasuda, M.; Hachiya, I. Chem.
Lett. 1996, 407.
ˆ ´
A. A.; Pytkowicz, J.; Cote, A.; Charette, A. B. J. Am. Chem.
Soc. 2003, 125, 14260. (i) Trifonova, A.; Diesen, J. S.;
Chapman, C. J.; Andersson, P. G. Org. Lett. 2004, 6, 3825. For
Ru-catalyzed transfer hydrogenation, see: (j) Samec, J. S. M.;
12. Activation of other trichlorosilanes with Lewis basic organo-
catalysts has now been well established. For a review on chiral
phosphoramides, see: (a) Denmark, S. E.; Fu, J. Chem. Rev.
2003, 103, 2763. For bipyridine-type N,N-bisoxides, see: (b)
Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto, S. J. Am.
Chem. Soc. 1998, 120, 6419. (c) Nakajima, M.; Saito, M.;
Hashimoto, S. Chem. Pharm. Bull. 2000, 48, 306. (d)
Nakajima, M.; Saito, M.; Uemura, M.; Hashimoto, S.
Tetrahedron Lett. 2002, 43, 8827. (e) Shimada, T.; Kina, A.;
Ikeda, S.; Hayashi, T. Org. Lett. 2002, 4, 2799. (f) Shimada,
T.; Kina, A.; Hayashi, T. J. Org. Chem. 2003, 68, 6329. (g)
Malkov, A. V.; Orsini, M.; Pernazza, D.; Muir, K. W.; Langer,
¨
Backvall, J. E. Chem. Eur. J. 2002, 8, 2955. For Rh-catalyzed
hydrogenation of enamides, see the following: (j) Hu, X.-P.;
Zheng, Z. Org. Lett. 2004, 6, 3585.
3. (a) Reding, M. T.; Buchwald, S. L. J. Org. Chem. 1998, 63,
6344. (b) Verdaguer, X.; Lange, U. E. W.; Buchwald, S. L.
Angew. Chem., Int. Ed. 1998, 37, 1103. (c) Hansen, M. C.;
Buchwald, S. L. Org. Lett. 2000, 2, 713. (d) Vedejs, E.;
Trapencieris, P.; Suna, E. J. Org. Chem. 1999, 64, 6724. (e)
Nishikori, H.; Yoshihara, R.; Hosomi, A. Synlett 2003, 561. (f)
Lipshutz, B. H.; Noson, K.; Chrisman, W. J. Am. Chem. Soc.
2001, 123, 12917. (g) Lipshutz, B. H.; Shimizu, H. Angew.
Chem., Int. Ed. 2004, 43, 2228.
ˇ
V.; Meghani, P.; Kocovsky, P. Org. Lett. 2002, 4, 1047. (h)
´
Malkov, A. V.; Bell, M.; Orsini, M.; Pernazza, D.; Massa, A.;
4. Kadyrov, R.; Riermeier, T. H. Angew. Chem., Int. Ed. 2003,
42, 5472.
ˇ
Herrmann, P.; Meghani, P.; Kocovsky, P. J. Org. Chem. 2003,
´
68, 9659. (i) Malkov, A. V.; Bell, M.; Vassieu, M.; Bugatti, V.;
ˇ
´
Kocovsky, P. J. Mol. Catal. A 2003, 196, 179. (j) Malkov,
´ ˇ
´
A. V.; Dufkova, L.; Farrugia, L.; Kocovsky, P. Angew. Chem.,
¨
5. Berkessel, A.; Groger, H. Asymmetric Organocatalysis;
Wiley-VCH: Weinheim, 2005.
6. For recent overviews, see (a) Feringa, B. L.; van Delden, R. A.
Angew. Chem., Int. Ed. 1999, 38, 3418. (b) Mikami, K.;
Terada, M.; Korenaga, T.; Matsumoto, Y.; Ueki, M.;
Angelaud, R. Angew. Chem., Int. Ed. 2000, 39, 3532. (c)
Fagnow, K.; Lautens, M. Angew. Chem., Int. Ed. 2002, 41, 26.
Int. Ed. 2003, 42, 3674.
13. (a) Iseki, K.; Mizuno, S.; Kuroki, Y.; Kobayashi, Y.
Tetrahedron 1999, 55, 977. See also: (b) Iseki, K.; Mizuno,
S.; Kuriki, Y.; Kobayashi, Y. Tetrahedron Lett. 1998, 39,
2767.
7. For
a recent review on chiral relay effect, see: (a)
14. (a) Iwasaki, F.; Omonura, O.; Mishima, K.; Kanematsu, T.;
Maki, T.; Matsumura, Y. Tetrahedron Lett. 2001, 42, 2525.
For a related reduction of ketones, see: (b) Iwasaki, F.;
Onomura, O.; Mishima, K.; Maki, T.; Matsumura, Y.
Tetrahedron Lett. 1999, 40, 7507.
Corminboeuf, O.; Quaranta, L.; Renaud, P.; Liu, M.; Jasperse,
C. P.; Sibi, M. P. Chem. Eur. J. 2003, 9, 28. For a recent
contribution, see: (b) Sibi, M. P.; Zhang, R.; Manyem, S.
J. Am. Chem. Soc. 2003, 125, 9306.
8. For recent, representative examples of our contribution, see,
for example, the following: Binaphthyl-type ligands (a)
15. To obtain 14 in high yield, it is crucial to add NaH (in small
portions) to a mixture of BOC-valine 13 and MeI. If the
deprotonation of 13 is carried out prior to the addition of MeI,
the methylation becomes inefficient.
ˇ
Vyskocil, S.; Jaracz, J.; Smrcina, M.; Stıcha, M.; Hanus, V.;
ˇ
ˇ
´ˇ ˇ
´
Polasek, M.; Kocovsky, P. J. Org. Chem. 1998, 63, 7727. (b)
ˇ
´
ˇ
ˇ
Vyskocil, S.; Smrcina, M.; Hanus, V.; Polasek, M.; Kocovsky,
ˇ
ˇ ˇ
P. J. Org. Chem. 1998, 63, 7738. (c) Kocovsky, P.; Vyskocil,
ˇ
ˇ
´ˇ
ˇ
´
´
16. (a) Andrus, M. B.; Li, W.; Keyes, R. F. J. Org. Chem. 1997, 62,

284
A. V. Malkov et al. / Tetrahedron 62 (2006) 264–284
5542. (b) Cheung, S. T.; Benoiton, N. L. Can. J. Chem. 1977,
55, 906.
32. While the 13C NMR spectrum of 3d exhibits one signal at
21.71 ppm for the methyls of the 3,5-dimethyanilide moiety,
the spectrum of a 1:1 mixture of 3d with Cl3SiH shows two
peaks at 21.69 and 21.76 ppm.
17. For the method, see the following: Sato, S.; Watanabe, H.;
Asami, M. Tetrahedron: Asymmetry 2001, 11, 4329.
18. Prushad, M.; Har, D.; Hu, B.; Kim, H. Y.; Repic, O.;
Blacklock, T. J. Org. Lett. 2003, 5, 125.
33. A similar effect has been observed by us for amides derived
from valine and picolinic acid, which served as ligands in the
Cu-catalyzed conjugate addition of Et2Zn. In this case, the
N-Me was optimal, while derivatives with other N-R groups
(RZH, Et, i-Pr, and Ph) were ineffective as catalysts.9
34. Preliminary experiments show striking conformational
differences in the X-ray structures of several of these
derivatives, which may lend further credence to this
hypothesis. Details will be published in due course.
19. Supuran, C. T.; Scozzafava, A. Eur. J. Pharm. Sci. 2000, 10,
67.
20. Aurelio, L.; Brownlee, R. T. C.; Hughes, A. B. Chem. Rev.
2004, 104, 5823.
21. Formamide 23b has been prepared previously as an oil:
Coppola, B. P.; Noe, M. C.; Schwartz, D. J.; Abdon, R. L.;
Trost, B. M. Tetrahedron 1994, 50, 93.
22. For another report on racemization, see the following: Davies,
J. S.; Mohamed, A. K. J. Chem. Soc., Perkin Trans. 1 1981,
2982.
35. For the oxidative removal of the N-(p-methoxyphenyl) group
to obtain the corresponding primary amine, see Ref. 2a.
36. High-level quantum chemistry calculations have demonstrated
that the p–p interaction between HCONH2 and C6H6 have a
23. For the use of N-Cbz (instead of N-BOC protection), see the
following: (a) Aurelio, L.; Brownlee, R. T. C.; Hughes, A. B.;
Sleebs, B. E. Aust. J. Chem. 2000, 53, 425. (b) Aurelio, L.;
Box, J. S.; Brownlee, R. T. C.; Hughes, A. B.; Sleebs, B. E.
J. Org. Chem. 2003, 68, 2652.
stabilizing effect of up to 8 kcal molK1: Vondrasek, J.;
´ˇ
´
Bendova, L.; Klusak, V.; Hobza, P. J. Am. Chem. Soc. 2005,
´
127, 2615.
37. Schnider, P.; Koch, G.; Pretot, R.; Wang, G.; Bohnen, F. M.;
´ ˆ
24. Kaur, N.; Monga, V.; Jain, R. Tetrahedron. Lett. 2004, 45,
6883.
Kru¨ger, C.; Pfaltz, A. Chem. Eur. J. 1997, 3, 887.
38. Barluenga, A.; Aznar, F. Synthesis 1975, 704.
39. Bunnelle, W. H.; Singam, P. R.; Narayanan, B. A.; Bradshaw,
C. W.; Liou, J. S. Synthesis 1997, 439.
25. La Ronde, F. J.; Brook, M. A. Inorg. Chim. Acta 1998, 296,
208.
ˇ
26. Amide 39a has been prepared previously: Liu, Y.; Svec, F.;
´
Frechet, J. M. J.; Juneau, K. N. Anal. Chem. 1997, 69, 61.
40. Aguilar, E.; Joslar, J.; Merino, I.; Olano, B.; Palacios, F.;
Fustero, S. Tetrahedron 2000, 56, 8179.
27. In the absence of the catalyst, the conversion after 24 h at room
temperature in CH2Cl2 and CHCl3 was !5%, and w10% in
MeCN.
41. Nettekoven, U.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124,
1166.
42. (a) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2000, 122,
9546. (b) Denmark, S. E.; Nakajima, N.; Nicaise, O. J.-C.
J. Am. Chem. Soc. 1994, 116, 8797.
28. See Ref. 12j and the following: (a) Malkov, A. V.; Bell, M.;
ˇ
Castelluzzo, F.; Kocovsky, P. Org. Lett. 2005, 7, 3219. (b)
´
´
Malkov, A. V.; Stewart Liddon, A. J. P.; Bendova, L.; Haigh,
43. Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L.
J. Am. Chem. Soc. 2001, 123, 984.
ˇ
´
D. Z.; Kocovsky, P. Unpublished results
29. Chloroform has been shown to be the solvent that most
strongly stabilizes the arene–arene interactions: Breault, G. A.;
Hunter, C. A.; Mayers, P. C. J. Am. Chem. Soc. 1998, 120,
3402.
44. Rossiter, B. E.; Eguchi, M.; Miao, G.; Swingle, N. M.;
Hernandez, A. E. Tetrahedron 1993, 49, 965.
45. Ozawa, F.; Okamoto, H.; Kawagishi, S.; Yamamoto, S.;
Minami, T.; Yoshifuji, M. J. Am. Chem. Soc. 2002, 124,
10968.
30. While imines 1a–d,f,g,k all exists as pure (E)-isomers, NMR
spectra of 1e,h indicate 11:1 and 14:1 (E/Z)-mixtures,
respectively.
46. (a) Fache, F.; Valot, F.; Milenkovic, A.; Lemaire, M.
Tetrahedron 1996, 52, 9777. (b) Gately, D. A.; Norton, J. R.
J. Am. Chem. Soc. 1996, 118, 3479.
31. This strategy is commonly used in design of chiral selectors in
chiral chromatography: Pirkle, W. H.; Koscho, M. E.
J. Chromatogr. A 1999, 840, 151.
47. In our preliminary communication (Ref. 10), the tR and tS
retention times were swapped for 2a,b,d,g by mistake.