Diastereoselective and highly enantioselective henry reactions using C 1-symmetrical copper(II) complexes

Article abstract of DOI:10.1002/adsc.201100157

Catalytic Henry reactions of aliphatic aldehydes and prochiral nitro compounds were investigated using copper(II) complexes of 14 C ₁-symmetrical ligands derived from (1R,2R)(-)-diaminocyclohexane. β-Nitro alcohols with syn:anti ratios of up to 5.7 and excellent ee values for both diastereosimers were obtained. Copyright

Full text of DOI:10.1002/adsc.201100157

FULL PAPERS
DOI: 10.1002/adsc.201100157
Diastereoselective and Highly Enantioselective Henry Reactions
using C1-Symmetrical Copper(II) Complexes
Antoinette Chougnet,a Guoqi Zhang,b Kegang Liu,a Daniel Hꢀussinger,a
Andreas Kꢀgi,c Thomas Allmendinger,c and Wolf-D. Woggona,*
a
Department of Chemistry, University of Basel, St. Johanns-Ring 19, CH-4056 Basel, Switzerland
Fax : (+41)-61-267-1103; e-mail: wolf-d.woggon@unibas.ch
Department of Chemistry, University of Basel, Spitalstrasse 51, CH-4056 Basel, Switzerland
Novartis Pharma AG, Klybeckstrasse 141, CH-4057, Switzerland
b
c
Received: March 7, 2011; Published online: July 1, 2011
Abstract: Catalytic Henry reactions of aliphatic alde- 5.7 and excellent ee values for both diastereosimers
hydes and prochiral nitro compounds were investi- were obtained.
gated using copper(II) complexes of 14 C1-symmetri-
cal ligands derived from (1R,2R)(À)-diaminocyclo- Keywords: copper(II) complexes; diastereoselectiv-
hexane. b-Nitro alcohols with syn:anti ratios of up to ity; enantioselectivity; Henry reaction; nitroaldol re-
action
Introduction
Results and Discussion
Enantioselective nitroaldol (Henry) reactions of We first investigated the reaction between 3-phenyl-
CH3NO2 and aromatic aldehydes have been intensive- propionaldehyde (2) and methyl 4-nitrobutyrate (3) in
ly investigated using organocatalysis[1] and metalor- the presence of catalyst 1 generated in situ from
ganic catalysts.[2] However, there are only a few exam- ligand 4 and Cu
ACHTUNGTRENNUNG
ples that demonstrate efficient reactions of aliphatic
aldehydes[3,4] and even less examples that use aliphatic contained two diastereoisomers 5 and 6 in the ratio of
aldehydes and prochiral nitroalkanes generating prod- 75:25. In order to obtain information on the relative
ucts with two chiral centres in high enantiomeric and absolute configurations of these b-nitro alcohols
excess (ee) and high distereoisomeric ratio (dr).[2e,g,p–t] the following experiments were pursued.
We have recently reported on a relatively rare C1-
The mixture of racemic 5 and 6, obtained by reac-
symmetrical Cu(II) complex 1 catalyzing Henry reac- tion of 2 and 3 with NEt3, was reduced and derivat-
tions of CH3NO2 with aromatic and aliphatic alde- ized[5] yielding the b-hydroxy amides 7 and 8 that
hydes and N-Boc-imines.[4] The structure of 1, shown were separated. Subsequently, racemic 7 was cyclized
in Scheme 1, is taken from X-ray crystallography of to furnish the cis-acetals 9 (Scheme 2); the latter dis-
1[4] which displayed an unusual M left-handed helix played a significant NOE effect (6%) between adja-
stabilized through hydrogen bonding between the cent protons at the five-membered heterocycle. In
À
non-coordinating pyridine and the N H adjacent to contrast, syn-b-hydroxy amides 8 gave trans-acetals
the phenolate and by p-stacking of the pyridines. Ex- displaying a very week NOE effect (0.7%) between H
periments suggested that this structure is also main- at C-4 and H at C-5. Since 7 was the minor compound
tained in solution.[4]
obtained from b-nitro alcohols produced by Henry re-
Subsequently we decided to screen the ligand actions catalyzed by 1 it was concluded that the reac-
system of complex 1 for the more challenging diaste- tion shown in Scheme 1 generates syn-5>anti-6. This
reoselective nitroaldol reaction between two aliphatic result was confirmed by 13C NMR of the products of
reaction partners; the results are reported here.
the catalytic reaction revealing resonances at
91.9 ppm and 91.1 ppm of C NO2 in the ratio of ca.
75:25. According to earlier investigations by See-
bach[6] and Ono[7], in general, the low field signal be-
longs to a syn-b-nitro alcohol whereas the high-field
signal refers to the anti-configured product. The ratio
À
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Scheme 1. Diastereo- and enantioselective Henry reaction using C1-symmetrical copper(II) complex 1.
Scheme 2. Determination of the relative configuration of b-nitro alcohols 5; racemic 5 and 6 were converted to racemic 7
and 8 that could be separated into diastereoisomers.
1
of syn-5:anti-6=3:1 was also visible in the H NMR
In order to determine the absolute configuration of
as the multiplets of the protons at C-5 of both com- syn-5 the major product of the enantioselective Henry
pounds are clearly separated. reaction (Scheme 1), the mixture of syn-5 and anti-6
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Adv. Synth. Catal. 2011, 353, 1797 – 1806

Diastereoselective and Highly Enantioselective Henry Reactions using C1-Symmetrical Copper(II) Complexes
Scheme 3. Determination of absolute configuration of nitro alcohol (4S,5S)-5.
was converted into b-hydroxy amides syn-(4S,5S)-8 and 13–24 (Table 1) b-nitro alcohols 5+6 can be ob-
and anti-(4R,5S)-7. After chromatographic separation tained in good yields, syn/anti ratios >75:25 can be
syn-(4S,5S)-8 was subsequently esterified with Mosh- accomplished and ee values are in general well above
erꢂs acid chloride (R)-10 to furnish 11. The absolute 90% for both diastereoisomers. With respect to dr
configuration of 11 and hence syn-5 was deduced and ee values best results were obtained with ligands
from the 1H NMR spectrum of the Mosher ester 13, 15 and 24 that carry a sterically demanding iso-
(Scheme 3). Accordingly, the combination of structur- heptyl substituent adjacent to the coordinating pheno-
al analysis and chiral HPLC led to the conclusion that late and a heterocycle that could form a helical struc-
catalyst 1 gave the nitro alcohols syn-(4S,5S)-5 and ture like 1, see above. Interestingly, the Cu(II) com-
anti-(4S,5R)-6 with 96% ee and dr of 75:25 in favour plexes of ligands 17–19 that have the heterocycle re-
of the syn diastereoisomer.
placed by a naphthyl, cyclohexyl and an alkyl chain,
Subsequently we prepared various ligands respectively, gave excellent ee values and syn/anti
(Figure 1) in order to investigate the impact of ligand ratios close to those of 1. Hence, it seems that the hel-
structure on ee and dr values. Ligands were accessible ical structure of 1 is not required to accomplish good
from (1R,2R)-(À)-diaminocyclohexane and commer- ee and dr values.
cially available aldehydes (except for 26 and 27) in
The preferred formation of the syn-5>anti-6
two steps and in yields between 40–70%. It is impor- (Table 1) is in agreement with calculations by Cossio
tant to note that good yields for these C1-symmetrical et al.[8] who computed inter alia the transition states
ligands are only obtained if (1R,2R) diaminocyclohex- of the reaction between the lithium nitronate of nitro-
ane reacts first with the less reactive aldehyde.
ethane and acetaldehyde. This work indicates that in
Figure 1 displays a representative selection of more the presence of a coordinating metal, aldehyde and
than 60 ligands that were prepared and of which the nitronate dipoles are not antiperiplanar oriented (as
Cu(II) complexes were investigated to catalyze the re- in the absence of a metal) and both the aldehyde and
action of 2 and 3. As a general trend in this survey ee the nitronate coordinate with one oxygen atom. Ac-
values around 90% and syn/anti ratios between 60/40 cording to these calculations the TS of lowest enrgy is
and 70/30 were observed. Exceptions are, for exam- associated with the syn diastereoisomer, although ste-
ple, half-reduced Schiff-bases such as 25 (low yields, reocontrol in this model reaction is quite low. The re-
low ee values) and C2-symmetrical ligands such 12 sults displayed in Table 1 clearly show that the prod-
(Figure 1) that gave racemic 5 and 6. With ligands 4 uct syn 5 is favoured by up to 5.7:1 over anti-6 when
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Figure 1. ACHTUNGTRENNUNG(1R,2R)-Diaminocyclohexane-derived ligands for Cu(II) complexes.
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Diastereoselective and Highly Enantioselective Henry Reactions using C1-Symmetrical Copper(II) Complexes
Table 1. Henry reactions of 2 and 3 catalyzed by Cu(II)
complexes of ligands 4, 12–25.[a]
Table 2. Henry reactions of aldehyde 2 with various prochi-
ral nitroalkanes catalyzed by 1.[a]
[d]
Entry Ligand Yield of 5+6[b] syn-5:anti-6[c] eesyn/anti
1
2
3
4
5
6
7
8
4
83%
80%
74%
87%
93%
80%
80%
87%
75%
96%
87%
76%
82%
20%
95%
75:25
85:15
83:17
84:16
76:24
76:24
75:25
78:22
75:25
81:19
85:15
77:23
85:15
80:20
46:54
96%/96%
99%/94%
99%/90%
99%/89%
99%/96%
99%/99%
99%/96%
99%/95%
99%/95%
99%/90%
99%/87%
99%/99%
99%/92%
55%/65%
racemic
13
14
15
16
17
18
19
20
21
22
23
24
25
12
R
Product/yield
syn:anti[b]
eesyn/anti [%][c]
9
[d]
CH3
28[2q,3a]/89%
29[2q,3a]/84%
30/94%
71:29
82:18
75:25
77:23
66:34
82:18
98/90
97/97
99/99
99/96
99/96
99/97
10
11
12
13
14
15
[d]
CH2-CH3
CH2OBn[e]
CH2OTBS[e]
CH2OH[e]
CH2Ph[e]
31/86%
32[3a]/74%
33[2a]/85%
[a]
[a]
Reaction conditions: 5 mol% CuACHTNUTRGNEUNG(OAc)2, 5 mol% ligand,
Reaction conditions:
2
(0.384 mmol), ligand
4
5 mol% diisopropylethylamine (DIPEA), 3/2=1.5 THF,
À128C, 48 h.
(6 mol%),Cu(OAc)2 (5 mol%), diisopropylethylamine
(DIPEA, 10 mol%), dioxane (0.4 mL), 08C, 24 h.
AHCTUNGTRENNUNG
[b]
[c]
[b]
Yield after column chromatography.
Determined by chiral HPLC at l=220, 230, 250 nm
1
(same syn/anti ratio within 1%), H NMR and 13C NMR
Determined by chiral HPLC at l=220, 230, 250 nm
1
(same syn/anti ratio within 1%), H NMR and 13C NMR.
spectroscopy.[6,7]
[d]
[c]
[d]
[e]
Determined by chiral HPLC.
Determined by chiral HPLC.
1.92 mmol nitroalkane (5 equiv.).
0.96 mmol nitroalkane (2.5 equiv.).
space for binding to the metal is sterically congested.
Results from several other groups using metal com-
plex-catalyzed Henry reactions confirm this
trend,[2q,t,3] but exceptions are also reported.[2r,3c]
Furthermore, we investigated the limitation and
scope of catalyst 1 in Henry reactions with aldehyde 2
and several nitro compounds (Table 2).
Table 3. Henry reactions of aromatic aldehydes 34 and 35
with nitro compounds catalyzed by 1.[a]
Regarding dr and ee values of products 28, 29 and
33 our results in Table 2 compare well with those ob-
tained with Shibasakiꢂs rare earth bimetallic BINOL
complexes;[3a] but the advantages of our system are i)
facile preparation of the ligand/catalyst, ii) easy han-
dling of the reaction and iii) reaction times are three
to four times shorter.
Interestingly catalyst 1 performs less selectively
with aromatic aldehydes such as benzaldehyde (34)
and p-nitrobenzaldehyde (35). As shown in Table 3
yields are very good but ee values and syn-anti ratios
drop considerably as compared to results with alde-
hyde 2 (Table 1 and Table 2).
Aldehyde Nitroalkane[d] Product/
yield
syn:anti[b] eesyn/anti
[%][c]
34
34
35
35
3
36
3
37[2q]/80% 63:37
70/80
91/26
60/27
82/35
38[2r]/80% 79:21
39[2q]/93% 61:39
40[3d]/94% 70:30
36
Conclusions
[a]
Reaction conditions: aldehyde (0.384 mmol), ligand 4
(6 mol%),Cu(OAc)2 (5 mol%), diisopropylethylamine
(DIPEA, 10 mol%), dioxane (0.4 mL), 08C, 24 h.
AHCTUNGTRENNUNG
The structure of C1-symmetrical ligand 4 and hence
the corresponding Cu(II) complexes have been modi-
fied to investigate the stereoselectivity of the Henry
reaction of 3-phenylpropionaldehyde (2) and methyl
4-nitrobutyrate (3). syn-5 and anti-6 were obtained in
very high enantioselectivity and in syn/anti ratios of
[b]
Determined by chiral HPLC at l=220, 230, 250 nm
1
(same syn/anti ratio within 1%), H NMR and 13C NMR
spectroscopy.[6,7]
[c]
[d]
Determined by chiral HPLC.
1.92 mmol nitroalkane (5 equiv.).
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idinecarboxaldehyde (2 mmol) in dichloromethane (10 mL)
was added in one portion at room temperature, the reaction
mixture was heated under reflux for 1 h and stirred over-
night at room temperature, yielding a mixture of imines
which was not separated. The reduction was performed as
described above, yielding an oil which was purified by
column chromatography on silica gel (solvent indicated
below).
up to 5.7. Similar results were obtained when 2 react-
ed with other prochiral nitro compounds in the pres-
ence of catalyst 1; however, under the same condi-
tions aromatic aldehydes react less selectively.
Experimental Section
General
Characteristic Data of Ligands
Reagents and solvents were purchased from Acros, Sigma–
Aldrich or Merck companies and used without further pu-
rification. For chromatography: TLC plates (Merck) and
silica gel 60 (Fluka) were used. 1H (400 MHz) and 13C
(100 MHz) NMR spectra were obtained with a Bruker
DPX-NMR spectrometer, using CDCl3 as solvent if not
stated otherwise. Two-dimensional NMR experiments
(COSY, NOESY, HMQC, HMBC) were performed on a
Bruker DRX-600 Avance instrument equipped with a self-
shielded z-gradient BBI probehead. Electron spray ioniza-
tion mass spectra (ESI-MS) were recorded with a Bruker
Esquire 3000plus, UV-VIS spectra with a Hewlet-Packard
8452A diode array spectrometer; FT-IR spectra were run
on a Shimadzu 8440S; high resolution mass spectra were ob-
tained with a Thermo Scientific LTQ Orbitrap XL; optical
rotations with a Perkin–Elmer 341, sodium lamp, 1-dm cuv-
ette length. HPLC was perfromed with a Shimadzu 20 A
device equipped with a Chiralcel ODH column 5 mm, 4.6ꢃ
250 mm (Daicel Chemical Industries, Ltd).
12: Chromatography CHCl3-MeOH-NH4OH 100–10–1, col-
1
ourless oil, yield: 62%. H NMR: d=8.34 (d, J=4.9 Hz,2H),
7.40(d, J=6.8 Hz, 2H), 7.05 (dd, J=4.9, 6.8 Hz, 2H), 4.02(d,
J=13.6 Hz, 2H), 3.78 (d, J=13.6 Hz, 2H), 2.37 (m, 2H),
2.33 (s, 6H), 2.12 (m, 2H), 1.75ACTHNUGTRNEUNG(m, 4H), 1.28 (m, 2H), 1.53
(m, 2H); 13C NMR (CDCl3): d=146.61, 137.94, 131.73,
122.16, 62.26, 50.75, 32.06, 25.46, 18.53; IR: n=2927, 2854,
1582, 1424 cmÀ1; [a]D20: À958 (c 0.287, CH2Cl2); ESI-MS:
m/z=347.2 (M+Na+), 325.3 (M+H+); HR-MS: m/z=
325.23877, D=0.3 ppm, C20H28N4.
13: Rf 0.3 (CH2Cl2-MeOH 3%), chromatography CH2Cl2-
MeOH 3%, yield: 54%, colorless oil. H NMR: d=8.50 (s,
1
1H), 8.42 (d, J=5 Hz, 1H), 7.42 (d, J=5 Hz, 1H), 7.08(d,
J=8 Hz, 1H), 6.84(d, J=8 Hz, 1H), 6.71 (t, J=8 Hz, 1H),
4.02 (d, J=11 Hz,1H), 4.01(d, J=11 Hz, 1H), 3.86(d,
J=12 Hz,1H), 3.80 (d, J=12 Hz, 1H), 1.86 (q, J=7 Hz, 6H),
0.64 (t, J=7 Hz,9H);13C NMR: d=157.6, 149.5, 148.4, 147.3,
133.5, 131.8, 129.1, 126.2, 124.2, 124.0, 118.1,62.6, 61.2, 51.4,
47.6, 44.6, 32.2, 31.4, 26.2, 25.4, 24.9, 8.9; IR: n=2926, 2870,
1586, 1436 cmÀ1; [a]D20: À68.78 (c 0.893, CH2Cl2); ESI-MS:
General Procedure for the Preparation of Ligands
m/z=444.4ACTHNUTRGNEUNG
(M+H+); HR-MS: m/z=444.27799. D=0.8 ppm,
C1-symmetrical ligands: A 50-mL two-necked, round bottom
flask equipped with a 0.5 cm, Teflon-coated stir bar, a con-
denser and a balloon filled with argon was charged with
(1R,2R)-1,2-diaminocyclohexane (114 mg, 1 mmol) dissolved
in dry dichloromethane (10 mL). By means of a syringe
pump a solution of a pyridinecarboxaldehyde (1 mmol) in
dichloromethane (10 mL) was added during 2 h at room
temperature. After completion of the addition, the reaction
mixture was stirred for another hour at room temperature.
C26H38ON3Cl.
14: Rf 0.5 (CH2Cl2-MeOH 10%), chromatography
CH2Cl2-MeOH 5%, yield: 44%, pale yellow crystals, mp 60–
1
63 8C. H NMR: d=8.50
G
(d, J=5 Hz, 1H), 6.92 (s, 1H), 6.67ACHTNUGTRENNUNG
1H), 3.99 (d, J=8 Hz, 1H),3.79 (d, J=6 Hz, 1H), 3.75 (d,
J=6 Hz, 1H), 2.23 (s, 3H); 13C NMR: d=155.3, 149.4,
148.4,147.3, 137.3, 131.7, 127.5, 126.9, 126.7, 124.2, 62.3, 61.3,
51.0, 47.5, 40.8, 37.6, 37.1, 32.2, 31.4, 29.5, 25.4, 24.9, 21.2;
IR: n=2898, 2844, 1744, 1446 cmÀ1; [a]D20: À668 (c 0.277,
CH2Cl2); ESI-MS: m/z=494.2 (M+H+); HR-MS: m/z=
494.29330, D=0.1 ppm, C30H40ON3Cl.
Subsequently
a
solution of
a
2-hydroxybenzaldehyde
(1 mmol) in dry dichloromethane (5 mL) was added in one
portion, the reaction mixture was then heated under reflux
for 1 h and stirred for 16 h at room temperature. The solu-
tion was then concentrated at 15 Torr and the yellow resi-
due, containing the imines, was dissolved in methanol
(15 mL), an excess of NaBH4 (250 mg) was added and the
solution was stirred for 2 h at room temperature. The reac-
tion was quenched with 1N HCl (1 mL), 4N NaOH (3 mL)
was added and the mixture was poured into 30 mL saturated
aqueous NaHCO3 and extracted three times with ethyl ace-
tate (25 mL). The organic phase was washed with water and
finally dried over Na2SO4. Removal of the solvents under re-
duced pressure yielded an oil that was purified by chroma-
tography on silica gel (solvent indica-ted) to obtain the de-
sired pure ligand.
15: Rf 0.5 (CH2Cl2-MeOH 5%), chromatography CH2Cl2-
MeOH 2%, yield: 48%, colorless oil. H NMR: d=8.51 (s,
1
1H), 8.44 (d, J=5 Hz, 1H), 7.40 (d, J=5 Hz, 1H), 7.14
(s,1H), 6.96 (s, 1H), 4.02 (d, J=10 Hz,1H), 3.90 (m, 2H),
3.76(d, J=10 Hz,1H), 1.81 (q, J=7 Hz, 6H), 0.63 (t, J=
7 Hz,9H); 13C NMR: d=156.8, 149.6, 144.4, 147.2, 136.8,
136.3, 131.8, 128.6, 125.8, 124.2, 110.7, 62.8, 61.3, 51.1, 47.7,
44.9, 31.4, 26.0, 25.4, 24.9, 8.8; IR: n=2926, 2873, 1586,
1446 cmÀ1; [a]D20: À52.18 (c 0.803, CH2Cl2); ESI-MS: m/z=
522.3, 524.2 (M+H+); HR-MS: m/z=522.18828, D=
0.3 ppm, C26H37ON3ClBr.
16: Rf 0.1 (CH2Cl2-MeOH 5%), chromatography CH2Cl2-
MeOH 5%, yield: 70%, pale yellow oil. H NMR: d=8.45
1
C2-symmetrical ligands:
A
50-mL two-necked, round
(s, 1H), 7.66 (d, J=8 Hz, 1H), 7.22 (d, J=7 Hz, 1H), 7.12
(d, J=8 Hz, 1H), 6.89 (d, J=7 Hz, 1H), 6.75 (t, J=7 Hz,
1H), 4.02 (d, J=14 Hz,1H), 4.95 (d, J=13 Hz, 1H), 3.86 (d,
J=14 Hz,1H), 3.70 (d, J=13 Hz, 1H), 2.7 (t, J=7 Hz,2H),
1.78 (m, 2H), 1.0 (t, J=7 Hz,3H): 13C NMR: d=161.3,
bottom flask equipped with a 0.5 cm, Teflon-coated stir bar,
a condenser and a balloon filled with argon was charged
with (1R,2R)-1,2-diaminocyclohexane (114 mg, 1 mmol) dis-
solved in dry dichloromethane (10 mL). A solution of a pyr-
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Diastereoselective and Highly Enantioselective Henry Reactions using C1-Symmetrical Copper(II) Complexes
157.5, 149.1, 136.9, 136.5, 133.1, 126.2, 125.8, 124.2, 122.7,
118.2, 62.4, 60.0, 50.9, 48.0, 40.2, 34.8, 31.2, 29.7, 25.3, 24.8,
23.3, 14.1; IR: n=2929, 2870, 1435 cmÀ1; [a]D20: À101.48 (c
d=7.91 (d, J=8 Hz, 1H), 7.8 (d, J=8 Hz, 1H), 7.4 (t, J=
8 Hz, 1H), 7.34 (t, J=8 Hz, 1H), 7.17 (d, J=7 Hz 1H), 6.86
(d, J=7 Hz, 1H), 6.68 (t, J=7 Hz, 1H), 4.34 (d, J=
16 Hz,1H), 4.22 (d, J=16 Hz, 1H), 4.07(d, J=14 Hz, 1H),
3.87 (d, J=14 Hz, 1H), 2.45 (m, 1H), 2.31 (m,2H), 2.17 (m,
1H) 1.41 (s, 9H);13C NMR: d=157.7, 153.7, 126.5, 126.3,
126.0, 125.1, 124.5, 123.0, 122.2, 118.4, 62.5, 60.9, 51.2, 48.9,
35.1, 32.2, 31.5, 29.9, 25.4, 24.9; IR: n=2924, 2855,
1435 cmÀ1; [a]D20: À78.18 (c 0.525, CH2Cl2); ESI-MS: m/z=
424.3 (M+H+); HR-MS: m/z=424.24185, D=0.3 ppm,
C25H34ON3S.
0.519, CH2Cl2); ESI-MS;: m/z=410.3ACTHNUTRGNEUNG
(M+H+); HR-MS:
m/z=410.31652, D=0.8 ppm, C26H39ON3.
17: Rf 0.3 (CH2Cl2-MeOH 5%), chromatography CH2Cl2-
1
MeOH 5%, yield: 48%, colourless oil. H NMR: d=8.08 (d,
J=9 Hz 1H), 7.83 (d, J=8 Hz, 1H), 7.75 (d, J=8 Hz, 1H),
7.4 (m, 4H), 7.16 (d, J=8 Hz, 1H), 6.77 (d, J=7 Hz,
1H),6.67 (t, J=8 Hz,1H) 4.38 (d, J=13 Hz,1H), 4.12(d,
J=13 Hz, 1H), 3.91(d, J=13 Hz,1H), 3.75 (d, J=13 Hz, 1H),
2.46 (m, 1H), 2.36 (m, 1H), 2.23 (m, 1H), 2.13 (m,1H), 1.7
(m,2H), 1.4 (s,9H); 13C NMR: d=157.2, 137.0, 136.5, 134.2,
132.2, 129.0, 128.3, 126.6, 126.5, 126.4, 126.0, 125.8, 125.7,
124.5, 124.1, 118.3, 62.7, 61.2, 51.0, 49.3, 35.0, 32.3, 31.4, 29.9,
25.7, 25.0; IR: n=2926, 2896, 1589, 1434 cmÀ1; [a]D20: À93.78
23: Rf 0.46 (CH2Cl2-MeOH 5%), chromatography
1
CH2Cl2-MeOH 2%, yield: 58%, pale brown oil. H NMR:
d=7.83 (d, J=8 Hz, 1H), 7.7 (d, J=8 Hz, 1H), 7.32 (s, 1H),
7.28ACTHNUTRGNE(NUG m, 2H), 7.4, 7.17 (d, J=7 Hz 1H), 6.80 (d, J=7 Hz,
1H), 6.68 (t, J=7 Hz, 1H), 4.21 (d, J=15 Hz,1H), 4.0 (d,
J=15 Hz, 1H), 3.9(d, J=14 Hz, 1H), 3.78 (d, J=14 Hz, 1H),
2.43 (m, 1H), 2.29 (m,2H), 2.17 (m, 1H) 1.42 (s,
9H);13C NMR: d=157.6, 141.1, 138.7, 137.1,135.7, 126.4,
125.9, 124.7, 124.5, 124.4, 123.4, 123.3, 122.1, 118.4, 62.6,
60.9, 51.0, 45.2, 35.0, 32.2, 31.4, 29.9, 25.6, 25.0; IR: n=2922,
2854, 1446 cmÀ1; [a]D20: À77.98 (c 0.569, CH2Cl2); ESI-MS:
m/z=423.3 (M+H+): HR-MS 423.24663, D=0.4 ppm,
C26H35ON2S.
24: Rf 0.31 (CH2Cl2-MeOH 3%), chromatography
CH2Cl2-MeOH 2%, then ethyl acetate-cyclohexane 1:1,
yield: 15%, colourless oil. 1H NMR: d=7.07 (d, J=7 Hz
1H), 6.84 (d, J=7 Hz, 1H), 6.68 (t, J=7 Hz, 1H), 3.90 (m,
2H), 1.87 (q, J=7 Hz, 6H) 1.45 (s,9H) 0.636 (t, J=7 Hz,
9H); 13C NMR: d=157.5,. 156.0, 155.7, 132.8, 128.94, 128.9,
126.6, 124.59, 124.54, 118.48, 118.43, 80.3, 80.0, 62.2, 61.9,
61.6, 58.48, 58.2, 54.2, 50.76, 50.68, 47.4, 46.8, 44.5, 31.7,
31.46, 31.45, 31.13, 31.12, 30.9, 29.6, 29.3, 28.2, 28.1, 25.9,
25.3, 25.17, 25.13, 23.99, 23.13, 8.1; IR: n=2924, 2855, 1684,
1435 cmÀ1; [a]D20: À268 (c 0.219, CH2Cl2); ESI-MS: m/z=
502.5 (M+H+); HR-MS: m/z=502.40061, D=0.6 ppm,
C30H52O3N3.
25: Rf 0.16 (CH2Cl2-MeOH 3%), chromatography
CH2Cl2-MeOH 2%, then ethyl acetate-cyclohexane 1:1,
yield: 20%, yellow oil. 1H NMR (600 MHz, MeOD-d4,
280 K): d=8.5 (s, 1H), 7.27 (d, J=7 Hz 1H), 7.20 (d, J=
7 Hz, 1H), 6.83 (t, J=7 Hz, 1H), 3.90 (m, 2H), 1.90 (q, J=
7 Hz, 6H) 1.41 (s, 9H), 0.636 (t, J=7 Hz, 9H); 13C NMR
(600 MHz, MeOD-d4, 280 K): d=168.2, 167.8, 161.6, 161.59,
156.8, 156.4, 134.3, 133.8, 133.7, 131.43, 131.4, 120.06, 119.12,
119.0, 81.2, 80.8, 75.2, 74.9, 63.8, 63.6, 58.9, 58.8, 52.2, 51.6,
47.9, 47.4, 45.6, 35.2, 35.1, 32.1, 31.9, 30.4, 30.0, 29.0, 28.9,
26.0, 25.8, 25.7, 24.6, 23.7, 8.1; IR: n=2924, 2855, 1688,
1435 cm À1; [a]D20: À69.58 (c 0.399, CH2Cl2); ESI-MS: m/z=
500.5 (M+H+); HR-MS: m/z=500.38488, D=0.4 ppm,
C30H50O3N3.
(c 1.386, CH2Cl2); ESI-MS: m/z=417.4
m/z=417.28997, D=0.2 ppm, C28H37ON2.
(M+H+): HR-MS:
ACHTUNGTRENNUNG
18: Rf 0.5 (cyclohexane-ethyl acetate 1:1), chromatogra-
phy cyclohexane-ethyl acetate 2:1 yield: 25%, colourless oil.
1H NMR: d=7.16 (d, J=7 Hz, 1H), 6.86 (d, J=7 Hz, 1H),
6.68 (t, J=7 Hz, 1H), 4.0 (d, J=13 Hz,1H), 3.86 (d, J=
13 Hz, 1H), 2.54 (m,1H), 2.28 (m,1H) 2.17 (m,4H), 1.41 (s,
9H); 13C NMR: d=157.8, 137.1, 126.4, 125.9, 124.6, 118.3,
61.5, 54.06, 54.04, 51.1, 49.6, 38.9, 35.0, 31.9, 31.8, 31.4, 29.96,
29.92, 27.1, 26.47, 26.42, 25.6, 25.1; IR: n=2923, 2851, 1586,
1433 cmÀ1, [a]D20: À1188 (c 0.10, CH2Cl2); ESI-MS: m/z=
373.4 (M+H+); HR-MS: m/z=373.32142, D=0.2 ppm,
C24H41ON2.
19: Rf 0.15 (CH2Cl2-MeOH 3%), chromatography
1
CH2Cl2-MeOH 3%, yield: 24%, colourless oil. H NMR: d=
7.17 (d, J=7 Hz 1H), 6.86 (d, J=7 Hz, 1H), 6.68 (t, J=
7 Hz, 1H), 4.01 (d, J=13 Hz,1H), 3.84 (d, J=13 Hz, 1H),
2.72 (m, 1H), 2.41 (m, 1H), 2.23 (m, 1H), 1.41 (s, 9H);
13C NMR: d=157.8, 137.1, 126.4, 125.9, 124.7, 118.3, 62.8,
61.2, 51.2, 47.4, 35.0, 32.4, 32.3, 31.4, 31.1, 30.03, 30.00, 99.99,
29.93, 29.7, 27.7, 25.6, 25.0, 23.1, 14.5; IR: n=2894,
1435 cmÀ1; [a]D20: À90.18 (c 0.518, CH2Cl2); ESI-MS: m/z=
417.5 (M+H+); HR-MS: m/z=417.38403, D=0.2 ppm,
C27H49 ON2.
20: Rf 0.47 (CH2Cl2-MeOH 10%), chromatography
1
CH2Cl2-MeOH 3%, yield: 65%, pale brown oil. H NMR:
d=7.17 (d, J=7 Hz 1H), 6.86 (d, J=7 Hz, 1H), 6.68 (t, J=
7 Hz, 1H), 4.01 (d, J=13 Hz,1H), 3.84 (d, J=13 Hz, 1H),
3.26 (m, 2H), 2.68 (broad s, 2H), 1.45 (s, 9H), 1.41 (s, 9H);
13C NMR: d=157.7, 137.1, 126.3, 125.9, 124.6, 118.3, 85.4,
62.7, 60.9, 57.6, 51.2, 49.3, 35.0, 32.4, 31.4, 29.9, 28.9, 25.6,
25.0; IR: n=2969, 2928, 1687, 1435, 1364 cmÀ1
;
[a]2D0:
À100.38 (c 0.471, CH2Cl2); ESI-MS: m/z=460.4 (M+H+);
HR-MS: m/z=460.35355, D=0.4 ppm, C27H46O3N3.
21: Rf 0.47 (CH2Cl2-MeOH 10%), chromatography
1
CH2Cl2-MeOH 3%, yield: 69%, pale brown oil. H NMR:
d=7.17 (d, J=7 Hz 1H), 6.86 (d, J=7 Hz, 1H), 6.68 (t, J=
7 Hz, 1H), 4.01 (d, J=13 Hz,1H), 3.84 (d, J=13 Hz, 1H),
3.26 (m, 2H), 3.0 (broad s, 1H), 2.3 (br s, 1H) 1.45 (s, 9H),
Preparation of Aldehyde 26
To a solution of 2-(1,1-diethylpropyl)-phenol[9] (5.26 g ,
25.2 mmol) and 2,6-lutidine (2.4 mL, 20.2 mmol) in toluene
(55 mL) was added SnCl4 (1.31 g, 5.03 mmol) and parafor-
maldehyde (3.02 g, 100 mmol formaldehyde) at room tem-
perature. The yellowish suspension was heated to 90–958C
for 6 h. After cooling the mixture was filtered through a pad
of silica gel (6 g) and eluted with ethyl acetate (100 mL).
The filtrate was washed with 0.4N HCl (300 mL) and brine
1.41ACHTUNGTRENNUNG
(s, 9H); 13C NMR: d=157.8, 126.4, 125.9, 125.89, 124.5,
118.3, 77.6, 62.9, 58.5, 51.2, 51.0, 38.9, 35.0, 31.4, 29.9, 28.9,
25.6, 25.0; IR: n=2926, 2855, 1684, 1435, 1364 cmÀ1; [a]D20:
À438 (c 0.209, CH2Cl2); ESI-MS: m/z=460.4 (M+H+); HR-
MS: m/z=460.35333, D=0.1 ppm, C27H46O3N3.
22: Rf 0.52 (CH2Cl2-MeOH 5%), chromatography
1
CH2Cl2-MeOH 2%, yield: 31%, pale brown oil. H NMR:
Adv. Synth. Catal. 2011, 353, 1797 – 1806
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1803

Antoinette Chougnet et al.
FULL PAPERS
(200 mL), dried with Na2SO4 and evaporated. The crude
product was purified by flash chromatography on silica gel
(120 g, hexane/ethyl acetate, 95:5) to obtain aldehyde 26 as
a colourless solid; yield: 2.18 g (9.9 mmol, 39%); mp 35–
deep green solution the aldehyde (0.384 mmol) was added
by syringe and the mixture cooled to 08C. Finally diisopro-
pylethylamine (DIPEA, 6 mL, 0.038 mmol) was added and
the reaction stirred for 24 h at 08C. Work-up was performed
as described above.
1
378C. H NMR: d=11.86 (s, 1H), 9.87 (s, 1H), 7.45 (d, J=
7.7 Hz, 1H), 7.39 (d, J=7.7 Hz, 1H), 6.95 (t, J=7.7 Hz,
1H), 1.87 (q, J=7.4 Hz, 4H), 0.64 (t, J=7.4 Hz, 3H);
13C NMR: d=197.7, 161.6, 137.5, 135.1, 132.3, 120.7, 119.3,
45.0, 26.0, 8.7; HR-MS: m/z=219.13906 [MÀH]À, D=
0.3 ppm, C14H19O2.
Characteristic Data of 5+6
The b-nitro alcohol 5+6 were synthesized using catalyst 1
and purified according to the general procedure for catalytic
reactions, the compound was obtained as a colourless oil;
yield: 83%. HPLC-analysis on a Chiralcel OD-H column re-
vealed syn-5/anti-6=75:25 and 96% ee for both diastereo-
isomers; spectroscopic data are in agreement with literature
values.[2q] 1H NMR: d=7.30–7.18 (m, 5H), 4.62–4.55 (m,
1H), 4.11–4.07 (m, 0.25H), 3.90–3.85 (m, 0.75H), 3.69 (s,
3H), 2.91–2.83 (m, 1H), 2.76–2.70 (m, 1H), 2.50–2.10 (m,
5H), 1.94–1.72 (m, 2H); 13C NMR: d=172.7, 141.0, 129.0,
128.8, 126.7, 91.9, 91.1, 71.7, 71.6, 52.4, 35.6, 35.2, 32.1, 31.9,
30.1, 30.0, 25.9 23.3.
Preparation of Aldehyde 27
4-Bromo-2-(1,1-diethylpropyl)-phenol[9] (4.02 g, 14.4 mmol),
2,6-lutidine (1.3 mL, 11.5 mmol), SnCl4 (0.75 g, 2.9 mmol)
and paraformaldehyde (1.727 g, 57.5 mmol formaldehyde)
were dissolved in toluene (31 mL) and heated at 90–958C
for 6 h. After cooling the mixture was filtered through a pad
of silica gel (6 g) and eluted with ethyl acetate (50 mL). The
filtrate was washed with 0.4N HCl (300 mL) and brine
(100 mL), dried with Na2SO4 and evaporated. The crude
product was purified by flash chromatography on silica gel
(70 g, hexane/ethyl acetate 95:5) to obtain aldehyde 27 as a
colourless solid; yield: 1.80 g (6.0 mmol, 42%); mp 84–868C.
1H NMR: d=11.80 (s, 1H), 9.80 (s, 1H), 7.52 (d, J=2.4 Hz,
1H), 7.50 (d, J=2.4 Hz, 1H), 1.84 (q, J=7.4 Hz, 4H), 0.64
(t, J=7.4 Hz, 3H); 13C NMR: d=196.6, 160.6, 140.2, 138.4,
134.1, 121.7, 111.6, 45.5, 25.9, 8.7; HR-MS: m/z=297.04948
(100), 299.04722 (98) [MÀH]À, D=0.3 ppm, C14H18O2Br.
Preparation of b-Hydroxy Amide syn-ACTHNUTRGNE(NUG 4S,5S)-8
To a solution of b-nitro alcohols 5+6 (140 mg, 0.5 mmol,
syn/anti 75:25; 96% ee, see Table 1 entry 1) in MeOH
(2 mL) a saturated aqueous solution of NH4Cl (2 mL) was
added at 08C, followed by slow addition of Zn powder
(340 mg, 5 mmol).[7] The mixture was stirred at 08C for
30 min and after addition of AcOH (50 mL) stirring was con-
tinued for 2 h at 08C. The reaction was quenched with a sa-
turated aqueous solution of NaHCO3, subsequently Ac2O
(0.2 mL) was added and the mixture stirred at room temper-
ature for 15 h. Then, the reaction mixture was filtered
through celite and the filtrate extracted three times with
EtOAc (10 mL), washed with 10% HCl (10 mL), water
(10 mL). Finally the organic phase was dried over Na2SO4
and evaporated to yield an oily residue that displayed two
spots on TLC (silica gel, CH2Cl2, 10% MeOH) in the ratio
of ca. 75 (Rf =0.43) :25 (Rf =0.37). The mixture was subject-
ed to flash chromatography (silica gel, CH2Cl2, 3% MeOH)
and hydroxyamide syn-(4S,5S)-8, Rf =0.43, was isolated as a
colourless oil; yield: 90 mg (62%). 1H NMR: d=7.30–7.17
(m, 5H), 5.78 (d, J=9.2 Hz, 1H), 3.89–3.86 (m, 1H), 3.67 (s,
3H), 3.60–3.52 (m, 1H) 2.80–2.64 (m, 2H), 2.44–2.32 (m,
2H), 1.99 (s, 3H), 1.90–1.84 (m, 2H), 1.80–1.72 (m, 2H);
13C NMR: d=174.8, 171.4, 142.1, 128.8, 126.4, 72.0, 54.6,
52.2, 35.6, 32.8, 31.3, 24.2, 23.7; MS (ESI): m/z=316 [M+
Na+], calcd. for C16H23NO4 [M]+: 293.16
General Procedure for Catalytic Reactions
Ligand screening (Table 1): The ligand (0.025 mmol,
0.05 equiv.) was dissolved in dry THF (1 mL), CuACTHNUTRGNEUNG(OAc)2
(4,5 mg, 0.025 mmol, 0.05 equiv) was added and the mixture
stirred for 30 min at room temperature before addition of
diisopropylethylamine (DIPEA) (25 mL of a 1M stock solu-
tion in THF, 0.025 mmol). Methyl 4-nitrobutyrate (3)
(185 mL, 220 mg, 1.5 equiv.) was added after 10 min at room
temperature, the mixture was cooled at À128C before addi-
tion of 3-phenylpropionaldehyde (2) (67 mL, 67 mg,
0.5 mmol, 1 equiv.). The mixture was stirred at À128C for
48 h.
Work-up for HPLC analysis: An aliquot (50 mL) of the
mixture was filtered through a small silica gel column (ca.
2 g) in hexane-ethyl acetate 1:1. After evaporation of the
solvents, the residue was re-dissolved in isopropyl alcohol
and subjected to HPLC analysis using a Chiralcel ODH
column 5 mm, 4.6ꢃ250 mm (Daicel Chemical Industries,
Ltd), isocratic, heptane-isopropyl alcohol 93/7, 1 mLminÀ1.
Work-up for determination of yield: The crude product
was purified after evaporation of the solvent (THF) by
column chromatography on silica gel. Elution was per-
formed first by CH2Cl2 (elimination of the residual alde-
hyde) then by using a 10/1 mixture of CH2Cl2 and MeOH).
Preparation of Mosher Ester (S)-4S,5S-11
Hydroxy amide syn-(4S,5S)-8 (14 mg, 0.048 mmol) was dis-
solved in pyridine (220 mL), (R)-(À)-a-methoxy-a-trifluoro-
methylphenylacetyl chloride (156 mg, 0.62 mmol) was added
and the reaction was stirred for 15 h at room temperature.
The reaction was quenched with 10% HCl (1 mL) and ex-
tracted three times with EtOAc (5 mL). The organic phase
was washed with water (5 mL), dried over Na2SO4 and final-
ly evaporated at 20 Torr. The residue was subjected to chro-
matography on preparative TLC plates (silica gel 20ꢃ20 cm,
CH2Cl2 5% MeOH); the ester (S)-4S,5S-11 was eluted from
silica gel with CH2Cl2 10% MeOH; yield: 14 mg
(0.028 mmol, 58%). 1H NMR (600 MHz, CD3CN): d=7.59
Henry Reactions of Various Aldehydes and Nitro
Compounds Catalyzed by Cu(II) complex 1 (Table 2
and 3)
Ligand 4 (8.46 mg, 0.023 mmol) was dissolved in dioxane
(0.4 mL), Cu
ACHTUNGTRENNUNG(OAc)2 (3.47 mg, 0.019 mmol) was added and
the mixture stirred for 30 min at room temperature. To the
1804
asc.wiley-vch.de
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1797 – 1806

Diastereoselective and Highly Enantioselective Henry Reactions using C1-Symmetrical Copper(II) Complexes
(m, 2H, o-HAryl-Mosher), 7.48 (m, 3H, m,p-HAryl-Mosher),
7.27 (m, 2H, m-HAryl), 7.18 (m, 1H, p-HAryl), 7.09 (m, 2H, o-
HAryl), 6.15 (d, J=9.4 Hz, 1H, NH), 5.13 (m, 1H, H5), 4.24
Characteristic Data of 30
According to conditions described in the general procedures
and in the footnote of Table 2, the b-nitro alcohol 30 was
synthesized using catalyst 1. The purified compound was ob-
tained as a colourless oil; yield: 94%. HPLC analysis (Chir-
alcel AD-H column, n-heptane:i-PrOH 95:5, 0.5 mLminÀ1):
antimajor tr =48.8, antiminor tr =59.9, synmajor tr =78.5, synminor
tr =58.5. syn-isomer, revealing syn/anti-30=75/25 and 99%
ee for both diastereoisomers. The syn/anti ratio was con-
firmed by 13C NMR[5,6] displaying resonances of 13C-NO2 at
91.3 ppm (syn) and 90.4 ppm (anti).
4
(m, 1H, H4), 3.61 (s, 3H, COOMe), 3.55 (q, JH,F =0.9 Hz,
3H, OMe-Mosher), 2.49 (m, 2H, H-7a,b), 2.32 (m, 2H, H-
2a,b), 1.87 (m, 1H, H-6a), 1.84 (s, 3H, amide-CH3), 1.83 (m,
1H, H-3a), 1.82 (m, 1H, H-6b), 1.64 (m, 1H, H-3b);
13C NMR (from HSQC, HMBC): d=174.17 (ester-CO),
171.51 (amide-CO), 167.07 (Mosher ester-CO), 142.20 (i-
CAryl), 132.81 (i-CAryl-Mosher), 130.87 (p-CAryl-Mosher),
129.53 (m-CAryl-Mosher), 129.30 (m-CAryl), 129.10 (o-CAryl),
128.30 (o-CAryl-Mosher), 126.87 (p-CAryl), 85.05 (Cq-Mosher),
78.64 (C-5), 56.34 (OMe-Mosher), 52.02 (OMe), 50.59 (C-4),
33.07 (C-6), 31.64 (C-7), 30.82 (C-2), 26.89 (C-3), 22.83
(amide-Me).
syn-isomer: 1H NMR: d=7.15–7.35 (m, 10H), 4.67 (m,
1H), 4.52 (s, 2H), 4.03 (m, 1H), 4.02 (dd, 1H, J=10.8,
8.0 Hz), 3.83 (dd, 1H, J=10.8, 3.6 Hz), 2.65–2.90 (m, 2H),
1.73–1.85 (m, 2H); 13CNMR(125 MHz, CDCl3): d=140.80,
136.97, 128.73, 128.69, 128.56, 128.23, 127.91, 126.39, 91.33,
73.66, 69.29, 68.21, 35.25, 31.50.
Characteristic Data of Mosher Ester (S)-4R,5R-11
anti-isomer: 1H NMR: d=7.14–7.36 (m, 10H), 4.68 (m,
1H), 4.55 (s, 2H), 4.17 (m, 1H), 4.10 (dd, 1H, J=11.2,
8.0 Hz), 3.96 (dd, 1H, J=11.2, 3.6 Hz), 2.64–2.90 (m, 2H),
1.73–1.86 (m, 2H); 13C NMR: d=140.77, 137.02, 128.73,
128.69, 128.56, 128.23, 127.94, 126.39, 90.38, 73.73, 70.62,
67.08, 35.44, 31.81; MS (ESI): m/z=338.1 [M+Na]+; anal.
calcd. for C18H21NO4: C 68.55, H 6.71, N 4.44; found: C
68.68, H 6.80, N 4.46.
The following NMR data are taken from a sample of (S)-
4S,5S-11+(S)-4R,5R-11 prepared from 4S,5S-8+4R,5R-8
(racemic syn-8) as described above. 1H NMR (600 MHz,
CD3CN): d=7.59 (m, 2H, o-HAryl-Mosher), 7.48 (m, 3H,
m,p-HAryl-Mosher), 7.29 (m, 2H, m-HAryl), 7.18 (m, 3H, o,p-
HAryl), 6.05 (d, J=9.4 Hz, 1H, NH), 5.12 (m, 1H, H-5), 4.21
4
(m, 1H, H-4), 3.59 (s, 3H, COOMe), 3.56 (q, JH,F =0.9 Hz,
3H, OMe-Mosher), 2.66 (m, 2H, H-7a,b), 2.22 (m, 2H, H-
2a,b), 1.93 (m, 1H, H-6a), 1.92 (m, 1H, H-6b), 1.82 (s, 3H,
amide-CH3), 1.64 (m, 1H, H-3a), 1.44 (m, 1H, H-3b);
13C NMR (from HSQC): d=130.9 (p-CAryl-Mosher), 129.5
(m-CAryl-Mosher), 129.40 (m-CAryl), 129.28 (o-CAryl), 128.3
(o-CAryl-Mosher), 126.87 (p-CAryl), 78.61 (C-5), 56.34 (OMe-
Mosher), 51.99 (OMe), 50.36 (C-4), 33.29 (C-6), 31.95 (C-7),
30.97 (C-2), 27.00 (C-3), 22.91 (amide-Me).
Characteristic Data of 31
According to the conditions described in the general proce-
dures and in the footnote of Table 2. the b-nitro alcohol 31
was synthesized using catalyst 1. The purified compound
was obtained as a colourless oil; yield: 86%. HPLC analysis
(Chiralcel AD-H column, n-heptane:i-PrOH 97:3,
0.5 mLminÀ1): antimajor tr =22.5, antiminor tr =25.2, synmajor tr =
27.9, synminor tr =26.3, revealing syn/anti-31=77/23 and 99%
and 96% ee for the syn- and the anti-diastereoisomer, re-
spectively. The diastereomeric ratio was confirmed by
1H NMR.
Preparation of cis- and trans-9
Racemic b-hydroxy amides anti-7 (30 mg, 0.1 mmol) were
dissolved in dry toluene (2 mL), p-TsOH (1.7 mg,
0.01 mmol) and 2,2-dimethoxypropane (84 mg, 0.8 mmol)
were added and the mixture was heated at 908C. According
to TLC [silica gel CH2Cl2 5% MeOH, Rf(7)=0.4] the reac-
tion was completed after for 4 h. Subsequently a saturated
aqueous solution of NaHCO3 (10 mL) was added and the
mixture extracted three times with tert-butyl methyl ether
(10 mL). The organic phases were combined, washed with
water (10 mL) dried over Na2SO4 and finally evaporated at
20 Torr to obtain racemic cis-9; yield: 33 mg (0.1 mmol,
syn-isomer, 1H NMR: d=7.18–7.32 (m, 5H), 4.55 (m,
1H), 4.16 (dd, 1H, J=11.2, 7.6 Hz), 4.03 (m, 1H), 4.02 (dd,
1H, J=11.2, 3.6 Hz), 2.71–2.91 (m, 2H), 2.40 (d, 1H, J=
8.0 Hz),1.75–1.85 (m, 2H), 0.85 (s, 9H), 0.04 (s, 3H), 0.03 (s,
3H); 13C NMR: d=140.90, 128.79, 128.63, 126.44, 93.34,
68.95, 62.43, 35.33, 31.64, 25.79, 18.25, À5.48, À5.55.
anti-isomer: 1H NMR: d=7.18–7.32 (m, 5H), 4.53 (m,
1H), 4.24 (dd, 1H, J=11.2, 7.6 Hz), 4.18 (m, 1H), 4.13 (dd,
1H, J=11.2, 3.6 Hz), 2.64–2.95 (m, 2H), 2.63 (d, 1H, J=
5.2 Hz),1.77–1.87 (m, 2H), 0.87 (s, 9H), 0.08 (s, 3H), 0.07 (s,
3H); 13C NMR: d=140.88, 128.79, 128.61, 126.45, 92.05,
70.59, 61.34, 35.62, 31.90, 25.83, 18.27, À5.44, À5.53; MS
(ESI): m/z=362.1 [M+Na]+; anal. calcd. for C17H29NO4Si:
C 60.14, H 8.61, N 4.13; found: C 60.21, H 8.56, N 4.07.
1
quantitative). H NMR (600 MHz, CDCl3): d=7.30 (m, 2H,
m-HAryl), 7.21 (m, 3H, o,p-HAryl), 4.01 (m, 1H, H-5), 3.71
(m, 1H, H-4), 3.67 (s, 3H, COOMe), 2.90 (m, 2H, H-7a),
2.68 (m, 2H, H-7b), 2.39 (m, 2H, H-2a,b), 2.11 (m, 1H, H-
3a), 2.08 (s, 3H, amide-CH3), 1.95 (m, 1H, H-6a), 1.81 (m,
1H, H-6b), 1.80 (m, 1H, H-3b), 1.64 (s, 3H, anti-CMe), 1.56
(s, 3H, syn-CMe); 13C NMR: d=173.34 (ester-CO), 167.64
(amide-CO), 141.24 (i-CAryl), 128.80 (o-CAryl), 128.71 (m-
CAryl), 126.41 (p-CAryl), 94.40 (CMe2), 75.85 (C-5), 59.83 (C-
4), 52.03 (OMe), 32.60 (C-7), 31.02 (C-6), 30.95 (C-2), 26.91
(anti-CMe), 25.96 (C-3), 23.96 (amide-Me), 23.68 (syn-
CMe).
Acknowledgements
We thank Francis Roll, Novartis Pharma, Analytical Sciences
for measuring the high-resolution mass spectra.
Racemic acetals trans-9 were prepared from syn-8 in the
same manner. 2D-NMR spectra revealed that for trans-9 the
NOE between H at C-4 and H at C-5 is 0.7% whereas for
cis-9 the NOE was measured as 6%.
Adv. Synth. Catal. 2011, 353, 1797 – 1806
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1805

Antoinette Chougnet et al.
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