The homo-PADAM protocol: Stereoselective and operationally simple synthesis of α-oxo- or α-hydroxy-γ-acylaminoamides and chromanes

Article abstract of DOI:10.1002/chem.201300023

A straightforward and fully stereoselective synthesis of a new class of peptidomimetics, that is α-oxo-γ-acylaminoamides, was achieved starting from various benzaldehydes by a sequence of 1) an asymmetric organocatalytic Mannich reaction, 2) a Passerini multicomponent reaction, 3) an amine deprotection-acyl migration protocol, and 4) a final oxidation. The whole sequence can be performed without purification of the intermediates and represents the first example of a homo-Passerini-amine deprotection-acyl migration (PADAM) strategy. Highly stereoselective reduction of the α-oxo-γ-acylaminoamides afforded α-hydroxy-γ- acylaminoamides as well. In some cases both diastereomers were obtained by simply changing the reducing agent. Finally, starting from protected salicylaldehyde, the same sequence, followed by a Mitsunobu cyclization, afforded highly substituted chromanes. Copyright

Full text of DOI:10.1002/chem.201300023

FULL PAPER
DOI: 10.1002/chem.201300023
The homo-PADAM Protocol: Stereoselective and Operationally Simple
Synthesis of a-Oxo- or a-Hydroxy-g-acylaminoamides and Chromanes**
Fabio Morana, Andrea Basso, Renata Riva, Valeria Rocca, and Luca Banfi*[a]
Abstract: A straightforward and fully
stereoselective synthesis of a new class
of peptidomimetics, that is a-oxo-g-acy-
laminoamides, was achieved starting
from various benzaldehydes by a se-
quence of 1) an asymmetric organoca-
talytic Mannich reaction, 2) a Passerini
multicomponent reaction, 3) an amine
deprotection–acyl migration protocol,
and 4) a final oxidation. The whole se-
quence can be performed without puri-
fication of the intermediates and repre-
sents the first example of a homo-Pass-
erini–amine deprotection–acyl migra-
tion (PADAM) strategy. Highly stereo-
selective reduction of the a-oxo-g-
acylaminoamides afforded a-hydroxy-
g-acylaminoamides as well. In some
cases both diastereomers were ob-
tained by simply changing the reducing
agent. Finally, starting from protected
salicylaldehyde, the same sequence, fol-
lowed by a Mitsunobu cyclization, af-
forded highly substituted chromanes.
Keywords: asymmetric synthesis ·
ketones
· multicomponent reac-
tions · organocatalysis · peptidomi-
metics
Introduction
In 2000, inspired by the work on the Ugi reaction of a-
amino aldehydes carried out by Hulme and co-workers,[1] we
introduced the PADAM protocol (Passerini–amine depro-
tection–acyl migration)[2] as a step- and atom-economical ap-
proach to the synthesis of a-hydroxy- or a-oxo-b-acylami-
noamides. The PADAM procedure starts from protected
enantiomerically pure a-amino aldehydes and represents the
most efficient access to these peptidomimetics, which are
very important protease inhibitors.[3] An attractive extension
of this methodology would be the “homo-PADAM” proto-
col, involving instead the use of b-aminoaldehydes, and
leading to a different, poorly explored,[4] class of peptidomi-
metics, represented by a-hydroxy- or a-oxo-g-acylaminoa-
mides of the general formula 1 and 2 (see Scheme 1). How-
ever, although a-aminoaldehydes can be easily prepared
from a huge variety of commercially available enantiomeri-
cally pure a-amino acids, b-amino acids are less accessible
and their conversion into aldehydes 3 could be troublesome,
especially when an a stereogenic center is present.[5]
Scheme 1. Retrosynthetic approach.
plied[7] but, to our knowledge, the aldehyde functional group
of the Mannich adducts has never been directly exploited in
À
C C bond formation reactions. In all cases this group was
either reduced to a primary alcohol[7a,b] or oxidized to a car-
boxylic acid[6a,7a–d] or to a ketone[7g] in the early steps of the
synthesis, probably because of the stereochemical instability
of adducts 3.[5] Despite this instability, we reasoned that the
mild, neutral conditions of the Passerini reaction would be
ideal for an epimerization-free addition to these aldehydes.
The combination of an organocatalytic asymmetric process
with an ensuing multicomponent reaction has been seldom
exploited so far[8] but we anticipate a great utility in it. Our
retrosynthetic approach is depicted in Scheme 1 and entails
the sequence of an asymmetric Mannich reaction followed
by the homo-PADAM protocol and by a final oxidation.
In 2007, List and co-workers reported that proline is able
to efficiently catalyze the asymmetric Mannich reaction of
N-Boc imines (Boc=tert-butyloxycarbonyl) to afford alde-
hydes 3.[6] Since then this methodology has been widely ap-
[a] Dr. F. Morana, Dr. A. Basso, Prof. Dr. R. Riva, V. Rocca,
Prof. L. Banfi
Department of Chemistry and Industrial Chemistry
University of Genova
via Dodecaneso, 31, 16146 Genova (Italy)
Fax : (+39)010-3536118
Results and Discussion
E-mail: banfi@chimica.unige.it
In an exploratory study, ureidosulfone 5a (R1 =Ph) was con-
verted by using cesium carbonate,[9] into Boc-imine 4a,
which was reacted, under the conditions of List et al.,[6b]
[**] PADAM=Passerini–amine deprotection–acyl migration.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300023.
Chem. Eur. J. 2013, 19, 4563 – 4569
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4563

purified 8a had an enantiomeric excess (ee) of 99%. It is
worth noting that the whole sequence from 5a to 8a re-
quired minimal operations: 1) filtration and evaporation of
the filtrate after generation of the Boc-imine,[13] 2) an aque-
ous washing after the Mannich reaction, 3) a series of three
evaporations during the one-pot sequence from 3a to 8a.
Only a single chromatography was needed at the end of the
sequence. The reaction conditions are simple (0–508C), do
not require strict exclusion of moisture or oxygen, and do
not use any metal. The overall protocol generates four new
bonds, allows the introduction of four diversity points, and is
fully stereoselective.
The scope of the methodology is displayed in Table 1. All
four diversity points were varied. When protected amino
acids were employed, extended peptidomimetics were ob-
tained. Analogous results were achieved when a-isocyano
esters were used as the isonitrile moiety. The enantioselec-
tivity and the diastereoselectivity are excellent in all studied
cases and both enantiomers can be accessed by using l- or
d-proline. The overall yields were good to excellent, with
few exceptions; the most critical step appears to be the
Mannich reaction, which was slightly less efficient for the N-
Boc imine of 3-bromobenzaldehyde.
Obviously, the sequence can be terminated at the level
the of a-hydroxy-g-acylamino amides 6 and 7 as well. How-
ever, due to the typical poor diastereoselectivity of the Pass-
erini reaction,[14] an approximately 1:1 mixture of the epi-
mers 6 and 7 was obtained. Even if the epimers can be sepa-
rated in all cases by chromatography, the use of a stereose-
lective protocol in the synthesis of these peptidomimetics
would be more elegant. For this reason we submitted the ke-
tones 8a 8b, 8j, and 8m to reduction with various borohy-
drides. The most selective one turned out to be l-selectride
Scheme 2. Synthesis of peptidomimetics 6–8. pTol =para-methylphenyl.
with propanal to afford (S,S)-3a, with high diastereo- and
enantioselectivity (Scheme 2). The crude aldehyde 3a was
directly subjected to a one-pot sequence involving: 1) the
Passerini reaction[10] with cyclohexyl isocyanide and me-
thoxyacetic acid, 2) treatment with trifluoroacetic acid
(TFA) to remove the tert-butyl urethane, 3) treatment with
Et3N to promote N,O acyl migration[11] affording a diaster-
eomeric mixture of alcohols 6 and 7, and d) a Dess–Martin
oxidation. The diastereomerically pure ketone (S,S)-8a was
obtained in an excellent overall yield of 68% from ureido-
sulfone 5a (six steps).
1H NMR analysis of crude 8a before chromatography
showed a syn/anti ratio of 96:4, corresponding to the ratio
determined at the level of aldehyde 3a. The minor anti
isomer was completely removed by chromatography.[12] The
(lithium tri-sec-butylACTHNUTRGNE(NUG hydrido)borate) (Table 2, entries 1–4).
Surprisingly, the prevailing isomer depended on the nature
of the R2 group. With R2 =Me (Table 2, entries 1 and 4), 6
Table 1. Scope of the Mannich–homo-PADAM–oxidation to give a-oxo-g-acylaminoamides.[a]
Entry
Final
product
R1
R2
R3
R4
Proline
used[b]
Yield
[%][c]
syn/anti[d]
ee [%][e]
1
2
8a
8b
8c
8d
8e
8 f
8g
8h
8i
Ph
Ph
Ph
Ph
Me
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
Me
MeOCH2
MeOCH2
Ph
ZNHCH2
l-ZNHCH
cyHex[f]
cyHex
l, d
l, d
l
l
l, d
l
l, d
l
l
l, d
l
l, d
l, d
68
64
59
66
58
46
15
38
18
57
35
58
35
96:4
98:2
96:4
98:2
98:2
96:4
99:1
86:14
88:12
99:1
99:1
89:11
93:7
>99
96
96
3[g]
4
cyHex
[h]
Bn[i]
96
5[g]
6[g]
7
4-MeOC6H4
4-MeOC6H4
3-BrC6H4
3-BrC6H4
3-BrC6H4
4-MeC6H4
4-MeC6H4
2-BnOC6H4
2-BnOC6H4
(iPr)
Me
96[j]
96
Et
4-BnOC6H4CH2CH2
iPr
2,6-Me2C6H4
4-(BnO2C)C6H4
nBu
5-Cl-2-thienyl
l-ZNHCH(Bn)
99
8
9
99[j]
99
ꢀ
nPr-C C
Et
10[g]
11[g]
12
13
8j
8k
8l
92
92
À
Ph
PhCH2
MeOCH2
EtO2C CH2
nPent
96
8m
cyHex
99[k]
[a] For the reaction conditions, see the typical procedure given in the Experimental Section. [b] With l-proline, (S,S)-8 was obtained; with d-proline,
(R,R)-8 was obtained. [c] Yield of pure syn-8 after chromatography (calculated from the starting ureidosulfone 5). The yields obtained from l- or d-pro-
line were quite similar. Only the best one is reported. [d] Determined by 1H NMR spectroscopic analysis of crude 8 before chromatography [e] Deter-
mined by HPLC on a chiral stationary phase. The ee obtained from l- or d-proline were identical or very close. Only the best one is reported.
[f] cyHex=cyclo-hexyl. [g] In this case the reaction time for the N,O-acyl migration step was 14 h. [h] Z=benzyloxycarbonyl. [i] Bn=benzyl. [j] In this
case it is actually a diastereomeric excess (de). [k] Determined through the method using the Mosherꢁs ester, after reduction to 6m.
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Chem. Eur. J. 2013, 19, 4563 – 4569

Stereoselective Synthesis of Acylaminoamides and Chromanes
FULL PAPER
lation-controlled reaction.[16,17] In our case, if chelation con-
trol occurred, product 7, not 6 should be obtained. So the
explanation for this puzzling reversed stereoselectivity must
be different. The observation of an intense gas evolution
after addition of DIBALH and the fact that more than
three equivalents of DIBALH are needed in order to ach-
ieve full conversion, suggest that DIBALH, in the presence
of MgBr2, gives an acid–base reaction with the two secon-
dary amides. Interestingly, when using DIBALH alone, that
is, without MgBr2, no gas evolution is observed, and 1.5
equivalents of the reagent are enough to give full conversion
even at À788C, although with poor stereoselection (6j/7j=
60:40). Therefore, MgBr2 is essential in order to promote
the acid–base reaction of DIBALH with the two amides to
give a covalent adduct that renders the main chain more en-
cumbered than the isopropyl group (Scheme 3, bottom).
Thanks to this stereodivergent reduction, four of the eight
possible stereoisomers of the alcohols 6b and 6j as well as
7b and 7j can be obtained with high stereochemical control.
A full exploration of the stereochemical diversity, obtaining
all eight possible stereoisomers, seems feasible, by imple-
menting anti-selective Mannich reactions.[7b,c,e,f] Studies to-
wards this goal are in progress.
Table 2. Stereoselective reduction of ketones 8.
Entry
Ketone
R2
Reducing agent[a]
Yield [%][b]
6/7[c]
1
2
3
4
5
6
7
8
8a
8b
8j
8m
8a
ent-8b
8j
8m
Me
iPr
iPr
Me
Me
iPr
iPr
Me
l-selectride
l-selectride
l-selectride
l-selectride
MgBr2–DIBALH
MgBr2–DIBALH
MgBr2–DIBALH
MgBr2–DIBALH
88
86
90
77
94
98
99
90
89:11
6:94
<1:99
96:4
93:7
95:5
93:7
83:17
[a] Reductions with L-selectride were carried out in THF at À788C; re-
ductions with MgBr2–diisobuylaluminium hydride (DIBALH) were car-
ried out in CH2Cl2/Et2O (1:2) at À458C. [b] Overall yield of both isolated
diastereomers after chromatography. [c] Determined by 1H NMR spec-
troscopic analysis of crude 6 and 7 before chromatography.
was obtained,[4b] whereas the other epimer 7 was the major
one when R2 =iPr (Table 2, entries 2 and 3). In all cases the
diastereoselectivity was excellent. The absolute configura-
tion of the newly formed stereogenic center, and hence the
relative configurations of 6 and 7 was determined by the
Mosherꢁs method[15] as detailed in the Supporting Informa-
tion.
Both results can be explained by alternative Felkin–Anh
On the other hand, when R2 =Me the MgBr2–DIBALH
models where either the ArCH
N
system again affords alcohol 6 as the major product
the iPr groups play the role of the “large” group
(Scheme 3).
(Table 2, entries 5 and 8), and thus, in this case the method-
ology is not complementary to l-selectride. This outcome
confirms the model proposed in Scheme 3.
When an additional functional group is placed into one of
the diversity points, the alcoholic moiety in 6 and 7 can be
exploited for a further cyclization step,[18] opening the way
to various drug-like heterocyclic structures. As a first exam-
ple, we report here the synthesis of dihydrobenzopyrans
(chromans). These are “privileged structures”, quite often
employed in medicinal chemistry.[19,20]
The two epimeric alcohols 6m and 7m were obtained in
45% overall yield as a nearly 1:1 mixture from ureidosul-
fone 5e. In this case, the Mannich–homo-PADAM sequence
was stopped before the final oxidation, and the epimers
were separated by chromatography (Scheme 4). Alcohol 6m
could also be obtained stereoselectively by reduction with l-
selectride of ketone (S,S)-8m. These alcohols were inde-
pendently hydrogenolized and then cyclized under Mitsuno-
bu conditions to the chromanes 9 and 10. Their relative con-
1
figuration was established by H NMR spectroscopy, on the
basis of the vicinal coupling constants (see the Supporting
Information for details). The cyclization was therefore dem-
onstrated to be completely stereospecific (proceeding with
inversion of the configuration).
Scheme 3. Models for the rationalization of the diastereoselective reduc-
tion of 8.
In an attempt to find a stereoselective access to the minor
products of the reduction with l-selectride, we screened a
series of alternative reducing reagents. We were pleased to
find that, when R2 =iPr (Table 2, entries 5 and 6), the
MgBr2–DIBALH system,[16] leads to alcohol 6 with excellent
stereoselection, making this method fully complementary
with the reduction by l-selectride. Usually, the combination
of DIBALH with Lewis acids is expected to promote a che-
The enantiomers of 9 and 10 have also been prepared by
simply using d-proline instead of l-proline as a catalyst in
the Mannich reaction. Thus, four of the eight possible ster-
eoisomers of these chromanes have been synthesized.
Chem. Eur. J. 2013, 19, 4563 – 4569
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4565

L. Banfi et al.
CeACHTUNRGTEN(UNG SO4)2·4H2O (1 g) in H2SO4 (31 mL) and H2O (469 mL) and warming)
or, only to detect free amines after Boc deprotection, with ninhydrin
(ninhydrin (900 mg) in nBuOH (300 mL) and AcOH (9 mL, Ac=acyl),
followed by warming). Rf values were measured after an elution of 7–
9 cm. In [a]D the units are: 8cm3 gÀ1dmÀ1 for [a] and 100 gcmÀ3 for c.
HPLC analyses were performed (unless otherwise stated) on a Daicel
Chiral Pak AD 250ꢂ4.6 mm column, at 25–288C with
a flow of
1 mLminÀ1 (UV detection at l=220 nm). Column chromatography was
done with the “flash” methodology by using 220–400 mesh silica. Petrole-
um ether (40–608C) is abbreviated as PE. In an extractive workup, aque-
ous solutions were always re-extracted three times with the appropriate
organic solvent. Organic extracts were always dried over Na2SO4 and fil-
tered, before evaporation of the solvent under reduced pressure. All re-
actions employing dry solvents were carried out under a nitrogen atmos-
phere.
Ureidosulfones 5a (R1 =Ph),[6b,21] 5b (R1 =p-MeOC6H4),[22] and 5d (R1 =
p-tolyl)[22a] were already previously reported. The preparation and char-
acterization of 5c and 5e is reported in the Supporting Information.
Typical procedure for the synthesis of ketones 8
AHCTUNGTERG(NNUN 3S,4S)-N-Cyclohexyl-4-(2-methoxyacetamido)-3-methyl-2-oxo-4-phenyl-
butanamide (8a): Ureidosulfone 5a (R1 =Ph) (300 mg, 0.83 mmol) was
dissolved in dry THF (9 mL), treated with Cs2CO3 (540 mg, 1.66 mmol),
and heated at 508C for 3 h. After cooling, the white suspension was fil-
tered through a celite cake and the residue was washed with THF. The
filtrate was evaporated, dissolved in dry CH3CN (7.5 mL), cooled to 08C,
and treated with l-proline (19 mg, 0.166 mmol) and with freshly distilled
propanal (120 mL, 1.67 mmol). The mixture was stirred at 08C for 18 H;
and then quenched with water (5 mL). The mixture was extracted with
CH2Cl2 (3ꢂ10 mL) and the organic extract was dried (Na2SO4), evaporat-
ed to dryness, and dissolved in CH2Cl2 (3.5 mL). Methoxyacetic acid
(83 mL, 1.08 mmol) and cyclohexyl isocyanide (135 mL, 1.08 mmol) were
added and the solution was stirred for 20 h at room temperature. Tri-
fluoroacetic acid (0.85 mL) was added and the solution was stirred for
3 h at room temperature and then evaporated to dryness (with the aid of
n-heptane for azeotropical removal of all TFA). The residue was dis-
solved in CH2Cl2 (3.5 mL) and treated with Et3N (480 mL). After 3 h the
solution was evaporated to dryness, the residue was dissolved in dry
CH2Cl2 (9 mL) and treated with Dess–Martin periodinane (1,1,1-triace-
toxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one) (385 mg, 0.91 mmol). The
reaction mixture was stirred overnight at room temperature, and then the
reaction was quenched with solid Na2S2O3 (288 mg, 1.82 mmol) and satu-
rated aqueous NaHCO3 (5 mL). After stirring for 10 min, the mixture
was extracted with AcOEt (3ꢂ15 mL), dried (Na2SO4), evaporated, and
purified by chromatography through 220–400 mesh silica gel (PE/AcOEt
50:50) to afford pure 8a as a foamy white solid (202 mg, 68%). Rf =0.45
(PE/AcOEt 1:1); [a]D = +19.8 (c=2, CHCl3); HPLC: hexane/iPrOH
Scheme 4. Cyclization of 6m and 7m to chromanes 9 and 10. DEAD=di-
ethyl azodicarboxylate. TBAD=di-tert-butyl azodicarboxylate.
Conclusion
In conclusion, we have developed a straightforward and effi-
cient entry to a-hydroxy-g-acylaminoamides, a-oxo-g-acyla-
minoamides, and dihydrobenzopyrans (chromanes) by cou-
pling an asymmetric organocatalytic Mannich reaction with
a Passerini multicomponent reaction (MCR) and a series of
post-MCR transformations. Although these complex se-
quences involve six to seven steps, most of them may be car-
ried out in a one-pot manner and the final products are ob-
tained in pure form performing just one or two chromato-
graphic purifications. This is, to our knowledge, the first ap-
plication of a homo-PADAM protocol. Four diversity inputs
may be varied at will, four to five new bonds are formed, up
to three stereogenic centers are fully controlled, and four
different stereoisomers may be independently obtained.
Therefore, we think that this methodology can find wide ap-
plication in diversity-oriented synthesis and in medicinal
chemistry.
90:10. Rt =15.38 min. (Rt of ent-8a: 14.03); ee> 99%; 1H NMR
3
(300 MHz, CDCl3, 258C, TMS): d=7.35–7.22 (m, 5H), 7.17 (d, J
N
9.3 Hz, 1H; H2C
5.61 (dd, 3J(H,H)=9.3, 5.7 Hz, 1H; H-4), 4.13 (dq, 3J
5.7 Hz (d), 1H; H-3), 3.92, 3.87 (AB syst., 2J
(H,H)=15.1 Hz, 2H;
CH2OMe), 3.79–3.65 (m, 1H; CHNH cyHex), 3.44 (s, 3H; OCH3), 1.95–
1.85 (m, 2H), 1.77–1.50 (m, 2H), 1.45–1.08 (m, 5H), 1.12 (d, 3J
(H,H)=
(C=O)-NH), 6.72 (d, 3J
ACHUTGTNRENNUG CAHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
6.9 Hz, 3H; CH3), 0.95–0.82 ppm (m, 1H); 13C NMR (75 MHz, CDCl3,
258C, TMS): d=200.1, 169.6, 159.5 (C=O), 139.8 (quat.), 129.0 (2ꢂ),
128.0, 126.9 (aromatic CH), 71.8 (CH2OMe), 59.2 (OCH3), 52.8 (C-4),
48.4 (CHNH cyHex), 44.5 (C-3), 32.3, 32.2, 25.0, 24.4, 24.3 (CH2 cyHex),
10.7 ppm (CH3CH); IR (ATR): n˜ =3326, 3287, 2991, 2928, 2854, 1673,
1651, 1526, 1449, 1296, 1193, 1113, 1024, 762, 695 cmÀ1; HRMS (ESI+):
m/z calcd for C20H29N2O4: 361.2127 [M+H]+; found: 361.2127.
Experimental Section
General conditions: NMR spectra were taken at room temperature in
CDCl3 at 300 MHz (1H) and 75 MHz (13C) by using as internal standards:
trimethylsilane (TMS) for 1H NMR spectroscopy and the central peak of
CDCl3 (at d=77.02 ppm) for 13C NMR spectroscopy. Chemical shifts are
reported in ppm (d scale), coupling constants are reported in Hertz. Peak
assignments were also made with the aid of gCOSY gHSQC, and
gHMBC experiments. In an ABX system, the proton A is considered up-
field and the B proton is considered downfield. HRMS was performed by
employing an ESI+ ionization method. IR spectra were recorded as
CHCl3 solutions or directly on solid, oil, or foamy samples, with the ATR
(attenuated total reflectance) technique. TLC analyses were carried out
on silica gel plates and viewed at UV (l=254 nm) and developed with
Hanessian stain (dipping into a solution of (NH4)4MoO4·4H2O (21 g) and
Typical procedure for the reduction of ketones 8 to alcohols 6 or 7 with
l-selectride
AHCTUNGTERG(NNUN 2R,3S,4S)-N-Cyclohexyl-3-isopropyl-2-hydroxy-4-(2-methoxyacetamido)-
4-phenylbutanamide 7b: A solution of ketone 8b (124 mg, 0.319 mmol)
in dry THF (1 mL) was cooled to À788C and treated with a solution of
l-selectride (lithium tri(sec-butoxy)borohydride) (1.0m, 960 mL,
0.960 mmol). After 3 h, the reaction was quenched with a saturated aque-
ous solution of NH4Cl (5 mL) and extracted with AcOEt. Evaporation
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Stereoselective Synthesis of Acylaminoamides and Chromanes
FULL PAPER
gave a pure solid, corresponding to a 94:6 mixture of 7b and 6b. Chro-
matographic purification gave the pure diastereomer 7b as a white solid
(101 mg, 83%). Overall yield: 88%. M.p. 238.6–240.08C; Rf =0.50 (PE/
Analytical data for 6m: White foam; Rf =0.39 (PE/AcOEt 10:90); [a]D =
À53.5 (c=1, CHCl3); ee=99%, determined by transformation into
Mosherꢁs ester by using either the (R)- or (S)-acyl chloride. Reverse-
phase HPLC analysis (column: Synergi Hydro RP 150ꢂ3 mm 4 mm; iso-
cratic elution with H2O/CH3CN 35:65; flow: 0.5 mLminÀ1; detection: l=
220 nm) showed a diastereomeric ratio of 99.3:0.7 ((S) Mosher ester:
Rt =20.94; (R) Mosher ester: Rt =22.43 min); 1H NMR (300 MHz,
AcOEt 4:7 +0.5% MeOH); [a]D =À10.8 (c=2, CHCl3); 1H NMR
3
(300 MHz, CDCl3, 258C, TMS): d=7.40–7.22 (m, 5H), 7.13 (d, J
N
9.1 Hz, 1H; H2C
5.36 (dd, 3J(H,H)=7.3, 9.1 Hz, 1H; H-4), 3.95 (dd, 3J
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG ACHTUNGTRENNUNG
(C=O)-NH), 6.99 (d, 3J
G
CDCl3,
MeOCH2CONH), 7.55–7.35 (m, 5H), 7.30–7.19 (m, 2H), 7.04–6.95 (m,
2H), 6.61 (d, 3J(H,H)=8.1 Hz, 1H; NH cyHex), 5.53 (dd, 3J
(H,H)=3.6,
9.3 Hz, 1H; H-4), 5.29 (d, 3J
(H,H)=5.4 Hz, 1H; OH), 5.13 (s, 2H;
CH2Ph), 3.85 (s, 2H; CH2OMe), 3.70 (dd, 3J
(H,H)=5.4, 7.6 Hz., 1H; H-
2), 3.78–3.60 (m, 1H; HNCH cyHex), 3.18 (s, 3H; OCH3), 2.25 (dquint,
3J
(H,H)=7.2 (q), 3.6 Hz (d), 1H; H-3), 1.96–1.75 (m, 2H), 1.75–1.53 (m,
3H), 1.42–1.00 (m, 5H), 1.02 ppm (d, 3J
(H,H)=7.2 Hz, 3H; CH3);
258C,
TMS):
d=8.19
(d,
3J
G
1H;
1H; H-2), 3.92, 3.87 (AB syst., 2J
ACTHNUTRGNE(UNG H,H)=15.3 Hz, 2H; CH2OMe), 3.82–
3.66 (m, 1H; CHNH cyHex), 3.44 (s, 3H; OCH3), 3.07 (d, 3J
(H,H)=
3
A
ACHTUNGTRENNUNG
5.7 Hz, 1H; OH), 2.51 (dt, J
A
of heptuplet, 3J
(m, 2H), 1.75–1.52 (m, 2H), 1.43–1.00 (m, 6H), 1.07 (d, J
3H; CH3), 1.06 ppm (d, 3J(H,H)=6.9 Hz, 3H; CH3); 13C NMR (75 MHz,
ACHTUNGTRENNUNG(H,H)=5.1 (d), 6.9 Hz (hept), 1H; CHACHTUNGTRENNUNG
AHCTUNGTRENNUNG
3
AHCTUNGTRENNUNG
AHCTUNGTREGUN(NN H,H)=6.9 Hz,
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
CDCl3, 258C, TMS): d=172.8, 169.7 (C=O), 141.5 (quat.), 129.2 (2ꢂ),
127.8, 127.2 (2ꢂ) (aromatic CH), 73.0 (C-2), 71.8 (CH2OMe), 59.2
(OCH3), 53.1 (C-4), 50.4 (C-3), 47.8 (CHNH cyHex), 32.6, 32.5, 25.2,
AHCTUNGTRENNUNG
13C NMR (75 MHz, CDCl3, 258C, TMS): d=171.7, 170.7 (C=O), 156.2
(C-OBn), 136.2, 127.66 (quat.), 129.5, 128.70, 128.68 (2ꢂ), 128.2, 127.69
(2ꢂ), 121.4, 112.4 (aromatic CH), 74.3 (CHOH), 71.5 (CH2O), 70.5
(CH2Ph), 59.0 (OCH3), 51.9 (C-4), 47.6 (cyHex CHNH), 44.6 (C-3), 33.1,
32.8, 25.5, 24.8 (2ꢂ) (cyHex CH), 11.5 ppm (CH3); IR (CHCl3): n˜ =3677,
3613, 3408, 3008, 2971, 2931, 2853, 1655, 1519, 1476, 1421, 1382, 1332,
1198, 1114, 1042, 926 cmÀ1; HRMS (ESI+): m/z calcd for C27H37N2O5
[M+H]+: 469.2702; found: 469.2695.
24.5, 24.4 (CH2 cyHex), 26.7 (CHACHTNUGRTNEUNG(CH3)2), 21.6, 21.2 ppm (CH3CH); IR
(ATR): n˜ =3390, 3216, 3060, 2930, 2856, 1666, 1647, 1520, 1451, 1259,
1245, 1196, 1118, 1011, 765, 702, 631, 557 cmÀ1; HRMS (ESI+): m/z calcd
for C22H35N2O4 [M+H]+: 391.2597; found: 391.2594.
Typical procedure for the reduction of ketones 8 to alcohols 6 by using
MgBr2–DIBALH
ACHTUNGTRENNUNG(2S,3S,4S)-N-Butyl-2-hydroxy-3-isopropyl-4-(4-methylphenyl)-4-(propana-
Analytical data for 7m: White foam; Rf =0.56 (PE/AcOEt 10:90); [a]D =
1
mido)butanamide 6j: Ketone 8j (72 mg, 0.2 mmol) was dissolved in dry
CH2Cl2 (4 mL) and diluted with dry diethyl ether (8 mL). MgBr2·Et2O
(310 mg, 1.2 mmol) was added and the resulting suspension was stirred at
room temperature for 30 min. Complete dissolution was observed. The
temperature was lowered to À458C and diisobutylaluminum hydride
(DIBALH) (1.0m in toluene, 1.2 mL, 1.2 mmol) was added. Intense gas
evolution was observed. After stirring for 2 h, the reaction was quenched
by adding a saturated aqueous solution of NaHCO3 (10 mL) and a 20%
solution of sodium potassium tartrate (10 mL). Extraction with AcOEt
and evaporation of the solvent afforded the crude 93:7 mixture of alco-
hols 6j and 7j as a solid, which was rather pure as confirmed by
À14.8 (c=0.6, CHCl3); H NMR (300 MHz, CDCl3, 258C, TMS): d=7.65
(d, 3J
ACHTNUTRGNEUNG(H,H)=9.6 Hz., 1H; MeOCH2CONH), 7.55–7.32 (m, 5H), 7.28–
7.19 (m, 2H), 7.02–6.90 (m, 2H), 6.81 (d, 3J
NH), 5.26 (t, 3J
(H,H)=9.1 Hz, 1H; H-4), 5.16 (s, 2H; CH2Ph), 3.87, 3.84
(AB syst., 2J(H,H)=15.2 Hz, 2H; CH2OMe), 3.83 (dd, 3J
(H,H)=3.0,
4.8 Hz., 1H; H-2), 3.78–3.67 (m, 1H; HNCH cyHex), 3.63 (brs, 1H;
OH), 3.28 (s, 3H; OCH3), 2.62 (ddq, 3J
(H,H)=6.9 (q), 3.0, 9.0 Hz (d),
1H; H-3), 1.96–1.75 (m, 2H), 1.75–1.53 (m, 3H), 1.42–1.00 (m, 5H),
0.89 ppm (d, 3J(H,H)=6.9 Hz, 3H; CH3). 13C NMR (75 MHz, CDCl3,
ACHTUNGERTN(NUNG H,H)=8.7 Hz, 1H; cyHex
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
258C, TMS): d=171.5, 169.5 (C=O), 156.0 (C-OBn), 136.2, 127.3 (quat.),
129.0, 128.9, 128.8 (2ꢂ), 128.3, 127.8 (2ꢂ), 121.7, 113.0 (aromatic CH),
73.0 (CHOH), 71.8 (CH2O), 71.0 (CH2Ph), 59.1 (OCH3), 52.8 (C-4), 47.7
(cyHex CHNH), 41.8 (C-3), 33.1, 32.9, 25.5, 24.8 (2ꢂ) (cyHex CH),
9.6 ppm (CH3); IR (CHCl3): n˜ =3668, 3602, 3401, 3034, 2984, 2931, 2852,
1H NMR spectroscopy. Chromatography (PE/AcOEt 30:70
+ 0.5%
MeOH) afforded the pure major diastereomer 6j (66 mg, 92%) as a
white solid. Overall yield: 99%. M.p.: 241.1–242.78C; Rf =0.45 (PE/
AcOEt 37 + 0.5% MeOH); [a]D =À72.4 (c=0.25, CHCl3); 1H NMR
1649, 1601, 1508, 1450, 1374, 1350, 1313, 1287, 1247, 1111, 1009, 918 cmÀ1
;
HRMS (ESI+): m/z calcd for C27H37N2O5 [M+H]+: 469.2702; found:
(300 MHz, CDCl3, 258C, TMS): d=7.22, 7.13 (AB syst., 3J
ACHTUNGTRENNUNG
8.0 Hz, 4H), 6.80 (t, 3J
8.7 Hz, 1H; NHCH), 5.00 (dd, 3J
3J
(H,H)=2.2, 9.0 Hz, 1H; H-2), 4.16 (d, J
(dq, J
(H,H)=7.0 (q), 2J
(H,H)=2.2, 4.2, 7.8 Hz, 1H; H-3), 2.31 (s, 3H; ArCH3), 2.30 (q, 3J-
(H,H)=7.5 Hz, 2H; CH2CO), 1.92 (octuplet, 3J
(H,H)=6.9, 1H; CH-
(CH3)2), 1.48–1.25 (m, 2H), 1.40–1.24 (m, 2H), 1.19 (t, 3J
(H,H)=7.6 Hz,
2H; CH3CH2CO), 1.06 (d, 3J(H,H)=6.9 Hz, 3H; CH3), 1.00 (d, 3J-
ACHTUNGTRENNUNG ACHTUNGTRENNUNG
(H,H)=8.6 Hz, 1H; H2CNH), 6.10 (d, 3J
469.2704.
AHCTUNGTERG(NNUN 2R,3S,4S)-N-Cyclohexyl-4-(2-methoxyacetamido)-3-methylchroman-2-
AHCTUNGTRENNUNG
3
carboxamide (9): A solution of alcohol 6m (185 mg, 0.395 mmol) in 96%
EtOH (7 mL) was treated with 10% Pd/C (30 mg) and hydrogenated at
room temperature under the slight overpressure of an inflated balloon.
After stirring for 18 h, the suspension was filtered and evaporated. The
crude product was purified by chromatography (PE/AcOEt 2:8 + 0.5%
MeOH) to give analytically pure (2S,3S,4S)-N-cyclohexyl-2-hydroxy-4-(2-
hydroxyphenyl)-4-(2-methoxyacetamido)-3-methylbutanamide (11m) as
a white foam (106 mg, 70%). Rf =0.48 (PE/AcOEt 10:90); [a]D =À32.1
(c=1.3, CHCl3); 1H NMR (300 MHz, CDCl3, 258C, TMS): d=8.78 (s,
A
ACHTUNGERTN(NUNG H,H)=9.0 Hz, 1H; OH), 3.21
ACHTUNGTRENNUNG(H,H)=14.0 Hz (d), 1H; NHCHH), 3.04 (dq, J-
3
2
3
N
A
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG CAHTUTGNERN(NUGN H,H)=7.2 Hz, CH3CH2CH2);
(H,H)=6.6 Hz, 3H; CH3), 0.89 ppm (t, 3J
13C NMR (75 MHz, CDCl3, 258C, TMS): d=175.0, 174.6 (C=O), 138.9,
1H; phenolic OH), 7.56 (d, 3J
7.16–7.08 (m, 2H), 6.92–6.83 (m, 2H), 6.82 (d, 3J
cyHex NH), 5.23 (dd, 3J(H,H)=6.0, 8.6 Hz, 1H; H-4), 4.53 (d, 3J
7.0 Hz, 1H; OH), 3.96, 3.86 (AB syst., 2J
(H,H)=15.3 Hz., 2H;
CH2OMe), 3.88 (dd, 3J
(H,H)=4.2, 7.0 Hz., 1H; CHOH), 3.81–3.68 (m,
1H; HNCH cyHex), 3.42 (s, 3H; OCH3), 2.50 (ddq, 3J
(H,H)=7.2 (q),
6.0, 4.2 Hz (d), 1H; H-3), 1.98–1.84 (m, 2H), 1.79–1.55 (m, 3H), 1.42–
1.11 (m, 5H), 1.07 ppm (d, 3J(H,H)=7.2 Hz, 3H; CH3); 13C NMR
ACHTUNGTRENNUNG
137.6 (quat.), 129.8, 127.0 (aromatic CH), 72.5 (C-2), 51.9, 51.0 (C-3, C-
4), 38.8 (CH2NH), 31.2 (CH2CH2NH), 29.6 (CH2CO), 26.3 (CHACTHNUTRGNEUNG(CH3)2),
22.9, 20.7, 19.9, 19.7, 13.4, 9.4 ppm (CH3); IR (ATR): n˜ =3292, 2959,
2874, 1642, 1533, 1465, 1371, 1261, 1238, 1214, 1096, 1070, 862, 837, 816,
755, 696 cmÀ1 HRMS (ESI+): m/z calcd for C21H35N2O3 [M+H]+:
;
363.2648; found: 363.2650.
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG(2S,3S,4S)- and (2R,3S,4S)-4-(2-Benzyloxyphenyl)-N-cyclohexyl-2-hy-
AHCTUNGTRENNUNG
droxy-4-(2-methoxyacetamido)-3-methylbutanamide (6m) and (7m):
Compound 6m could be obtained stereoselectively by reduction of 8m
with l-selectride (see the typical procedure described above for 8b).
However, because the reduction with both l-selectride and the MgBr2–
DIBALH system afforded 6m as the major product, compound 7m was
prepared from ureidosulfone 5e following the usual Mannich–PADAM
procedure (see the synthesis of 8a), stopping it before the final oxidation.
The crude mixture, containing a 49:51 mixture of 6m and 7m, was puri-
fied by chromatography (PE/AcOEt 2:8 + 0.5% MeOH) to give pure
6m (lower Rf) and 7m (higher Rf) in 45% overall yield from 5e.
(75 MHz, CDCl3, 258C, TMS): d=172.5, 170.5 (C=O), 154.0 (C-OH),
128.9, 126.5, 120.5, 118.1 (aromatic CH), 127.1 (quat.), 73.7 (CHOH),
71.5 (CH2O), 59.3 (OCH3), 49.2 (C-4), 48.4 (cyHex CHNH), 42.6 (C-3),
32.9, 32.7, 25.4, 24.8 (2ꢂ) (cyHex CH), 11.5 ppm (CH3); IR (CHCl3): n˜ =
3401, 3250 (broad), 3008, 2931, 2853, 1648, 1510, 1451, 1382, 1350, 1249,
1216, 1151, 1094, 1009, 918 cmÀ1
; HRMS (ESI+): m/z calcd for
C20H31N2O5 [M+H]+: 379.2233; found: 379.227. A solution of alcohol
11m (89 mg, 236 mmol) in dry CH2Cl2 (10 mL) was treated with polystyr-
ene-supported PPh3 (Polymer Laboratories, 150–300 mm, 1.52 mmolgÀ1
)
(388 mg, 590 mmol) and with 40% diethyl azodicarboxylate (DEAD) in
Chem. Eur. J. 2013, 19, 4563 – 4569
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4567

L. Banfi et al.
toluene (163 mL, 356 mmol). The suspension was shaken in an orbit
shaker for 20 h at room temperature. Filtration and chromatography
(PE/AcOEt 20:80) afforded pure 9 as a white foam (64 mg, 75%). Com-
pound 9 has also been obtained in 55% overall yield (from 6m) without
intermediate purification of alcohol 11m. Rf =0.42 (PE/AcOEt 20:80);
[a]D =À50.90 (c=1.3, CHCl3); 1H NMR (300 MHz, CDCl3, 258C, TMS):
227–235; c) A. Basso, L. Banfi, R. Riva, P. Piaggio, G. Guanti, Tet-
rahedron Lett. 2003, 44, 2367–2370.
[3] a) P. Weyermann, A. Von Sprecher, M. Hennebçhle, H. Herzner, C.
Lescop, H. Siendt, 2006, WO 2006021413; b) L. Banfi, G. Guanti, R.
Riva, A. Basso, E. Calcagno, Tetrahedron Lett. 2002, 43, 4067–4069;
c) S. Faure, T. Hjelmgaard, S. P. Roche, D. J. Aitken, Org. Lett. 2009,
11, 1167–1170; d) T. D. Owens, G.-A. Araldi, R. F. Nutt, J. E.
Semple, Tetrahedron Lett. 2001, 42, 6271–6274; e) T. D. Owens, J. E.
Semple, Org. Lett. 2001, 3, 3301–3304.
[4] a) Y. Xu, G. Lu, S. Matsunaga, M. Shibasaki, Angew. Chem. 2009,
121, 3403–3406; Angew. Chem. Int. Ed. 2009, 48, 3353–3356; b) G.
Lu, H. Morimoto, S. Matsunaga, M. Shibasaki, Angew. Chem. 2008,
120, 6953–6956; Angew. Chem. Int. Ed. 2008, 47, 6847–6850.
[5] In our hands, these aldehydes tend to partially epimerize under
basic or acidic conditions or even upon silica gel chromatography.
[6] a) J. W. Yang, M. Stadler, B. List, Angew. Chem. 2007, 119, 615–617;
Angew. Chem. Int. Ed. 2007, 46, 609–611; b) J. W. Yang, S. C. Pan,
B. List, Org. Synth. 2009, 86, 11–17.
[7] a) J. Vesely, R. Rios, I. Ibrahem, A. Cꢃrdova, Tetrahedron Lett.
2007, 48, 421–425; b) T. Kano, Y. Yamaguchi, K. Maruoka, Angew.
Chem. 2009, 121, 1870–1872; Angew. Chem. Int. Ed. 2009, 48, 1838–
1840; c) P. Galzerano, D. Agostino, G. Bencivenni, L. Sambri, G.
Bartoli, P. Melchiorre, Chem. Eur. J. 2010, 16, 6069–6076; d) L.
Deiana, G.-L. Zhao, P. Dziedzic, R. Rios, J. Vesely, J. Ekstrom, A.
Cordova, Tetrahedron Lett. 2010, 51, 234–237; e) Y.-M. Chuan, G.-
H. Chen, J.-Z. Gao, H. Zhang, Y.-G. Peng, Chem. Commun. 2011,
47, 3260–3262; f) J. Gao, Y. Chuan, J. Li, F. Xie, Y. Peng, Org.
Biomol. Chem. 2012, 10, 3730–3738; g) B. Tiwari, J. Zhang, Y. R.
Chi, Angew. Chem. 2012, 124, 1947–1950; Angew. Chem. Int. Ed.
2012, 51, 1911–1914.
[8] Previous examples of tandem organocatalysis MCR: a) S. Umbreen,
M. Brockhaus, H. Ehrenberg, B. Schmidt, Eur. J. Org. Chem. 2006,
4585–4595; b) F. Morana, A. Basso, M. Bella, R. Riva, L. Banfi,
Adv. Synth. Catal. 2012, 354, 2199–2210; c) E. Riguet, J. Org. Chem.
2011, 76, 8143–8150; d) A. M. Deobald, A. G. Correa, D. G. Rivera,
M. W. Paixao, Org. Biomol. Chem. 2012, 10, 7681–7684. For recent
examples of organocatalytic MCRs, see: e) S. Saha, J. N. Moorthy, J.
Org. Chem. 2010, 75, 396–402; f) S.-e. Syu, Y.-T. Lee, Y.-J. Jang, W.
Lin, J. Org. Chem. 2011, 76, 2888–2891; g) D. Enders, C. Wang, M.
Mukanova, A. Greb, Chem. Commun. 2010, 46, 2447–2449; h) J. M.
Goss, S. E. Schaus, J. Org. Chem. 2008, 73, 7651–7656; i) M. Radi,
V. Bernardo, B. Bechi, D. Castagnolo, M. Pagano, M. Botta, Tetrahe-
dron Lett. 2009, 50, 6572–6575; j) D.-W. Wang, S.-e. Syu, Y.-T.
Hung, P.-y. Chen, C.-J. Lee, K.-W. Chen, Y.-J. Chen, W. Lin, Org.
Biomol. Chem. 2011, 9, 363–366.
d=7.30–7.23 (m, 2H; H-6 and H-8), 7.00 (dt, 3J
ACHTUNGTRENNUNG
(d), 1H; H-7), 6.96 (dd, 3J
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
3
3
NH), 4.83 (dd, J
1H; H-2), 3.94, 3.91 (AB syst., 2J
3.84 (m, 1H; cyHex CH), 3.35 (s, 3H; CH3O), 2.69 (tq, 3J
(q), 1.9 Hz (t), 1H; H-3), 2.04–1.85 (m, 2H), 1.82–1.56 (m, 4H), 1.50–
1.10 (m, 4H), 0.88 ppm (d, 3J(H,H)=7.2 Hz, 3H; CH3CH); 13C NMR
A
ACHTUNGTREN(NUNG H,H)=2.4 Hz,
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
(75 MHz, CDCl3, 258C, TMS): d=168.9, 168.6 (C=O), 153.0 (C-10),
131.9 (C-8), 130.0 (C-6), 122.5 (C-7), 120.2 (C-5), 117.2 (C-9), 74.2 (C-2),
71.8 (CH2O), 58.9 (OCH3), 48.7 (C-4), 47.8 (CHNH cyHex), 34.6 (C-3),
33.0, 32.7, 25.2, 24.6, 24.5 (cyHex CH2), 10.8 ppm (CH3CH); IR (ATR):
n˜ =3286, 2930, 2854, 1647, 1520, 1486, 1451, 1382, 1350, 1316, 1259, 1233,
1198, 1151, 1119, 1103, 1065, 1015, 990, 942, 891, 873, 798, 755, 730 cmÀ1
;
HRMS (ESI+): m/z calcd for C20H29N2O4 [M+H]+: 361.2127; found:
361.2130.
ACHTUNGTRENNUNG(2S,3S,4S)-N-Cyclohexyl-4-(2-methoxyacetamido)-3-methylchroman-2-
carboxamide (10): Alcohol 7m (225 mmol) was hydrogenated as descri-
bed above to give crude (2R,3S,4S)-N-cyclohexyl-2-hydroxy-4-(2-hydrox-
yphenyl)-4-(2-methoxyacetamido)-3-methylbutanamide
G
This
crude alcohol was not purified but directly taken up in dry CH2Cl2
(10 mL) and treated with polystyrene-supported PPh3 (Polymer Labora-
tories, 150–300 mm, 1.52 mmolgÀ1) (222 mg, 338 mmol) and with di-tert-
butyl azodicarboxylate (TBAD) (78 mg, 338 mmol). The suspension was
shaken in an orbit shaker for 20 h at room temperature. Filtration and
chromatography (PE/AcOEt 20:80) afforded pure 10 as a white foam
(49 mg, 60% overall yield from 7m). Rf =0.50 (PE/AcOEt 20:80); [a]D =
À68.5 (c=1, CHCl3); 1H NMR (300 MHz, CDCl3, 258C, TMS): d=7.32–
3
7.19 (m, 2H; H-6 and H-8), 6.98 (dt, J
N
7), 6.93 (dd, 3J
1H; C-4-NH), 6.25 (d, 3J
(H,H)=8.9, 5.0 Hz, 1H; H-4), 4.43 (d, 3J
(s, 2H; CH2OMe), 3.85–3.70 (m, 1H; cyHex CH), 3.38 (s, 3H; CH3O),
A
ACHTUNGTREN(NUNG H,H)=8.9 Hz,
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
3
2.61 (tq, J
ACHTUNGTRENNUNG
1.63 (m, 2H), 1.63–1.00 (m, 7H), 1.17 ppm (d, 3J
AHCTUNGTRENNUNG
CH3CH); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=169.4 (O=C
CH2OMe), 168.7 (OC-NH cyHex), 151.8 (C-10), 130.3 (C-8), 129.4 (C-6),
122.1 (C-7), 121.9 (C-5), 116.5 (C-9), 78.8 (C-2), 71.9 (CH2O), 59.1
(OCH3), 47.9 (C-4), 47.7 (CHNH cyHex), 34.7 (C-3), 32.72, 32.69, 25.4,
24.6 (2ꢂ) (cyHex CH2), 16.4 ppm (CH3CH); IR (CHCl3): n˜ =3675, 3612,
3419, 3008, 2971, 2932, 2855, 1667, 1512, 1477, 1421, 1202, 1099, 1030,
927, 909, 874 cmÀ1; HRMS (ESI+): m/z calcd for C20H29N2O4 [M+H]+:
361.2127; found: 361.2130.
À
[9] The use of cesium carbonate instead of potassium carbonate repre-
sents an improvement over the previously reported conditions[6b] be-
cause elimination of sulfinate was complete in a shorter time at a
lower temperature.
[10] L. Banfi, R. Riva, in Organic Reactions, Vol. 65 (Ed.: L. E. Over-
man), Wiley, New York, 2005, pp. 1–140.
[11] Acyl migration was slower than in the original PADAM protocol,
but it was usually complete after 3 h at room temperature. However,
in some cases, a longer reaction time was needed and the solution
was stirred overnight.
Acknowledgements
[12] Although compounds 8 have some tendency to epimerize upon pro-
loged standing in solution at room temperature, during chromatog-
raphy, epimerization was negligible and the syn/anti ratio deter-
mined by weight corresponded to the one mesaured on the crude
product.
[13] In order to further simplify the protocol, we attempted the one-pot,
proline-catalyzed, Mannich reaction starting from ureidosulfone 5a.
However, under the reported conditions (in situ elimination with
KF),[7d] we obtained a rather poor syn/anti ratio.
[14] a) L. Banfi, A. Basso, G. Guanti, R. Riva in Multicomponent Reac-
tions (Eds.: J. Zhu, H. Bienaymꢄ), Wiley-VCH, Weinheim, 2005,
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We thank Carlo De Santis and Manuel Anselmo for their collaboration
to this work and Dr. Andrea Armirotti for performing the HRMS analy-
ses. We thank MIUR (PRIN 2009 project “Synthetic Methodologies for
Generation of Biologically Relevant Molecular Diversity”) for financial
assistance.
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Received: January 3, 2013
Published online: February 12, 2013
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