PADAM reactions of α-aminoaldehydes: Identity of major and minor diastereomers from the Passerini reaction

Article abstract of DOI:10.1016/j.tet.2018.04.065

The Passerini reaction was conducted using N-Boc-L-phenylalaninal and a variety of achiral or chiral acids and isocyanides to prepare a library of 27 Passerini products. Reaction diastereoselectivity varied between 1.7:1 and 2.5:1 and in most cases isolat

Full text of DOI:10.1016/j.tet.2018.04.065

Tetrahedron xxx (2018) 1e17
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
PADAM reactions of
a-aminoaldehydes: Identity of major and minor
diastereomers from the Passerini reaction
Memory Zimuwandeyi, Fatima Kola, Andreas Lemmerer, Dean Brady,
*
Amanda L. Rousseau, Moira L. Bode
Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Private Bag 3, PO WITS, 2050, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 March 2018
Received in revised form
The Passerini reaction was conducted using N-Boc-L-phenylalaninal and a variety of achiral or chiral
acids and isocyanides to prepare a library of 27 Passerini products. Reaction diastereoselectivity varied
between 1.7:1 and 2.5:1 and in most cases isolation of the individual diastereomers was possible.
Passerini products were subjected to a deprotection and acyl migration sequence to give a library of
18 April 2018
Accepted 20 April 2018
Available online xxx
peptidomimetic a-hydroxy-b-acylaminoamides in generally excellent yield. Single crystal X-ray analysis
of two of the final products enabled identification of the major diastereomer as having an (R) configu-
ration at the newly-formed stereogenic centre, which corresponds to anti-Felkin-Anh addition of the
isocyanide to the aldehyde.
Keywords:
Passerini
PADAM
©
2018 Elsevier Ltd. All rights reserved.
Diastereoselectivity
a
-aminoaldehydes
Major diastereomer
1
. Introduction
is followed by a Mumm rearrangement (step C, Scheme 2), a step
3,4
that is assisted by an additional carboxylic acid molecule. The
Mumm rearrangement product gives rise to the Passerini product
as shown in step D (Scheme 2).
Interest in isocyanide-based multi-component reactions (MCRs)
1
has grown exponentially in recent years. Although the Ugi reaction
is more widely used, the Passerini reaction has also found use in
specific applications. One such application is the preparation of
peptidomimetic compounds using the so-called Passerini - amine
When starting with chiral starting materials, a degree of dia-
stereoselectivity may be observed in the Passerini reaction. For
example, Banfi et al. determined the reaction diastereoselectivity
5
2
deprotection - acyl migration (PADAM) strategy. In this case the
when using six different N-protected
a-aminoaldehydes in com-
three-component Passerini reaction is carried out using a protected
bination with achiral isocyanides and chiral or achiral carboxylic
2
a
a
-aminoaldehyde 1, a carboxylic acid 2 and an isocyanide 3. This is
acids. They found that the diastereoselectivity varied between
1.3:1 and 2.5:1. Other workers using the PADAM approach have
followed by deprotection of the amino group of the Passerini
product 4, and O, N-migration of the acyl group to give compound 5
6
reported similar diastereoselectivities in their Passerini reactions,
(
Scheme 1).
but in none of these cases was the identity of the major and minor
diastereomer determined.
A concerted reaction pathway for the Passerini reaction, sup-
ported by a gas phase quantum mechanical study, was proposed by
Maeda et al.3 More recently, Ramozzi and Morokuma performed
DFT calculations for the Passerini reaction in dichloromethane, and
proposed a revised step-wise mechanism (Scheme 2) proceeding
Our own interest in this chemistry stems from our use of the
PADAM approach, starting from N-Boc-phenylalaninal (1, R ¼ Bn),
for the preparation of compounds such as 6 (Fig. 1), which was
found to exhibit activity as an HIV-1 protease inhibitor. All but one
of the FDA-approved HIV-1 protease inhibitors have been designed
7
4
through a nitrilium intermediate. It is in this first step leading to
the nitrilium intermediate (step A, Scheme 2), that a new stereo-
genic centre is formed. Formation of the imidate (step B, Scheme 2)
as peptidomimetic transition-state mimics to resemble the tetra-
8
hedral intermediate formed during peptide bond cleavage.
A
common cleavage site for HIV-1 protease is adjacent to phenylal-
9
anine, thus most inhibitors have a benzyl and hydroxyl group in
close proximity, generally adjacent to each other. Based on differ-
ences in the relative stereochemistry between the adjacent benzyl
*
Corresponding author.
E-mail address: Moira.Bode@wits.ac.za (M.L. Bode).
https://doi.org/10.1016/j.tet.2018.04.065
040-4020/© 2018 Elsevier Ltd. All rights reserved.
0
Please cite this article in press as: Zimuwandeyi M, et al., PADAM reactions of
a-aminoaldehydes: Identity of major and minor diastereomers
from the Passerini reaction, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.04.065

2
M. Zimuwandeyi et al. / Tetrahedron xxx (2018) 1e17
Scheme 1. PADAM strategy.
Scheme 3. Preparation of starting materials. Reagents and conditions: (a) i. 1.2 eq.CDI,
ꢀ
4
, THF, 0 C; (c)
CH
2
Cl
2
, rt; ii. 1.2 eq. N,O-dimethylhydroxylamine HCl; (b) 1.5 eq. LiAlH
O; (d) PPh , CCl , DIPEA, CH Cl , rt.
excess HCOOH, Ac
2
3
4
2
2
1.34:1 and 2.49:1. The two best diastereoselectivities were obtained
for compounds 33 and 39, where the chiral acid N-Boc-L-phenyl-
alanine (9) was used. Thus, N-Boc-L-phenylalaninal (1a) and N-Boc-
L-phenylalanine (9) appear to represent a matched pair, while
isocyanide ent-11 did not impact negatively on diastereoselectivity.
The two poorest diastereoselectivities were observed for com-
pounds 35 and 36, where the chiral isocyanide 11 was used. Thus,
N-Boc-L-phenylalaninal (1a) and isocyanide 11 appear to represent
a mismatched pair.
Scheme 2. Revised mechanism of the Passerini reaction after Ramozzi and
Morokuma.
4
However, the fact that a roughly 2:1 ratio was obtained even
when using achiral carboxylic acids and isocyanides shows that the
dominant factor controlling diastereoselectivity is the stereo-
chemistry of the aldehyde. Interestingly, when compound 13 was
prepared by means of microwave irradiation using a general
11
method described by Barreto et al. all diastereoselectivity was
lost, and equal amounts of the two diastereomers were obtained.
Passerini products 4 (13e33) were then subjected to depro-
tection and acyl migration to give rise to PADAM products 5
(Table 2). Where possible, the diastereomeric Passerini products
were separated by means of semi-preparative HPLC to give a pure
major (4A) and minor (4B) diastereomer prior to deprotection and
migration to give 5A and 5B, respectively. As expected, no race-
misation of the stereogenic centres was observed during the
deprotection-migration sequence. Good to excellent yields were
obtained for all but a few examples in the cyclohexyl isocyanide
series.
Fig. 1. Our previously identified HIV-1 protease inhibitor 6 and FDA-approved HIV-1
protease inhibitors amprenavir 7 and atazanavir 8.
and hydroxyl groups in FDA-approved HIV-1 protease inhibitors
such as amprenavir 7 and atazanavir 8 (Fig. 1), we were interested
to determine whether the relative stereochemistry of our major
diastereomer corresponded to that of amprenavir or atazanavir.
Thus, we undertook to investigate the Passerini reaction between
N-Boc-phenylalaninal (1a, R ¼ Bn) and various isocyanides and
carboxylic acids in order to determine the reaction diaster-
eoselectivity and the configurations of the resulting major and
minor diastereomers.
Of interest to us was the trend that the minor diastereomers
were generally less soluble than the major diastereomers for both
the Passerini and PADAM products. In addition, although rotamers
can often be observed for compounds containing amide bonds, our
NMR spectroscopic data showed that the minor diastereomers
were far more likely to show the presence of rotamers than the
13
major diastereomers. For example, in the C NMR spectrum for
minor diastereomer 47B, two signals each were observed for most
of the carbon atoms present in the compound, while for major
diastereomer 47A, the expected number of signals was observed.
This effect may also be the result of intramolecular hydrogen
bonding through formation of a six-membered ring that may be
more energetically favoured in one diastereomer over the other.
None of the separated Passerini diastereomers (4A or B) proved
amenable to single crystal X-ray analysis. However, the PADAM
product 40B, obtained from minor diastereomer 13B after depro-
tection and acyl migration, was crystalline and was shown by single
crystal X-ray diffraction to have the (S)-configuration at the newly-
formed C-2 stereogenic centre (Fig. 2). Similarly, PADAM product
56A, obtained from major diastereomer 29A, was found by single
crystal X-ray diffraction to have the (R)-configuration at C-2 (Fig. 3).
Based on these results, obtained from two different isocyanide
series, we propose that the same major and minor diastereomer is
2
. Results and discussion
The aldehyde component used in all the Passerini reactions was
N-Boc-L-phenylalaninal (1a), which was prepared from N-Boc-L-
phenylalanine (9) via Weinreb amide 10 (Scheme 3), as previously
described.10 Chiral isocyanide 11 was also prepared from 9 by for-
mylation to give 12, followed by dehydration (Scheme 3) while
compound ent-11, was prepared in an analogous fashion from N-
Boc-D-phenylalanine. All other isocyanides and carboxylic acids
used were commercially available.
Results from the Passerini reaction of the different substrates are
shown in Table 1. In most cases the yield of the Passerini reaction
was excellent. In line with previous work done on these kinds of
substrates, the diastereomeric ratio was found to range between
13
seen for all compounds synthesised. This is supported by the
C
Please cite this article in press as: Zimuwandeyi M, et al., PADAM reactions of
a-aminoaldehydes: Identity of major and minor diastereomers
from the Passerini reaction, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.04.065

M. Zimuwandeyi et al. / Tetrahedron xxx (2018) 1e17
3
Table 1
Passerini reaction of 1a with various acids 2 and isocyanides 3 to give 4.
4
Product
2 Acid
3 Isocyanide
Yielda (%)
drc (A:B)
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
3
acetic
c-hexyl
c-hexyl
c-hexyl
c-hexyl
c-hexyl
c-hexyl
c-hexyl
xylyl
xylyl
xylyl
xylyl
xylyl
93
85
69
51
97
94
2.14:1
1.94:1
1.87:1
2.01:1
2.08:1
1.93:1
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
chloro-acetic
propionic
butanoic
pivalic
t-butylacetic
N-Boc-
b
d
L
-phenylalanine
100
nd
acetic
99
85
99
82
99
94
49
100
82
100
87
92
93
78
92
45
100
77
98
50
1.88:1
1.72:1
1.83:1
2.06:1
1.88:1
2.21:1
1.75:1
1.96:1
1.97:1
1.75:1
1.95:1
2.12:1
2.01:1
2.49:1
2.08:1
1.52:1
1.34:1
1.78:1
2.03:1
2.46:1
chloro-acetic
propionic
butanoic
pivalic
t-butylacetic
N-Boc-
acetic
chloro-acetic
propionic
butanoic
pivalic
t-butylacetic
N-Boc-
N-Boc-
acetic
xylyl
xylyl
L-phenylalanine
adamantyl
adamantyl
adamantyl
adamantyl
adamantyl
adamantyl
adamantyl
adamantyl
11
11
11
11
ent-11
L-phenylalanine
D
-phenylalanine
propionic
N-Boc-
N-Boc-
N-Boc-
L
-phenylalanine
-phenylalanine
-phenylalanine
D
L
a
b
c
Isolated yield after column chromatography.
Precipitated out of reaction mixture.
dr calculated using HPLC peak areas.
Insoluble; nd: not done.
d
Table 2
Deprotection and acyl migration of Passerini products 4 to give 5.
Reactant (4)
C-2 13C NMR shift for 4 (ppm)
Product (5)
Yield 4/5a (%)
Reactant (4)
C-2 13C NMR shift for 4 (ppm)
Product (5)
Yield 4/5a (%)
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
3A
3B
4A
4B
5A
5B
6
7A
7B
8A
8B
9
0A
0B
1
2
3
73.9
74.4
75.1
76.0
73.7
74.2
74.1, 73.5
73.3
73.9
73.4
73.9
75.9, 74.1
74.1
74.9
75.5, 76.5
73.9, 74.8
73.9, 74.8
40A
40B
41A
41B
42A
42B
43
44A
44B
45A
45B
46
47A
47B
48
49
50
84
95
88
90
42
56
36
93
65
86
73
68
81
70
76
98
74
24
25
26
73.6, 74.6
73.6, 74.5
75.0, 76.2
73.8
74.5
75.0
75.9
73.5
74.3
73.5
74.1
73.3
74.1
73.5
73.9
74.3
75.7
51
52
53
96
91
92
93
99
88
77
99
88
94
100
70
70
82
100
84
89
27A
27B
28A
28B
29A
29B
30A
30B
31A
31B
32A
32B
33A
33B
54A
54B
55A
55B
56A
56B
57A
57B
58A
58B
59A
59B
60A
60B
a
Isolated yield after column chromatography.
Fig. 3. Configuration of major diastereomer 56A.
Fig. 2. Configuration of minor diastereomer 40B.
entire series of compounds prepared where diastereomers were
1
3
NMR spectroscopic chemical shift values observed for the new
stereogenic centre of the major and minor diastereomers. For the
separated, the C NMR spectroscopic shift value is further upfield
for the major diastereomer than that for the corresponding minor
Please cite this article in press as: Zimuwandeyi M, et al., PADAM reactions of
a-aminoaldehydes: Identity of major and minor diastereomers
from the Passerini reaction, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.04.065

4
M. Zimuwandeyi et al. / Tetrahedron xxx (2018) 1e17
diastereomer (Table 2). Thus, for our active HIV-1 protease inhibitor
, the major diastereomer corresponds to the stereochemistry
4.2. Synthesis of starting materials
6
found in FDA-approved drug atazanavir (8).
4.2.1. (S)-2-Isocyano-N-methoxy-N-methyl-3-phenyl propanamide
Based on our results, we propose that the stereochemical
outcome of the Passerini reaction can be rationalised by treating
the reaction as a simple nucleophilic addition of the isocyanide to
the a-aminoaldehyde and applying the chelation-controlled Felkin-
Anh model (Fig. 4).
11
To
(S)-tert-butyl(1-(methoxy(methyl)amino)-1-oxo-3-
phenylpropan-2-yl)carbamate 10 (3.15 g, 15.1 mmol) was added
excess formic acid (20 ml) and acetic anhydride (5 ml). TFA
(0.46 ml, 60 mmol) was added dropwise and the reaction was
allowed to stir at room temperature for 4 h. To the mixture was
added ethyl acetate (200 ml) and brine (200 ml). The organic layer
According to this model, observed for certain simple nucleo-
12
philic addition reactions to mono-substituted a-aminoaldehydes,
hydrogen bonding between the amine proton and the aldehyde
carbonyl oxygen atom makes Si face attack more favourable, so as to
avoid a steric clash between the incoming nucleophile and the
benzyl group. This results in the major diastereomer being the anti-
Felkin-Anh product, as observed in our reactions. Our model is
supported by the results of Riva et al. who found that addition of
3
was separated and solid NaHCO was added until effervescence
ceased. The organic layer was washed with water (200 ml) and after
separation, the aqueous layer was extracted with ethyl acetate
(2 ꢁ 100 ml). Combined organic layers were dried over anhydrous
4
MgSO and the solvent removed in vacuo. Crude formylated prod-
2 2 2
uct (12) was dissolved in anhydrous CH Cl (60 ml) under N at
the chelating Lewis acid ZnBr
an N-benzyl-azetidine-derived aldehyde lacking an amino proton
also led to the anti-Felkinh-Anh product.
2
to Passerini reactions conducted on
room temperature. To this was added triphenylphosphine (4.59 g,
17.5 mmol), carbon tetrachloride (2.69 g, 17.5 mmol) and Hünig's
base (2.26 g, 17.5 mmol) and the reaction was stirred overnight.
Solvent was removed under reduced pressure and compound 11
13
was isolated as a brown oil (2.06 g, 81%) after column chromatog-
ꢂ1
raphy (elution ethyl acetate/hexane 3:7). IR:
(
n
max(cm ): 2940
3
. Conclusion
We have found that the major diastereomer formed in Passerini
1
3
CeH), 2143 (CN), 1676 (C]O); H NMR (500 MHz, CDCl )
d
7.32e7.29 (5H, m, Ar-H), 4.85e4.77 (1H, m, CHNC), 3.66 (3H, s,
O), 3.25e3.22 (4H, m, CH N and CHaHbPh), 3.10 (1H, dd,
J ¼ 13.5, 8.5 Hz, CHaHbPh); C NMR (126 MHz, CDCl 165.88 (C]
O), 159.28 (C^N), 135.26 (Ar-C), 129.33 (Ar-C), 129.00 (Ar-C), 128.27
Ar-C), 61.66 (CH O), 55.45 (CHN), 38.70 (CH Ph), 32.53 (CH N).
CH
3
3
reactions of N-Boc-L-phenylalaninal has the (R)-configuration at
the newly-formed stereogenic centre C-2. This corresponds to the
anti-Felkin-Anh product, and can be rationalised by considering
these reactions to be chelation-controlled nucleophilic addition
reactions. Chelation control comes about as a result of hydrogen
bonding between the proton of the amino group and the aldehyde
carbonyl oxygen atom.
13
3
) d
(
3
2
3
4.2.2. (R)-2-Isocyano-N-methoxy-N-methyl-3-phenylpropanamide
ent-11
In analogous fashion to that described for 11, ent-11 was ob-
ꢂ1
tained as a light brown oil. IR
n
max(cm ): 2939 (CeH), 2145 (CN),
1
1653 (C]O); H NMR (300 MHz, CDCl
3
)
d
7.41e7.23 (5H, m, Ar-H),
O), 3.30e3.23 and 3.21
N and CHaHbPh), 3.19e3.05 (1H, m,
CHaHbPh). C NMR (75 MHz, CDCl 165.83 (C]O), 159.24
C^N), 135.24 (Ar-C), 129.31 (Ar-C), 128.63 (Ar-C), 127.55 (Ar-C),
4
.85e4.74 (1H, m, CHNC), 3.66 (3H, s, CH
3
4
. Experimental section
(
4H, m overlapped with s, CH
3
13
3
) d
4.1. General
(
6
1.66 (CH
3
O), 55.51 (CHN), 38.70 (CH
2
Ph), 32.50 (CH
3
N); HRMS (m/
Reagents were purchased from Sigma-Aldrich and used without
þ
z), calculated for C12
H
15
N
2
O
2
: 219.1134, found (M þ H) : 219.1144.
purification. Infrared spectra were recorded neat using a Bruker
TENSOR 27 single channel infrared spectrometer. Melting points
are uncorrected and were collected on a Stuart SMP 10 melting
point apparatus. 1H and C NMR spectra were recorded using
either a Bruker AVANCE 111300 or 500 MHz spectrometer in
4.3. General procedure for the preparation of Passerini products
13e39
13
2 2
N-Boc-L-phenylalaninal 1a (1 eq.) was dissolved in CH Cl , fol-
3
deuterated chloroform (CDCl ) with trimethylsilane (TMS) as in-
lowed by drop-wise addition of isocyanide (1 eq.) and carboxylic
acid (1 eq.). The reaction mixture was allowed to stir at room
temperature in air for 3 d. Excess solvent was then removed in
vacuo and the product was purified by normal phase silica gel
1
13
ternal standard (
d
¼ 0) for H NMR, and CDCl
3
(d
¼ 77.0 ppm) for
C
NMR. The chemical shift (
d
) is reported in ppm and the coupling
constants (J) in Hz. High resolution mass spectral data was collected
on a Waters Synapt G2 using an ESI positive source and a cone
voltage of 15 V. TLC was performed on aluminium-backed Merck
silica gel 60 F254 plates. The purification of compounds was carried
out using gravity column chromatography on silica gel 60 (particle
size 0.063e0.200 mm) purchased from Merck.
3
column chromatography (elution CHCl /MeOH 1:0 to 49:1). The
mixture of diastereomers was then analysed by HPLC to establish
the diastereomeric ratio. Separation by preparative HPLC was car-
ried out in cases when base-line separation of diastereomers was
achieved by dissolving the compounds in HPLC grade acetonitrile
and injecting the solution onto a C-18 column where diastereomers
were separated by gradient elution (5:5 to 8:2 acetonitrile/H
2
O)
and collected separately.
4
4
.3.1. 3-[(Tert-butoxycarbonyl)amino]-1-(cyclohexylamino)-1-oxo-
-phenylbutan-2-yl acetate 13
Product 13 (1.56 g, 93%) was isolated as a white solid and this
material was separated into two diastereomers 13A and 13B.
4
.3.1.1. (2R,3S)-3-[(tert-butoxycarbonyl)amino]-1-(cyclo-
Fig. 4. Chelation-controlled Felkin-Anh model showing formation of major and minor
diastereomers.
ꢀ
hexylamino)-1-oxo-4-phenylbutan-2-yl acetate 13A. M.p. 162 C; IR
Please cite this article in press as: Zimuwandeyi M, et al., PADAM reactions of
a-aminoaldehydes: Identity of major and minor diastereomers
from the Passerini reaction, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.04.065

M. Zimuwandeyi et al. / Tetrahedron xxx (2018) 1e17
5
ꢂ1
(
1
1
5
4
solid) vmax(cm ): 3341 (NH), 3290 (NH), 2922 (CeH), 2851 (CeH),
735 (C]O), 1686 (C]O), 1652 (C]O), 1533 (C]C), 1257 (CeO),
168 (CeC); 1H NMR (300 MHz, CDCl
7.39e7.14 (5H, m, Ar-H),
.93e5.75 (1H, m, NH), 5.28e5.02 (2H, m, NH and H-2),
.38e4.23 (1H, m, H-3), 3.86e3.68 (1H, m, cyclohexyl-CH), 2.83
CO), 1.98e1.81 (2H, m) and
), 1.35e1.04 (12H, m, (CH C and
); C NMR (75 MHz, CDCl 169.15 and 166.95
cyclohexyl-CH
2
), 1.77e1.66 (2H, m, cyclohexyl-CH
), 1.47e1.02 (14H, m, (CH
); C NMR (126 MHz, CDCl 166.15 and 165.80 (C]O), 155.69
(Boc C]O), 137.14 (Ar-C), 129.13 (Ar-C), 128.57 (Ar-C), 126.74 (Ar-C),
79.94 ((CH C), 75.96 (C-2), 53.09 (C-3), 48.27 (cyclohexyl-CH),
40.72 (CH Cl), 36.71 (C-4), 32.80 and 29.71 (cyclohexyl-CH ), 28.26
Boc ((CH
calculated for C23
2
), 1.66e1.56 (1H,
) C and cyclohexyl-
3 3
m, cyclohexyl-CH
2
13
3
)
d
CH
2
3
) d
3 3
)
(
1
2H, d, J ¼ 7.2 Hz, H-4), 2.10 (3H, s, CH
3
2
2
.79e1.52 (5H, m, cyclohexyl-CH
2
3
)
3
3
)
3
C), 25.44 and 24.64 (cyclohexyl-CH
34ClN
2
); HRMS (m/z),
: 453.2156, found, (M þ H) : 453.2156.
13
þ
cyclohexyl-CH
(
2
3
)
d
H
2
O
5
C]O), 155.03 (Boc C]O), 137.34 (Ar-C), 129.28 (Ar-C), 128.51 (Ar-
C), 126.61 (Ar-C), 79.61 ((CH C), 73.86 (C-2), 52.88 (C-3), 48.35
cyclohexyl-CH), 38.14 (C-4), 32.78 and 32.92 (cyclohexyl-CH ),
C), 25.46 and 24.77 (cyclohexyl-CH
HRMS (m/z), calculated for C23
3 3
)
4
4
.3.3. 3-[(Tert-butoxycarbonyl)amino]-1-(cyclohexylamino)-1-oxo-
-phenylbutan-2-yl propionate 15
(
2
2
8.24 ((CH
3
)
3
2
), 20.69 (CH
: 419.2546, found (M þ H) :
3
CO);
Product 15 was isolated as a white solid (360 mg, 69%) that was
separated to give the two diastereomers 15A and 15B.
þ
35
H N
2
O
5
4
19.2537.
4
.3.1.2. (2S,3S)-3-[(tert-butoxycarbonyl)amino]-1-(cyclo-
4.3.3.1. (2R,3S)-3-[(tert-butoxycarbonyl)amino]-1-(cyclo-
hexylamino)-1-oxo-4-phenylbutan-2-yl propionate 15A. H NMR
1
hexylamino)-1-oxo-4-phenylbutan-2-yl acetate 13B. M.p. 164
-
ꢀ
ꢂ1
165 C; IR (solid) vmax(cm ): 3370 (NH), 3063 (CeH), 2933 (CeH),
(300 MHz, CDCl
3
)
d
7.34e7.12 (5H, m, Ar-H), 5.91 (1H, d, J ¼ 8.1 Hz,
2
854 (CeH), 1749 (C]O), 1685 (C]O), 1648 (C]O), 1512 (C]C),
NH), 5.26e5.07 (2H, m, NH and H-2), 4.37e4.25 (1H, m, H-3),
3.86e3.68 (1H, m, cyclohexyl-CH), 2.82 (2H, d, J ¼ 7.0 Hz, H-4),
1
1
5
4
3
222 (CeO); H NMR (300 MHz, CDCl ) d 7.38e7.14 (5H, m, Ar-H),
.99 (1H, d, J ¼ 8.3 Hz, NH), 5.26e4.93 (2H, m, NH and H-2),
2.49e2.26 (2H, m, CH
2
CO), 1.97e1.81 (2H, m, cyclohexyl-CH
2
),
C,
172.59
and 167.08 (C]O), 155.01 (Boc C]O), 137.38 (Ar-C), 129.28 (Ar-C),
128.47 (Ar-C), 126.57 (Ar-C), 79.48 ((CH C), 73.67 (C-2), 52.89 (C-
3), 48.28 (cyclohexyl-CH), 38.11 (C-4), 32.90 and 32.76 (cyclohexyl-
.37e4.19 (1H, m, H-3), 3.88e3.71 (1H, m, cyclohexyl-CH), 2.94 (2H,
1.76e1.53 (3H, m, cyclohexyl-CH
2
), 1.46e1.05 (17H, m, (CH
3 3
)
13
d, J ¼ 7.6 Hz, H-4), 2.14 (3H, s, CH
3
CO), 1.99e1.82 (2H, m) and
), 1.36e1.01 (12H, m, (CH C and
); C NMR (75 MHz, CDCl 169.89 and 166.65
CH
3
CH
2
and cyclohexyl-CH
2
); C NMR (75 MHz, CDCl
3
) d
1.81e1.52 (5H, m, cyclohexyl-CH
2
3 3
)
13
cyclohexyl-CH
2
3
)
d
3 3
)
(
1
(
(
(
C]O), 155.57 (Boc C]O), 137.42 (ArC), 129.19 (Ar-C), 128.51 (Ar-C),
26.63 (Ar-C), 79.56 ((CH C), 74.42 (C-2), 53.38 (C-3), 48.26
cyclohexyl-CH), 37.30 (C-4), 32.91 (cyclohexyl-CH ), 28.28
3
)
3
CH
CH
2
), 28.24 ((CH C), 27.40 (CH
3
)
3
2
CO), 25.46 and 24.73 (cyclohexyl-
2
2
), 9.08 (CH CH ).
3
2
(CH
3
)
3
C), 25.46 and 24.75 (cyclohexyl-CH
2
), 20.89 (CH
3
CO); HRMS
þ
m/z), calculated for C23
35
H N
2
O
5
: 419.2546, found (M þ H) :
4
.3.3.2. (2S,3S)-3-[(tert-butoxycarbonyl)amino]-1-(cyclo-
419.2532.
1
hexylamino)-1-oxo-4-phenylbutan-2-yl propionate 15B. H NMR
300 MHz, CDCl
7.27e7.07 (5H, m, Ar-H), 5.92 (1H, d, J ¼ 8.3 Hz,
NH), 5.23e4.98 (1H, m, H-2), 4.94 (1H, d, J ¼ 9.2 Hz, NH), 4.29e4.11
1H, m, H-3), 3.81e3.63 (1H, m, cyclohexyl-CH), 2.87 (2H, d,
CO), 1.98e1.74 (2H, m,
), 1.71e1.46 (3H, m, cyclohexyl-CH ), 1.39e0.93
); C NMR (75 MHz,
(
3
) d
4
4
.3.2. 3-[(Tert-butoxycarbonyl)amino]-1-(cyclohexylamino)-1-oxo-
-phenylbutan-2-yl 2-chloroacetate 14
(
Product 14 was isolated as a white solid (776 mg, 85%) that was
J ¼ 7.5 Hz, H-4), 2.34 (2H, q, J ¼ 7.5 Hz, CH
2
separated into two diastereomers 14A and 14B.
cyclohexyl-CH
17H, m, (CH
CDCl
29.21 (Ar-C), 128.50 (Ar-C), 126.62 (Ar-C), 79.45 ((CH
C-2), 53.35 (C-3), 48.17 (cyclohexyl-CH), 37.45 (C-4), 32.90
2
2
13
(
3
)
3
C), CH
3
CH
2
and cyclohexyl-CH
2
4
.3.2.1. (2R,3S)-3-[(tert-butoxycarbonyl)amino]-1-(cyclo-
hexylamino)-1-oxo-4-phenylbutan-2-yl 2-chloroacetate 14A.
M.p.184e185 C; IR (solid) vmax(cm ): 3351 (NH), 3313 (NH), 2923
3
)
d
173.19 and 166.76 (C]O), 155.51 (Boc C]O), 137.45 (Ar-C),
C), 74.24
1
3 3
)
ꢀ
ꢂ1
(
(
(
(
(
CeH), 2552 (CeH), 1767 (C]O), 1687 (C]O), 1646 (C]O), 1524
C]C), 700 (CeCl); H NMR (500 MHz, CDCl ) d 7.32e7.26 (2H, m,
3
cyclohexyl-CH
cyclohexyl-CH
2
), 28.29 ((CH
3
)
3
2
C), 27.51 (CH CO), 25.47 and 24.72
1
2
), 9.93 (CH CH
3
2
).
Ar-H), 7.24e7.16 (3H, m, Ar-H), 6.11e5.95 (1H, m, NH), 5.30e5.10
2H, m, NH and H-2), 4.42e4.31 (1H, m, H-3), 4.03 (2H, s, CH Cl),
.82e3.71 (1H, m, cyclohexyl-CH), 2.85 (2H, d, J ¼ 7.1 Hz, H-4),
), 1.75e1.64 (2H, m, cyclohexyl-
), 1.64e1.56 (1H, m, cyclohexyl-CH ),1.41e1.09 (14H, m, (CH
); C NMR (126 MHz, CDCl 166.10 and
65.59 (C]O), 154.99 (Boc C]O), 137.10 (Ar-C), 129.23 (Ar-C),
28.57 (Ar-C), 126.71 (Ar-C), 79.73 ((CH C), 75.12 (C-2), 52.71 (C-
), 48.46 (cyclohexyl-CH), 40.46 (CH Cl), 38.05 (C-4), 32.83 and
2.65 (cyclohexyl-CH ), 28.25 ((CH C), 25.41 and 24.66 (cyclo-
(
3
1
CH
2
4.3.4. 3-[(Tert-butoxycarbonyl)amino]-1-(cyclohexylamino)-1-oxo-
4-phenylbutan-2-yl butyrate 16
.97e1.82 (2H, m, cyclohexyl-CH
2
2
2
3
)
3
C
Product 16 was isolated as a white solid (270 mg, 51%) that was a
13
ꢂ1
and cyclohexyl-CH
1
1
3
3
2
3
)
d
2.01:1 mixture of diastereomers. IR vmax(cm ): 3350 (NH), 3314
(NH), 2933 (CeH), 2854 (CeH), 1738 (C]O), 1686 (C]O), 1650 (C]
1
3
)
3
O), 1528 (C]C), 1251 (CeO); H NMR (300 MHz, CDCl
3
)
d
7.38e7.12
2
(5H, m, Ar-H), 5.98 (0.39H, d, J ¼ 8.2 Hz, NH), 5.82 (0.53H, d,
J ¼ 8.2 Hz, NH), 5.28e4.94 (2H, m, NH and H-2), 4.37e4.20 (1H, m,
H-3), 3.87e3.69 (1H, m, cyclohexyl-CH), 2.94 (1H, d, J ¼ 7.1 Hz, H-
2
3 3
)
hexyl-CH
found, (M þ H) : 453.2153.
2
); HRMS (m/z), calculated for C23
H34ClN
2
O
5
: 453.2156,
þ
4a), 2.82 (1H, d, J ¼ 7.1 Hz, H-4b), 2.46e2.22 (2H, m, CH
2
CO),
and
2
),
1
.99e1.80 (2H, m, cyclohexyl-CH
cyclohexyl-CH ), 1.46e1.08 (14H, m, (CH
1.04e0.92 (3H, m, CH
2 3 2
), 1.79e1.54 (5H, m, CH CH
4
.3.2.2. (2S,3S)-3-[(tert-butoxycarbonyl)amino]-1-(cyclo-
hexylamino)-1-oxo-4-phenylbutan-2-yl 2-chloroacetate 14B.
M.p. 193e194 C; IR (solid) vmax(cm ): 3373 (NH), 3330 (NH),
065 (CeH), 2931 (CeH), 2854 (CeH), 1767 (C]O), 1682 (C]O),
2
3
)
3
C and cyclohexyl-CH
13
3
CH
2
); C NMR (75 MHz, CDCl 172.42,
3
) d
ꢀ
ꢂ1
171.70, 167.05 and 166.72 (C]O), 155.62 and 154.97 (Boc C]O),
137.35 (Ar-C), 129.29 (Ar-C), 128.49 (Ar-C), 126.61 (Ar-C), 79.48
3
1
1
(
650 (C]O), 1514 (C]C), 1167 (CeO), 736 (CeCl); H NMR
500 MHz, CDCl 7.33e7.25 (2H, m, Ar-H), 7.25e7.16 (3H, m, Ar-
H), 6.41 (0.6H, d, J ¼ 8.1 Hz, NH), 5.17 (1H, d, J ¼ 3.5 Hz, H-2), 4.92
0.3H, d, J ¼ 9.1 Hz, NH), 4.39e4.24 (1H, m, H-3), 4.18 (1H, d,
((CH
48.16 (cyclohexyl-CH), 38.10 and 37.41 (C-4), 36.02 and 35.91
(CH CO), 32.94 and 32.78 (cyclohexyl-CH ), 28.27 ((CH C), 25.45
and 24.72 (cyclohexyl-CH ), 18.41 and 18.33 (CH CH ), 13.66 and
: 447.2859,
3 3
) C), 74.05 and 73.48 (C-2), 53.36 and 52.90 (C-3), 48.25 and
3
) d
2
2
3 3
)
(
2
3
2
J ¼ 14.7 Hz, CHaHbCl), 4.12 (1H, d, J ¼ 14.7 Hz, CHaHbCl) 3.86e3.74
13.63 (CH
found (M þ H) : 447.2855.
3
CH
2
); HRMS (m/z), calculated for C25
H
39
N
2
O
5
þ
(
1H, m, cyclohexyl-CH), 3.05e2.82 (2H, m, H-4), 1.97e1.83 (2H, m,
Please cite this article in press as: Zimuwandeyi M, et al., PADAM reactions of a-aminoaldehydes: Identity of major and minor diastereomers
from the Passerini reaction, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.04.065

6
M. Zimuwandeyi et al. / Tetrahedron xxx (2018) 1e17
4
4
.3.5. 3-[(Tert-butoxycarbonyl)amino]-1-(cyclohexylamino)-1-oxo-
-phenylbutan-2-yl pivalate 17
Product 17 was isolated as a white solid (450 mg, 97%) that was
4.3.6.2. (2S,3S)-3-[(tert-butoxycarbonyl)amino]-1-(cyclo-
hexylamino)-1-oxo-4-phenylbutan-2-yl 3,3-dimethylbutanoate 18B.
ꢀ
ꢂ1
M.p. 169e170 C; IR vmax(cm ): 3290 (NH), 2930 (CeH), 1738 (C]
1
separated into diastereomers 17A and 17B.
O), 1690 (C]O), 1658 (C]O), 1532 (C]C), 1366 (CeO); H NMR
3
(500 MHz, CDCl ) d 7.32e7.25 (2H, m, Ar-H), 7.25e7.15 (3H, m, Ar-
H), 6.00 (1H, d, J ¼ 8.2 Hz, NH), 5.26e5.01 (2H, m, NH and H-2),
4
.3.5.1. (2R,3S)-3-[(tert-butoxycarbonyl)amino]-1-(cyclo-
hexylamino)-1-oxo-4-phenylbutan-2-yl pivalate 17A. M.p.
59e161 C; IR (solid) vmax(cm ): 3341 (NH), 3265 (NH), 3030
CeH), 2928 (CeH), 1732 (C]O), 1689 (C]O), 1653 (C]O), 1529
4
.31e4.19 (1H, m, H-3), 3.84e3.73 (1H, m, cyclohexyl-CH),
.99e2.71 (2H, m, H-4), 2.34e2.22 (2H, m, CH CO), 1.97e1.83 (3H,
), 1.75e1.65 (2H, m, cyclohexyl-CH ), 1.65e1.57
1H, m, cyclohexyl-CH C and
), 1.41e1.03 (23H, m, 2 ꢁ (CH
); C NMR (126 MHz, CDCl 171.18 and 166.78
2
2
ꢀ
ꢂ1
1
m, cyclohexyl-CH
2
2
(
(
(
2
3 3
)
1
3
C]C), 1185 (CeO); H NMR (500 MHz, CDCl ) d 7.30e7.24 (2H, m,
13
cyclohexyl-CH
2
3
) d
Ar-H), 7.23e7.12 (3H, m, Ar-H), 5.83 (1H, d, J ¼ 8.2 Hz, NH),
.25e5.07 (2H, m, NH and H-2), 4.37e4.21 (1H, m, H-3), 3.84e3.71
1H, m, cyclohexyl-CH), 2.90e2.74 (2H, m, H-4), 1.96e1.82 (2H, m,
cyclohexyl-CH ), 1.74e1.52 (3H, m, cyclohexyl-CH ), 1.42e1.06
); C NMR (126 MHz, CDCl
176.38 and 167.20 (C]O), 154.95 (Boc C]O), 137.25 (Ar-C), 129.30
C), 73.28 (C-
C), 37.98 (C-4), 32.87
C), 27.07 (piv (CH C), 25.41
(
C]O), 155.42 (Boc C]O), 137.42 (Ar-C), 129.18 (Ar-C), 128.51 (Ar-
C),126.61 (Ar-C), 79.41 (Boc (CH C), 73.85 (C-2), 53.37 (C-3), 48.21
cyclohexyl-CH), 47.81 ((CH CCH ), 38.76 (C-4), 32.89 (cyclo-
hexyl-CH ), 30.98 ((CH CCH ), 29.66 ((CH CCH ), 28.30
(CH C), 25.45, 24.73 and 24.71 (cyclohexyl-CH
calculated for C27
5
(
3 3
)
(
3
)
3
2
2
2
13
2
3
)
3
2
3
)
3
2
(
d
23H, m, 2 ꢁ (CH
3
)
3
C, cyclohexyl-CH
2
3
)
(
3
)
3
2
); HRMS (m/z),
þ
H
43
N
2
O
5
: 475.3172, found, (M þ H) : 475.3161.
(
3 3
Ar-C), 128.48 (Ar-C), 126.59 (Ar-C), 79.48 (Boc (CH )
2
), 53.08 (C-3), 48.07 (C-12), 38.87 (piv (CH
), 28.25 (Boc (CH
3 3
)
4
.3.7. 3-[(Tert-butoxycarbonyl)amino]-1-(cyclohexyl amino)-1-
(
cyclohexyl-CH
2
3
)
3
3 3
)
oxo-4-phenylbutan-2-yl 2-((tert-butoxycarbonyl)amino)-3-phenyl
propanoate 19
and 24.58 (cyclohexyl-CH
2
); HRMS (m/z), calculated for
þ
C
H
26 41
N
2
O
5
: 461.3015, found (M þ H) : 461.3008.
Product 19 was isolated as a white solid that was a mixture of
ꢂ1
diastereomers (1.25 g, 100%). IR vmax(cm ): 3348 (NH), 3029
4
.3.5.2. (2S,3S)-3-[(tert-butoxycarbonyl)amino]-1-(cyclo-
pivalate 17B. M.p.
80e181 C; IR vmax(cm ): 3323 (NH), 3065 (CeH), 2926 (CeH),
(CeH), 1752 (C]O), 1689 (C]O), 1653 (C]O), 1497 (C]C), 1454
1
hexylamino)-1-oxo-4-phenylbutan-2-yl
1
(C]C); H NMR (500 MHz, CDCl
3
)
d
7.45e6.98 (10H, m, Ar-H),
ꢀ
ꢂ1
6.97e6.80 (1H, m, NH), 5.49e4.81 (2H, m, H-2 and NH),
4.64e4.12 (2H, m, H-3 and CHNH), 3.81e3.64 (1H, m, cyclohexyl-
1
1736 (C]O), 1689 (C]O), 1659 (C]O), 1526 (C]C); H NMR
(
500 MHz, CDCl 7.33e7.25 (2H, m, Ar-H), 7.24e7.13 (3H, m, Ar-
3
)
d
CH), 3.24e2.95 (2H, m, H-4), 2.93e2.38 (2H, m, CH
(2H, m, cyclohexyl-CH 1.78e1.55 (3H, m, cyclohexyl-CH
1.51e1.02 (23H, m, 2 ꢁ (CH
(126 MHz, CDCl 171.14, 170.76, 167.00 and 166.17 (C]O), 155.71
2
Ph), 1.95e1.79
),
3 3 2
) C and cyclohexyl-CH ); C NMR
H), 5.97 (1H, d, J ¼ 8.3 Hz, NH), 5.27e5.01 (1H, m, H-2), 4.98 (1H,
d, J ¼ 9.4 Hz, NH), 4.34e4.19 (1H, m, H-3), 3.85e3.70 (1H, m,
cyclohexyl-CH), 3.02e2.69 (2H, m, H-4), 1.97e1.80 (2H, m, cyclo-
2
)
2
13
3
) d
hexyl-CH
2
), 1.74e1.65 (2H, m, cyclohexyl-CH
), 1.44e1.02 (23H, s, 2 ꢁ (CH
); C NMR (126 MHz, CDCl 177.05 and 166.83 (C]O), 155.35
Boc C]O),137.32 (Ar-C),129.31 (Ar-C),128.49 (Ar-C),126.62 (Ar-C),
2
), 1.65e1.52 (1H, m,
) C and cyclohexyl-
3 3
and 154.77 (Boc C]O), 137.49 (Ar-C), 135.45 (Ar-C), 129.42 (Ar-C),
129.24 (Ar-C), 129.08 (Ar-C), 129.02 (Ar-C), 128.43 (Ar-C), 128.41
(Ar-C), 128.24 (Ar-C), 127.59 (Ar-C), 126.54 (Ar-C), 126.35 (Ar-C),
cyclohexyl-CH
2
13
CH
2
3
) d
(
80.75 ((CH
and 52.60 (C-3 and cyclohexyl-CH), 48.68, 37.61 and 37.15 (2 ꢁ
CH Ph), 32.79, 32.64, 32.50 (cyclohexyl-CH ), 28.39 and 28.29 Boc
((CH C), 25.55, 25.51, 25.09 and 24.99 (cyclohexyl-CH
3 3 3 3
) C), 79.14 ((CH ) C), 75.91 and 74.11 (C-2), 55.74, 54.87
7
9.37 (Boc (CH
8.87 (piv (CH
C), 27.08 (piv (CH
HRMS (m/z), calculated for C26
3
)
3
C), 73.94 (C-2), 53.16 (C-3), 47.94 (cyclohexyl-CH),
C), 37.57 (C-4), 32.85 (cyclohexyl-CH ), 28.29 (Boc
C), 25.43 and 24.58 (cyclohexyl-CH );
3
3
)
3
2
2
2
(CH
3
)
3
3
)
3
2
3
)
3
2
); HRMS
: 624.3679, found, (M þ H) :
þ
þ
H
41
N
2
O
5
: 461.3015, found, (M þ H) :
(m/z), calculated for C35
624.3653.
H
50
N
3
O
7
4
61.3017.
4
.3.8. 3-[(Tert-butoxycarbonyl)amino]-1-((2,6-dimethylphenyl)
4
4
.3.6. 3-[(Tert-butoxycarbonyl)amino]-1-(cyclohexylamino)-1-oxo-
-phenylbutan-2-yl 3,3-dimethylbutanoate 18
amino)-1-oxo-4-phenylbutan-2-yl acetate 20
Product 20 was isolated as a yellow solid (534 mg, 99%) that was
separated into two diastereomers 20A and 20B.
Product 18 was isolated as a white solid (1.07 g, 94%) that was
separated into two diastereomers 18A and 18B.
4
.3.8.1. (2R,3S)-3-[(tert-butoxycarbonyl)amino]-1-((2,6-
4
.3.6.1. (2R,3S)-3-[(tert-butoxycarbonyl)amino]-1-(cyclo-
dimethylphenyl)amino)-1-oxo-4-phenylbutan-2-yl acetate 20A.
M.p. 176e177 C; IR vmax (cm ): 3314 (NH), 3256 (NH), 2918
ꢀ
ꢂ1
hexylamino)-1-oxo-4-phenylbutan-2-yl 3,3-dimethylbutanoate 18A.
ꢀ
ꢂ1
M.p. 162e163 C; IR (solid) vmax(cm ): 3328 NH), 3032 (CeH),
742 (C]O), 1727 (C]O), 1682 (C]O), 1652 (C]O), 1525 (C]C),
(CeH), 2849 (CeH), 1738 (C]O), 1692 (C]O), 1676 (C]O), 1514
1
1
(C]C); H NMR (500 MHz, CDCl
3
)
d
7.35e7.14 (5H, m, Ar-H),
1
1
169 (CeO); H NMR (500 MHz, CDCl
.16e7.06 (3H, m, Ar-H), 5.82 (1H, d, J ¼ 8.1 Hz, NH), 5.22e5.00
2H, m, NH and H-2), 4.26e4.16 (1H, m, H-3), 3.76e3.63 (1H, m,
cyclohexyl-CH), 2.83e2.65 (2H, m, H-4), 2.28e2.13 (2H, m, CH CO),
.89e1.75 (2H, m, cyclohexyl-CH ), 1.68e1.57 (2H, m, cyclohexyl-
CH ), 1.57e1.49 (1H, m, cyclohexyl-CH
), 1.37e0.93 (23H, m, 2 ꢁ
CH ); C NMR (126 MHz, CDCl 170.33
and 167.10 (C]O), 154.95 (Boc C]O), 137.38 (Ar-C), 129.30 (Ar-C),
28.45 (Ar-C), 126.53 (Ar-C), 79.42 (Boc (CH C), 73.43 (C-2), 52.96
C-3), 48.25 (cyclohexyl-CH), 47.51 ((CH CCH ), 37.93 (C-4), 32.95
and 32.77 (cyclohexyl-CH ), 30.95 ((CH CCH ), 29.64
(CH CCH ), 28.26 (Boc (CH C), 25.44 and 24.74 (cyclohexyl-
CH
3
)
d
7.22e7.16 (2H, m, Ar-H),
7.14e6.97 (3H, m, Ar-H), 5.40e5.18 (1H, m, H-2), 5.18e5.05 (1H,
m, NH), 4.54e4.38 (1H, m, H-3), 2.99e2.80 (2H, m, H-4), 2.26e2.09
7
(
13
(9H, m, 3 ꢁ CH
CDCl 169.37 and 166.42 (C]O), 154.97 (Boc C]O), 137.07 (Ar-C),
135.49 (Ar-C), 132.63 (Ar-C), 129.36 (Ar-C), 128.61 (Ar-C), 128.23
(Ar-C), 127.65 (Ar-C), 126.75 (Ar-C), 79.70 ((CH C), 74.14 (C-2),
53.19 (C-3), 38.56 (C-4), 28.26 ((CH C), 20.67 (CH
CO), 18.38 (2 ꢁ
ArCH ); HRMS (m/z), calculated for C25 : 441.2389, found,
(M þ H) : 441.2380.
3 3 3
), 1.43e1.10 (9H, m, (CH ) C); C NMR (126 MHz,
2
3
) d
1
2
2
2
3 3
)
13
(
3
)
3
C and cyclohexyl-CH
2
3
)
d
3
)
3
3
3
33 2 5
H N O
þ
1
(
3 3
)
3
)
3
2
2
3
)
3
2
4.3.8.2. (2S,3S)-3-[(tert-butoxycarbonyl)amino]-1-((2,6-
(
3
)
3
2
3
)
3
dimethylphenyl)amino)-1-oxo-4-phenylbutan-2-yl acetate 20B.
ꢀ
ꢂ1
2
); HRMS (m/z), calculated for C27
43
H N
2
O
5
: 475.3172, found,
M.p. 166e167 C; IR vmax (cm ): 3317 (NH), 3264 (NH), 3030
(CeH), 2920 (CeH), 1744 (C]O), 1690 (C]O), 1662 (C]O), 1527
þ
(
M þ H) : 475.3163.
Please cite this article in press as: Zimuwandeyi M, et al., PADAM reactions of
a-aminoaldehydes: Identity of major and minor diastereomers
from the Passerini reaction, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.04.065

M. Zimuwandeyi et al. / Tetrahedron xxx (2018) 1e17
7
1
(
C]C); H NMR (500 MHz, CDCl
3
)
d
7.52 (1H, s, NH), 7.33e7.17 (5H,
m, H-3), 3.09 (0.31H, dd, J ¼ 14.0, 5.4 Hz, H-4a), 2.99e2.52 (1.72H,
m, H-4a and 4b), 2.51e2.32 (2H, m, CH
CO), 2.24e2.01 (6H, m, 2 ꢁ
ArCH ), 1.80e1.60 (2H, m, CH CH ), 1.44e1.02 (9H, m, (CH C),
1.05e0.92 (3H, m, CH ); C NMR (75 MHz, CDCl 172.49,
172.04, 166.59 and 166.46 (C]O), 155.43 and 155.02 (Boc C]O),
137.38 (Ar-C), 137.17 (Ar-C), 135.51 (Ar-C), 135.27 (Ar-C), 132.91 (Ar-
C), 132.79 (Ar-C), 129.39 (Ar-C), 129.29 (Ar-C), 128.54 (Ar-C), 128.45
(Ar-C), 128.25 (Ar-C), 128.18 (Ar-C), 127.56 (Ar-C), 127.54 (Ar-C),
m, Ar-H), 7.15e7.01 (3H, m, Ar-H), 5.36 (1H, d, J ¼ 3.9 Hz, H-2), 4.95
2
(
6
2
1H, d, J ¼ 9.2 Hz, NH), 4.43e4.34 (1H, m, H-3), 3.13 (1H, dd, J ¼ 14.1,
3
3
2
3 3
)
1
3
.0 Hz, H-4a), 3.06e2.88 (1H, m, H-4b), 2.23 (6H, s, 2 ꢁ ArCH
3
),
C
3
CH
2
3
) d
1
3
.21e2.13 (3H, m, CH
3
CO), 1.36 and 1.26 (9H, 2 ꢁ s, (CH
3
)
3
C);
NMR (126 MHz, CDCl
O), 137.31 (Ar-C), 135.49 (Ar-C), 135.24 (Ar-C), 132.72 (Ar-C), 129.24
Ar-C), 128.64 (Ar-C), 128.54 (Ar-C), 128.33 (Ar-C), 128.26 (Ar-C),
27.67 (Ar-C), 126.77 (Ar-C), 126.68 (Ar-C), 79.68 ((CH C), 74.93
C-2), 53.44 (C-3), 37.39 (C-4), 28.25 ((CH C), 20.87 (CH CO),18.53
3
) d 169.85 and 166.29 (C]O), 155.52 (Boc C]
(
1
(
3
)
3
126.67 (Ar-C), 126.57 (Ar-C), 79.60 ((CH
53.29 (C-3), 38.53 and 37.43 (C-4), 35.96 and 35.81 (CH
((CH ), 13.65 (CH
C), 18.50, 18.37 and 18.28 (2 ꢁ ArCH
HRMS (m/z), calculated for C27
: 466.2702, found, (M þ H) :
69.2702.
3
)
3
C), 74.77 and 73.92 (C-2),
CO), 28.23
CH );
3
)
3
3
2
and 18.39 (2 ꢁ ArCH
3
); HRMS (m/z), calculated for C25
H N
33 2
O
5
:
3
)
3
3
3
2
þ
þ
4
41.2389, found, (M þ H) : 441.2376.
37 2 5
H N O
4
4.3.9. 3-[(Tert-butoxycarbonyl)amino]-1-((2,6-dimethyl phenyl)
amino)-1-oxo-4-phenylbutan-2-yl 2-chloroacetate 21
4.3.12. 3-[(Tert-butoxycarbonyl)amino]-1-((2,6-dimethyl phenyl)
amino)-1-oxo-4-phenylbutan-2-yl pivalate 24
Product 21 was isolated as a white solid (423 mg, 85%) as a
ꢂ1
1
.72:1 mixture of diastereomers. IR vmax(cm ): 3328 (NH), 3241
Product 24 was obtained as a white solid (575 mg, 99%) that was
ꢂ1
(
NH), 3027 (CeH), 2978 (CeH), 1759 (C]O), 1689 (C]O), 1663 (C]
a 1.88:1 mixture of diastereomers. IR vmax(cm ): 3348 (NH), 3266
1
O), 1522 (C]C), 762 (CeCl); H NMR (500 MHz, CDCl
3
)
d
7.82
(NH), 3029 (CeH), 2975 (CeH), 2931 (CeH), 1734 (C]O), 1690 (C]
1
(
(
4
0.26H, s) and 7.53 (0.45H, s, NH), 7.41e7.15 (5H, m, Ar-H), 7.14e6.91
3H, m, Ar-H), 5.46e5.22 (1H, m, H-2), 5.22e4.88 (1H, m, NH),
.60e4.35 (1H, m, H-3), 4.26e3.89 (2H, m, CH Cl), 3.23e2.62 (2H,
m, H-4), 2.24e2.06 (6H, m, 2 ꢁ ArCH ), 1.43e1.02 (9H, m, (CH C);
171.52, 171.24, 166.13, 165.98, 165.85
and 165.58 (C]O), 155.60 and 154.99 (Boc C]O), 137.06 (Ar-C),
36.88 (Ar-C), 135.53 (Ar-C), 135.24 (Ar-C), 135.18 (Ar-C), 132.70 (Ar-
C), 132.60 (Ar-C), 129.34 (Ar-C), 129.29 (Ar-C), 129.19 (Ar-C), 128.64
Ar-C), 128.55 (Ar-C), 128.52 (Ar-C), 128.32 (Ar-C), 128.24 (Ar-C),
28.10 (Ar-C), 127.72 (Ar-C), 127.69 (Ar-C), 126.82 (Ar-C), 126.73 (Ar-
C), 79.90 ((CH C), 76.46 and 75.51 (C-2), 55.84 and 53.09 (C-3),
0.65 and 40.35 (CH Cl), 28.24 ((CH
O), 1663 (C]O), 1522 (C]C), 1152; H NMR (300 MHz, CDCl
3
)
d
7.62
(0.56H, s) and 7.46 (0.31H, s, NH), 7.37e7.16 (5H, m, Ar-H),
7.15e6.97 (3H, m, Ar-H), 6.45e6.28 (0.28H, m, NH) 5.59e5.26
(1H, m, H-2), 5.20e5.00 (0.65H, m, NH), 4.53e4.32 (1H, m, H-3),
2
3
3 3
)
1
3
C NMR (126 MHz, CDCl
3
)
d
3.22e2.64 (2H, m, H-4), 2.32e2.06 (6H, m, 2 ꢁ ArCH
3
), 1.46e1.05
13
(18H, m, 2 ꢁ (CH
3 3 3
) C); C NMR (75 MHz, CDCl ) d 177.16, 176.76
1
and 166.59 (C]O), 155.40 (Boc C]O), 137.34 (Ar-C), 137.15 (Ar-C),
135.47 (Ar-C), 135.18 (Ar-C), 132.88 (Ar-C), 132.74 (Ar-C), 129.40 (Ar-
C), 129.28 (Ar-C), 128.59 (Ar-C), 128.49 (Ar-C), 128.29 (Ar-C), 128.22
(Ar-C), 127.61 (Ar-C), 127.58 (Ar-C), 126.73 (Ar-C), 126.62 (Ar-C),
(
1
3
)
3
79.68 (Boc (CH
53.55 and 53.42 (C-3), 38.96 (piv (CH
28.25 (Boc (CH
18.39 (2 ꢁ ArCH
83.2859, found, (M þ H) : 483.2857.
3
)
3
C), 79.45 (Boc (CH
3
)
3
C), 74.57 and 73.64 (C-2),
C), 38.36 and 37.68 (C-4),
C), 18.55 and
); HRMS (m/z), calculated for C28
4
2
3
)
3
C), 18.53 and 18.37 (2 ꢁ
3
)
3
ArCH
3
); HRMS (m/z), calculated for C25ClH32
N
2
O
4
: 475.2000, found,
3 3 3 3
) C), 27.19, 27.11 and 27.08 (piv (CH )
þ
(
M þ H) : 475.2006.
3
39 2 5
H N O :
þ
4
4.3.10. 3-[(Tert-butoxycarbonyl)amino]-1-((2,6-dimethyl phenyl)
amino)-1-oxo-4-phenylbutan-2-yl propionate 22
4.3.13. 3-[(Tert-butoxycarbonyl)amino]-1-((2,6-dimethyl phenyl)
Product 22 was obtained as a white solid (908 mg, 99%) that was
a 1.83:1 mixture of diastereomers. NMR analysis revealed the
presence of rotamers. IR vmax(cm ): 3328 (NH), 3296 (NH), 2976
amino)-1-oxo-4-phenylbutan-2-yl 3,3-dimethylbutanoate 25
Product 25 was obtained as a white solid (936 mg, 94%) that was
ꢂ1
ꢂ1
a 2.21:1 mixture of diastereomers. IR vmax(cm ): 3337 (NH), 3275
(
(
7
CeH), 2933 (CeH), 1736 (C]O), 1686 (C]O), 1667 (C]O), 1518
C]C); 1H NMR (500 MHz, CDCl
7.34e7.16 (5H, m, Ar-H),
.14e7.01 (3H, m, Ar-H), 5.43e5.28 (1H, m, H-2), 5.12 (0.57H, d,
(NH), 3030 (CeH), 2960 (CeH), 2868, 1737 (C]O), 1679 (C]O),
1
3
)
d
1522 (C]O); H NMR (500 MHz, CDCl
3
)
d
7.59 (0.3H, br-s, NH), 7.28
(0.2H, br-s, NH), 7.46e7.14 (5H, m, Ar-H), 7.14e7.00 (3H, m, Ar-H),
5.49 (0.2H, br-s, NH), 5.45e5.27 (1H, m, H-2), 5.11 (0.52H, d,
J ¼ 9.4 Hz, NH), 4.97 (0.31H, d, J ¼ 9.0 Hz, NH), 4.50e4.32 (1H, m, H-
J ¼ 9.5 Hz, NH), 4.99 (0.40H, d, J ¼ 9.3 Hz, NH), 4.52e4.35 (1H, m, H-
3
2
), 3.18e3.09 (0.54H, m, H-4a), 3.05e2.80 (1.5H, m, H-4a and H-4b),
.59e2.40 (2H, m, CH ), 1.40e1.15
CO), 2.25e2.10 (6H, m, 2 ꢁ ArCH
C and CH ); C NMR (126 MHz, CDCl 173.25,
72.84, 166.54 and 166.41 (C]O), 155.51 and 155.00 (Boc C]O),
2
3
3), 3.20e2.68 (2H, m, H-4), 2.52e2.31 (2H, m, CH
2
CO), 2.28e2.10
C), 1.16e1.03 (9H,
3 3 3
m, piv (CH ) C); C NMR (126 MHz, CDCl ) d 171.20, 170.66, 166.59
13
(
12H, m, (CH
3
)
3
3
CH
2
3
)
d
3 3 3
(6H, m, 2 ꢁ ArCH ), 1.47e1.17 (9H, m, Boc (CH )
13
1
1
37.34 (Ar-C), 137.11 (Ar-C), 135.50 (Ar-C), 135.23 (Ar-C), 132.78 (Ar-
and 166.45 (C]O), 155.40 and 154.98 (Boc C]O), 137.38 (Ar-C),
137.18 (Ar-C), 135.52 (Ar-C), 135.29 (Ar-C), 132.85 (Ar-C), 132.66 (Ar-
C), 129.38 (Ar-C), 129.24 (Ar-C), 128.61 (Ar-C), 128.53 (Ar-C), 128.31
(Ar-C), 128.25 (Ar-C), 127.65 (Ar-C), 127.61 (Ar-C), 126.73 (Ar-C),
C), 132.65 (Ar-C), 129.37 (Ar-C), 129.25 (Ar-C), 128.61 (Ar-C), 128.53
(
1
7
(
Ar-C), 128.32 (Ar-C), 128.25 (Ar-C), 127.66 (Ar-C), 127.64 (Ar-C),
26.75 (Ar-C), 126.66 (Ar-C), 79.74 and 79.64 ((CH C), 74.77 and
3.91 (C-2), 53.44 and 53.29 (C-3), 38.55 and 37.48 (C-4), 28.25
(CH C), 27.51 and 27.41 (CH ),
3 3
)
126.65 (Ar-C), 79.65 (Boc (CH
53.42 (C-3), 47.78 and 47.46 (CH
((CH C), 29.66, 29.59 and 29.64 ((CH
18.57 and 18.42 (2
3
)
3
C), 74.53 and 73.57 (C-2), 53.57 and
CO), 38.42 and 37.26 (C-4), 30.95
C), 28.26 (Boc (CH C),
3
)
3
2
CO), 18.54 and 18.39 (2 ꢁ ArCH
3
2
9
4
.10 and 8.94 (CH
3
CH
2
); HRMS (m/z), calculated for C26
H N
35 2
O
5
:
3
)
3
3
)
3
3 3
)
þ
55.2546, found, (M þ H) : 455.2541.
ꢁ
ArCH
3
); HRMS (m/z), calculated for
þ
C
29
H
41
N
2
O
5
: 497.3015, found, (M þ H) : 497.3015.
4.3.11. 3-[(Tert-butoxycarbonyl)amino]-1-((2,6-dimethyl phenyl)
amino)-1-oxo-4-phenylbutan-2-yl butyrate 23
Product 23 was obtained as a white solid (460 mg, 82%) that was
a 2.06:1 mixture of diastereomers. IR vmax(cm ): 3339 (NH), 3257
4.3.14. 3-[(Tert-butoxycarbonyl)amino]-1-((2,6-dimethylphenyl)
amino)-1-oxo-4-phenylbutan-2-yl 2-((tert-butoxycarbonyl)
amino)-3-phenylpropanoate 26
ꢂ1
(
NH), 3029 (CeH), 2932 (CeH), 1735 (C]O), 1712 (C]O), 1687 (C]
Product 26 was obtained as a white solid (630 mg, 49%) that was
1
ꢂ1
O), 1670 (C]O), 1654 (C]O), 1522 (C]C), 1390 (CeO); H NMR
(
(
5
a 1.75:1 mixture of diastereomers. IR vmax(cm ): 3354 (NH), 2980
1
300 MHz, CDCl
0.46H, s, NH), 7.33e7.13 (5H, m, Ar-H), 7.11e6.87 (3H, m, Ar-H),
.53e5.23 (1H, m, H-2), 5.21e5.00 (1H, m, NH), 4.54e4.29 (1H,
3
)
d
7.74 (0.29H, s, NH), 7.61 (0.16H, s, NH), 7.38
(CeH), 1748 (C]O), 1688 (C]O), 1518 (C]C), 1366 (CeO); H NMR
(500 MHz, DMSO)
d 9.39 (0.48H, s, NH), 9.25 (0.55H, s, NH), 7.52
(0.52H, d, J ¼ 8.4 Hz, NH), 7.46 (0.50H, d, J ¼ 8.2 Hz, NH), 7.39e7.27
Please cite this article in press as: Zimuwandeyi M, et al., PADAM reactions of
a-aminoaldehydes: Identity of major and minor diastereomers
from the Passerini reaction, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.04.065

8
M. Zimuwandeyi et al. / Tetrahedron xxx (2018) 1e17
(
(
(
5H, m, Ar-H), 7.27e7.16 (5H, m, Ar-H), 7.14e6.99 (3H, m, Ar-H), 6.86
3
NMR (500 MHz, CDCl ) d 7.33e7.26 (2H, m, Ar-H), 7.25e7.14 (3H, m,
0.56H, d, J ¼ 9.4 Hz, NH), 6.67 (0.51H, d, J ¼ 9.7 Hz, NH), 5.22e5.12
Ar-H), 5.73 (1H, s, NH), 5.29e5.17 (1H, m, NH), 5.16e5.06 (1H, m, H-
2), 4.39e4.30 (1H, m, H-3), 4.00 (2H, s, CH Cl), 2.85 (2H, d,
J ¼ 7.3 Hz, H-4), 2.07 (3H, s, 3 ꢁ adamantyl CH), 2.03e1.93 (6H, m,
3 ꢁ adamantyl CH ), 1.72e1.62 (6H, m, 3 ꢁ adamantyl CH ),
1.45e1.27 (9H, m, (CH 165.94 and
165.43 (C]O), 154.95 (Boc C]O), 137.20 (Ar-C), 129.23 (Ar-C),
128.55 (Ar-C), 126.67 (Ar-C), 79.66 ((CH C), 75.01 (C-2), 52.77 (C-
3), 52.58 (adamantyl C), 41.35 (CH ),
Cl), 40.43 (3 ꢁ adamantyl CH
0.64H, m) and 5.06e4.94 (0.65H, m, H-2), 4.63e4.55 (0.61H, m),
2
4
.55e4.46 (0.65H, m) and 4.43e4.23 (1H, m, H-3 and CH
.32e3.19 (1H, m, CHaHbPh), 3.07e2.79 (2H, m, H-4), 2.76e2.65
),
C); C NMR (126 MHz, DMSO)
172.04, 171.90, 166.28 and 166.23 (C]O), 156.25, 156.23 and
55.31 (Boc C]O), 138.56 (Ar-C), 138.25 (Ar-C), 138.16 (Ar-C), 137.95
Ar-C), 136.06 (Ar-C), 135.86 (Ar-C), 134.66 (Ar-C), 134.60 (Ar-C),
29.72 (Ar-C), 129.70 (Ar-C), 129.68 (Ar-C), 129.60 (Ar-C), 128.66
Ar-C), 128.56 (Ar-C), 128.21 (Ar-C), 128.08 (Ar-C), 127.31 (Ar-C),
27.25 (Ar-C),126.96 (Ar-C),126.89 (Ar-C),126.76 (Ar-C), 126.62 (Ar-
C), 79.06, 78.97 and 78.54 ((CH C), 76.19 and 74.98 (C-2), 55.74,
5.50, 53.50 and 53.23 (C-2 and CH NH), 38.50, 36.98, 36.64 and
5.72 (C-4 and CH Ph), 28.59 and 28.48 ((CH C), 18.56 and 18.44
: 646.3492,
2
NH),
3
2
2
13
(
1
1H, m, CHaHbPh), 2.16 (3H, s) and 2.14e2.03 (3H, m, 2 ꢁ ArCH
3
3 3 3
) C); C NMR (126 MHz, CDCl ) d
13
.39e1.24 (18H, m, 2 ꢁ (CH
3 3
)
d
3 3
)
1
(
1
(
2
2
38.09 (C-4), 36.23 (3 ꢁ adamantyl CH ), 29.38 (3 ꢁ adamantyl CH),
2
28.29 ((CH
505.2469, found (M þ H) : 505.2461.
3
)
3
C); HRMS (m/z), calculated for
C
27
H38ClN
2
O
5
:
þ
1
3
)
3
4.3.16.2. (2S,3S)-1-adamantan-1-ylamino-3-[(tert-butoxycarbonyl)
amino]-1-oxo-4-phenylbutan-2-yl-2-chloroacetate 28B. M.p.
80e81 C; IR vmax (cm ): 3285 (NH), 3064 (CeH), 1770 (C]O),
5
3
2
ꢀ
ꢂ1
1
2
3 3
)
(
2 ꢁ ArCH
3
); HRMS (m/z), calculated for C37
H
38
N
3
O
7
3
1725 (C]O), 745 (CeCl); H NMR (500 MHz, CDCl ) d 7.34e7.17 (5H,
þ
found (M þ H) : 646.3482.
m, Ar-H), 5.87 (1H, s, NH), 5.14e5.01 (1H, m, H-2), 4.90 (1H, d,
J ¼ 9.1 Hz, NH), 4.35e4.25 (1H, m, H-3), 4.15 (1H, d, J ¼ 14.8 Hz,
CHaHbCl), 4.09 (1H, d, J ¼ 14.8 Hz, CHaHbCl), 3.05e2.89 (2H, m, H-
4), 2.13e2.06 (3H, m, 3 ꢁ adamantyl CH), 2.06e1.97 (6H, m, 3 ꢁ
4
1
.3.15. 1-Adamantan-1-ylamino-3-[(tert-butoxycarbonyl) amino]-
-oxo-4-phenylbutan-2-yl acetate 27
Product 27 was isolated as a white solid (637 mg, 100%) that was
adamantyl CH
1.26 (9H, 2 ꢁ s, (CH
65.67 (C]O), 155.53 (Boc C]O), 137.18 (Ar-C), 129.17 (Ar-C),
128.55 (Ar-C), 126.72 (Ar-C), 79.68 ((CH C), 75.94 (C-2), 53.20 (C-
3), 52.53 (adamantyl C), 41.44 (adamantyl CH ), 40.70 (CH Cl), 37.10
(C-4), 36.24 (adamantyl CH ), 29.39 (adamantyl CH), 28.32
((CH C); HRMS (m/z), calculated for C27 38ClN : 505.2469,
found (M þ H) : 505.2469.
2
), 1.74e1.65 (6H, m, 3 ꢁ adamantyl CH
2
), 1.38 and
13
separated into two diastereomers 27A and 27B.
3 3 3
) C); C NMR (126 MHz, CDCl ) d 165.96 and
1
4
.3.15.1. (2R,3S)-1-adamantan-1-ylamino-3-[(tert-butoxycarbonyl)
3 3
)
ꢀ
amino]-1-oxo-4-phenylbutan-2-yl acetate 27A. M.p. 156e157 C; IR
v
2
2
ꢂ1
max (cm ): 3284 (NH), 3085 (CeH), 2908 (CeH),1719 (C]O),1693
2
1
(
C]O), 1655 (C]O), 1535 (C]C), 1365 (CeO); H NMR (500 MHz,
CDCl 7.31e7.25 (2H, m, Ar-H), 7.24e7.15 (3H, m, Ar-H), 5.60 (1H,
s, NH), 5.20 (1H, d, J ¼ 9.6 Hz, NH), 5.08e4.97 (1H, m, H-2),
3
)
3
H
2 5
O
þ
3
) d
4
.34e4.23 (1H, m, H-3), 2.82 (2H, d, J ¼ 7.3 Hz, H-4), 2.19e2.03 (6H,
4.3.17. 1-Adamantan-1-ylamino-3-[(tert-butoxycarbonyl) amino]-
1-oxo-4-phenylbutan-2-yl propionate 29
Product 29 was isolated as a white solid (594 mg, 100%) that was
separated into two diastereomers 29A and 29B.
m, CH
3
CO and 3 ꢁ adamantyl CH), 1.99 (6H, s, 3 ꢁ adamantyl CH
), 1.40e1.19 (9H, m, (CH C);
169.09 and 166.76 (C]O), 154.97 (Boc
2
),
1
.72e1.60 (6H, m, 3 ꢁ adamantyl CH
2
3
)
3
1
3
3
C NMR (126 MHz, CDCl ) d
C]O), 137.38 (Ar-C), 129.24 (Ar-C), 128.47 (Ar-C), 126.56 (Ar-C),
9.45 ((CH C), 73.77 (C-2), 52.91 (C-3), 52.35 (adamantyl C), 41.36
3 ꢁ adamantyl CH ), 36.24 (C-4), 29.38
3 ꢁ adamantyl CH), 28.29 ((CH
7
(
(
3
)
3
4.3.17.1. (2R,3S)-1-adamantan-1-ylamino-3-[(tert-butoxycarbonyl)
ꢀ
2
), 38.16 (3 ꢁ adamantyl CH
2
amino]-1-oxo-4-phenylbutan-2-yl propionate 29A. M.p. 117e118 C;
ꢂ1
3
)
3
C), 20.70 (CH
3
CO); HRMS (m/z),
IR vmax (cm ): 3386 (NH), 3290 (NH), 3088 (CeH), 2977 (CeH),
þ
calculated for C27
H
39
N
2
O
5
: 471.2859, found (M þ H) : 471.2856.
1718 (C]O), 1685 (C]O), 1656 (C]O), 1515 (C]C), 1364 (CeO),
1
1
127; H NMR (500 MHz, CDCl
3
)
d
7.33e7.24 (2H, m, Ar-H),
4
.3.15.2. (2S,3S)-1-adamantan-1-ylamino-3-[(tert-butoxycarbonyl)
7.24e7.11 (3H, m, Ar-H), 5.62 (1H, s, NH), 5.22 (1H, d, J ¼ 9.6 Hz,
ꢀ
amino]-1-oxo-4-phenylbutan-2-yl acetate 27B. M.p. 156e157 C; IR
NH), 5.11e5.00 (1H, m, H-2), 4.35e4.23 (1H, m, H-3), 2.82 (2H, d,
ꢂ1
(
solid) vmax (cm ): 3299 (NH), 3030 (CeH), 2915 (CeH), 1748 (C]
J ¼ 7.3 Hz, H-4), 2.47e2.26 (2H, m, CH
mantyl CH), 1.99 (6H, s, 3 ꢁ adamantyl CH
mantyl CH ), 1.40e1.04 (12H, m, (CH C and CH
(126 MHz, CDCl 172.40 and 166.95 (C]O), 154.95 (Boc C]O),
137.44 (Ar-C), 129.25 (Ar-C), 128.44 (Ar-C), 126.52 (Ar-C), 79.40
((CH C), 73.54 (C-2), 52.96 (C-3), 52.29 (adamantyl-C), 41.39
(adamantyl-CH ), 38.11 (C-4), 36.24 (adamantyl-CH ), 29.69 (ada-
mantyl-CH), 28.29 ((CH C), 27.38 (CH CH ), 9.05 (CH
2
CH
3
), 2.07 (3H, s, 3 ꢁ ada-
1
O), 1696 (C]O), 1669 (C]O), 1529 (C]C), 1123; H NMR (500 MHz,
CDCl 7.32e7.25 (2H, m, Ar-H), 7.24e7.16 (3H, m, Ar-H), 5.77 (1H,
s, NH), 5.22e5.04 (1H, m, H-2), 4.97e4.82 (1H, m, NH), 4.33e4.18
1H, m, H-3), 2.93 (2H, d, J ¼ 7.8 Hz, H-4), 2.20e2.05 (6H, m, CH CO
and 3 ꢁ adamantyl CH), 2.04e2.00 (6H, m, 3 ꢁ adamantyl CH ),
.73e1.60 (6H, m, 3 ꢁ adamantyl CH ), 1.42e1.20 (9H, m, (CH C);
169.90 and 166.59 (C]O), 155.56 (Boc
C]O), 137.44 (Ar-C), 129.17 (Ar-C), 128.49 (Ar-C) 126.60 (Ar-C),
9.45 ((CH C), 74.48 (C-2), 53.36 (C-3), 52.38 (adamantyl C), 41.43
3 ꢁ adamantyl CH ), 29.70
3 ꢁ adamantyl CH), 28.32 ((CH
2
), 1.67 (6H, s, 3 ꢁ ada-
13
3
)
d
2
3
)
3
2 3
CH ); C NMR
3
) d
(
3
2
3 3
)
1
2
3
)
3
2
2
1
3
C NMR (126 MHz, CDCl
3
)
d
3
)
3
2
3
2
CH
3
); HRMS
þ
(m/z), calculated for C28
41
H N
2
O
5
: 485.3015, found (M þ H) :
7
(
(
3
)
3
485.3007.
2
), 37.34 (C-4), 36.26 (3 ꢁ adamantyl CH
2
3
)
3
C), 20.91 (CH
3
CO); HRMS (m/z),
4.3.17.2. (2S,3S)-1-adamantan-1-ylamino-3-((tert-butoxycarbonyl)
amino)-1-oxo-4-phenylbutan-2-yl propionate 29B. M.p.
25e126 C; IR vmax (cm ): 3333 (NH), 2916 (CeH), 1747 (C]O),
þ
calculated for C27
H
39
N
2
O
5
: 471.2859, found (M þ H) : 471.2854.
ꢀ
ꢂ1
1
1
4
1
.3.16. 1-Adamantan-1-ylamino-3-[(tert-butoxycarbonyl) amino]-
-oxo-4-phenylbutan-2-yl- 2-chloroacetate 28
1692 (C]O), 1664 (C]O), 1523 (C]C), 1365 (CeO), 1103; H NMR
(500 MHz, CDCl 7.32e7.25 (2H, m, Ar-H), 7.25e7.17 (3H, m, Ar-
3
) d
Product 28 was isolated as a white solid (495 mg, 82%) that was
separated into two diastereomers 28A and 28B.
H), 5.75 (1H, s, NH), 5.06 (1H, d, J ¼ 9.1 Hz, NH), 5.00e4.92 (1H,
m, H-2), 4.30e4.19 (1H, m, H-3), 2.94 (2H, d, J ¼ 7.6 Hz, H-4),
2
.50e2.35 (2H, m, CH
2
CH
3
), 2.14e2.05 (3H, m, 3 ꢁ adamantyl-CH),
4
.3.16.1. (2R,3S)-1-adamantan-1-ylamino-3-[(tert-butoxycarbonyl)
amino]-1-oxo-4-phenylbutan-2-yl-2-chloroacetate 28A. M.p.
43e144 C; IR vmax (cm ): 3281 (NH), 3064 (CeH), 2907 (CeH),
2.05e1.94 (6H, m, 3 ꢁ adamantyl-CH
adamantyl-CH ), 1.45e1.10 (12H, m, (CH
(126 MHz, CDCl 173.19 and 166.70 (C]O), 155.52 (Boc C]O),
137.46 (Ar-C), 129.19 (Ar-C), 128.48 (Ar-C), 126.59 (Ar-C), 79.38
2
), 1.73e1.61 (6H, m, 3 ꢁ
13
2
3 3 2 3
) C and CH CH ); C NMR
ꢀ
ꢂ1
1
1
3
) d
1
725 (C]O), 1692 (C]O), 1654 (C]O), 1555 (C]C), 745 (CeCl); H
Please cite this article in press as: Zimuwandeyi M, et al., PADAM reactions of
a-aminoaldehydes: Identity of major and minor diastereomers
from the Passerini reaction, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.04.065

M. Zimuwandeyi et al. / Tetrahedron xxx (2018) 1e17
9
þ
(
(CH
3
)
3
C), 74.27 (C-2), 53.38 (C-3), 52.32 (adamantyl-C), 41.45
), 37.49 (C-4), 36.26 (adamantyl-CH ), 29.38 (ada-
C), 27.50 (CH CH ), 8.94 (CH
m/z), calculated for C28
calculated for C30
45
H N
2
O
5
: 513.3328, found (M þ H) : 513.3326.
(
adamantyl-CH
2
2
mantyl-CH), 28.32 ((CH
(
4
3
)
3
2
3
2
CH
3
); HRMS
4.3.19.2. (2S,3S)-1-adamantan-1-ylamino-3-((tert-butoxycarbonyl)
amino)-1-oxo-4-phenylbutan-2-yl pivalate 31B. M.p. 132e133 C;
IR vmax (cm ): 3342 (NH), 3306 (NH), 3031 (CeH), 2912 (CeH),
þ
ꢀ
H
41
N
2
O
5
: 485.3015, found (M þ H) :
ꢂ1
85.3011.
2
852 (CeH), 1734 (C]O), 1691 (C]O), 1663 (C]O), 1547 (C]C),
1
4
1
.3.18. 1-Adamantan-1-ylamino-3-[(tert-butoxycarbonyl) amino]-
-oxo-4-phenylbutan-2-yl butyrate 30
Product 30 was isolated as a white solid (522 mg, 87%) that was
3
1103; H NMR (500 MHz, CDCl ) d 7.33e7.16 (5H, m, Ar-H), 5.74 (1H,
s, NH), 4.99 (1H, d, J ¼ 9.4 Hz, NH), 4.97e4.90 (1H, m, H-2),
4.32e4.18 (1H, m, H-3), 3.02e2.87 (2H, m, H-4), 2.09 (3H, s, 3 ꢁ
separated into two diastereomers 30A and 30B.
adamantyl-CH), 2.00 (6H, s, 3 ꢁ adamantyl-CH ), 1.69 (6H, s, 3 ꢁ
2
13
adamantyl-CH
(126 MHz, CDCl
137.43 (Ar-C), 129.23 (Ar-C), 128.49 (Ar-C), 126.60 (Ar-C), 79.29 (Boc
(CH C), 74.07 (C-2), 53.27 (C-3), 52.21 (adamantyl-CH), 41.51
(adamantyl-CH ), 38.82 (piv (CH C), 37.73 (C-4), 36.26 (ada-
mantyl-CH ), 29.39 (adamantyl-CH), 28.34 (Boc (CH C), 27.04 (piv
: 513.3328, found
2
), 1.42e1.13 (18H, m, 2 ꢁ (CH
3
)
3
C);
C NMR
4
.3.18.1. (2R,3S)-1-adamantan-1-ylamino-3-[(tert-butoxycarbonyl)
3
) d
176.93 and 166.79 (C]O), 155.35 (Boc C]O),
ꢀ
amino]-1-oxo-4-phenylbutan-2-yl butyrate 30A. M.p. 108e109 C;
IR vmax (cm ): 3286 (NH), 3067 (CeH), 1710 (C]O), 1691 (C]O),
ꢂ1
3 3
)
1
1656 (C]O), 1529 (C]C), 1169; H NMR (500 MHz, CDCl
3
)
2
3 3
)
d
7.31e7.24 (2H, m, Ar-H), 7.23e7.13 (3H, m, Ar-H), 5.62 (1H, s, NH),
.21 (1H, d, J ¼ 9.6 Hz, NH), 5.11e5.02 (1H, m, H-2), 4.33e4.22 (1H,
CO),
.07 (3H, s, 3 ꢁ adamantyl-CH), 1.99 (6H, s, 3 ꢁ adamantyl-CH ),
CH ), 1.41e1.18 (9H,
C), 1.06e0.92 (3H, m, CH ); C NMR (126 MHz, CDCl
2
3 3
)
5
(CH
3
)
3
C); HRMS (m/z), calculated for C30
45
H N
2
O
5
þ
m, H-3), 2.82 (2H, d, J ¼ 7.4 Hz, H-4), 2.42e2.23 (2H, m, CH
2
(M þ H) : 513.3322.
2
2
1.76e1.60 (8H, m, CH
2
3
and 3 ꢁ adamantyl-CH
2
4.3.20. 1-Adamantan-1-ylamino-3-[(tert-butoxycarbonyl) amino]-
1-oxo-4-phenylbutan-2-yl 3,3-dimethylbutanoate 32
13
m, (CH
3
)
3
2
CH
3
3
)
d
171.57 and 166.99 (C]O), 154.93 (Boc C]O), 137.45 (Ar-C), 129.27
Ar-C), 128.44 (Ar-C), 126.51 (Ar-C), 79.38 ((CH C), 73.48 (C-2),
2.98 (C-3), 52.28 (adamantyl-C), 41.40 (adamantyl-CH ), 38.10 (C-
), 36.25 (adamantyl-CH ), 35.91 (CH CO), 29.38 (adamantyl-CH),
8.29 ((CH C), 18.38 (CH CH ), 13.70 (CH
Product 32 was isolated as a white solid (588 mg, 93%) that was
separated into two diastereomers 32A and 32B.
(
3 3
)
5
4
2
2
2
2
4.3.20.1. (2R,3S)-1-adamantan-1-ylamino-3-[(tert-butoxycarbonyl)
3
)
3
2
3
2
CH
3
); HRMS (m/z),
amino]-1-oxo-4-phenylbutan-2-yl
3,3-dimethylbutanoate
M.p. 150e151 C; IR vmax (cm ): 3405 (NH), 3302 (NH), 3029
CeH), 2909 (CeH), 2850 (CeH), 1735 (C]O), 1720 (C]O), 1656
32A.
þ
ꢀ
ꢂ1
calculated for C29
43
H N
2
O
5
: 499.3172, found (M þ H) : 499.3169.
(
1
4
.3.18.2. (2S,3S)-1-adamantan-1-ylamino-3-((tert-butoxycarbonyl)
3
(C]O), 1535 (C]C), 1123; H NMR (500 MHz, CDCl ) d 7.30e7.24
ꢀ
amino)-1-oxo-4-phenylbutan-2-yl butyrate 30B. M.p. 139e140 C;
IR vmax (cm ): 3316 (NH), 3063 (CeH), 2908 (CeH), 1745 (C]O),
1
d
(2H, m, Ar-H), 7.23e7.14 (3H, m, Ar-H), 5.66 (1H, s, NH), 5.22 (1H, d,
J ¼ 9.6 Hz, NH), 5.14e5.03 (1H, m, H-2), 4.34e4.18 (1H, m, H-3),
ꢂ1
1
693 (C]O), 1665 (C]O), 1523 (C]C); H NMR (500 MHz, CDCl
3
)
2.90e2.74 (2H, m, H-4), 2.21 (2H, s, CH
2
CO), 2.07 (3H, s, 3 ꢁ
), 1.74e1.61
), 1.41e1.18 (9H, m, Boc (CH C), 1.07
170.17 and
167.12 (C]O), 154.90 (Boc C]O), 137.53 (Ar-C), 129.31 (Ar-C),
128.43 (Ar-C), 126.49 (Ar-C), 79.33 (Boc (CH C), 73.50 (C-2), 53.04
(C-3), 52.32 (adamantyl-C), 47.57 (CH CO), 41.44 (adamantyl-CH ),
37.88 (C-4), 36.26 (adamantyl-CH ), 30.96 (t-butyl (CH C), 29.69
(t-butyl (CH C), 29.40 (adamantyl-CH), 28.30 (Boc (CH
7.32e7.25 (2H, m, Ar-H), 7.25e7.16 (3H, m, Ar-H), 5.73 (1H, s, NH),
.07 (1H, d, J ¼ 9.4 Hz, NH), 5.00e4.93 (1H, m, H-2), 4.31e4.19 (1H,
CO),
adamantyl-CH), 2.03e1.91 (6H, m, 3 ꢁ adamantyl-CH
2
5
(6H, m, 3 ꢁ adamantyl-CH
2
3 3
)
13
m, H-3), 2.93 (2H, d, J ¼ 7.5 Hz, H-4), 2.45e2.27 (2H, m, CH
2
3 3 3
(9H, s, t-butyl (CH ) C); C NMR (126 MHz, CDCl ) d
2
.12e2.05 (3H, m, 3 ꢁ adamantyl-CH), 2.05e1.95 (6H, m, 3 ꢁ ada-
mantyl-CH
.44e1.15 (9H, m, (CH
126 MHz, CDCl
37.45 (Ar-C), 129.19 (Ar-C), 128.49 (Ar-C), 126.60 (Ar-C), 79.36
(CH C), 74.14 (C-2), 53.36 (C-3), 52.32 (adamantyl-C), 41.44
adamantyl-CH ), 37.49 (C-4), 36.26 (adamantyl-CH ), 36.03
CH CO), 29.70 (adamantyl-CH), 28.32 ((CH C), 18.32 (CH CH ),
3.65 (CH CH ); HRMS (m/z), calculated for C29 : 499.3172,
found (M þ H) : 499.3169.
2
), 1.75e1.60 (8H, m, 3 ꢁ adamantyl-CH
2
and CH
2
CH
3
),
3 3
)
13
1
(
1
(
(
(
3
)
3
C), 1.04e0.93 (3H, m, CH
2
CH
3
); C NMR
2
2
3
)
d
172.42 and 166.70 (C]O), 155.48 (Boc C]O),
2
3 3
)
3
)
3
3
)
3
C);
þ
3
)
3
HRMS (m/z), calculated for C31
527.3484.
H
47
N
2
O
5
: 527.3485, found (M þ H) :
2
2
2
3
)
3
2
3
1
2
3
43
H N
2
O
5
4.3.20.2. (2S,3S)-1-adamantan-1-ylamino-3-[(tert-butoxycarbonyl)
amino]-1-oxo-4-phenylbutan-2-yl 3,3-dimethylbutanoate 32B.
þ
ꢀ
ꢂ1
M.p. 144e145 C; IR vmax (cm ): 3267 (NH), 3087 (CeH), 2908
1
4
1
.3.19. 1-Adamantan-1-ylamino-3-[(tert-butoxycarbonyl) amino]-
-oxo-4-phenylbutan-2-yl pivalate 31
(CeH), 1735 (C]O), 1700 (C]O), 1653 (C]O), 1563 (C]C); H NMR
3
(500 MHz, CDCl ) d 7.31e7.25 (2H, m, Ar-H), 7.25e7.16 (3H, m, Ar-
Product 31 was isolated as a white solid (564 mg, 92%) that was
separated into two diastereomers 31A and 31B.
H), 5.72 (1H, s, NH), 5.17 (1H, d, J ¼ 9.0 Hz, NH), 4.99e4.88 (1H, m,
H-2), 4.29e4.17 (1H, m, H-3), 2.93 (2H, d, J ¼ 7.6 Hz, H-4), 2.35e2.19
(
2H, m, CH
2
CO), 2.12e2.05 (3H, m, 3 ꢁ adamantyl-CH), 2.05e1.94
4
.3.19.1. (2R,3S)-1-adamantan-1-ylamino-3-[(tert-butoxycarbonyl)
(6H, m, 3 ꢁ adamantyl-CH
1.44e1.19 (9H, m, (Boc CH
NMR (126 MHz, CDCl
O), 137.50 (Ar-C), 129.18 (Ar-C), 128.52 (Ar-C), 126.61 (Ar-C), 79.29
(Boc (CH C), 73.92 (C-2), 53.42 (C-3), 52.37 (adamantyl-C), 47.88
(CH CO), 41.44 (adamantyl-CH ), 37.61 (C-4), 36.27 (adamantyl-
CH ), 31.00 (t-butyl (CH C), 29.70 (t-butyl (CH C), 29.39 (ada-
mantyl-CH), 28.35 (Boc (CH
2
),1.74e1.60 (6H, m, 3 ꢁ adamantyl-CH
2
),
ꢀ
13
amino]-1-oxo-4-phenylbutan-2-yl pivalate 31A. M.p. 147e148 C;
3
)
3
C), 1.05 (9H, s, t-butyl (CH
3
)
3
C);
C
ꢂ1
IR vmax (cm ): 3417 (NH), 3351 (NH), 3063 (CeH), 2964 (CeH),
742 (C]O), 1717 (C]O), 1677 (C]O), 1530 (C]C); H NMR
3
) d 171.23 and 166.77 (C]O), 155.44 (Boc C]
1
1
(
(
3
500 MHz, CDCl
3
)
d
7.31e7.11 (5H, m, Ar-H), 5.63 (1H, s, NH), 5.24
3 3
)
1H, d, J ¼ 9.7 Hz, NH), 5.18e5.03 (1H, m, H-2), 4.37e4.18 (1H, m, H-
2
2
), 2.89e2.73 (2H, m, H-4), 2.07 (3H, s, 3 ꢁ adamantyl-CH),1.99 (6H,
2
3
)
3
3 3
)
s, 3 ꢁ adamantyl-CH
18H, m, 2 ꢁ (CH
2
), 1.67 (6H, s, 3 ꢁ adamantyl-CH
2
d
), 1.40e1.15
176.09 and
3
)
3
C); HRMS (m/z), calculated for
13
þ
(
1
1
(
(
3
)
3
C); C NMR (126 MHz, CDCl
3
)
C
31 47
H N
2
O
5
: 527.3485, found (M þ H) : 527.3484.
67.27 (C]O), 154.91 (Boc C]O), 137.43 (Ar-C), 129.32 (Ar-C),
28.45 (Ar-C), 126.53 (Ar-C), 79.36 (Boc (CH C), 73.29 (C-2), 53.18
C-3), 52.22 (adamantyl-C), 41.48 (adamantyl-CH ), 38.79 (piv
CH C), 37.96 (C-4), 36.24 (adamantyl-CH ), 29.69 (adamantyl-
C), 27.05 (piv (CH C); HRMS (m/z),
3
)
3
4.3.21. 1-Adamantan-1-ylamino-3-((tert-butoxycarbonyl) amino)-
1-oxo-4-phenylbutan-2-yl 2-((tert-butoxycarbonyl)amino)-3-
phenyl propanoate 33
2
3
)
3
2
CH), 28.29 (Boc (CH
3
)
3
3
)
3
Product 33 was isolated as a white solid (632 mg, 78%) that was
Please cite this article in press as: Zimuwandeyi M, et al., PADAM reactions of
a-aminoaldehydes: Identity of major and minor diastereomers
from the Passerini reaction, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.04.065

10
M. Zimuwandeyi et al. / Tetrahedron xxx (2018) 1e17
separated into two diastereomers 33A and 33B.
.3.21.1. (2S)-(2R,3S)-1-adamantan-1-ylamino-3-((tert-butox-
(adamantyl-C), 41.23 (adamantyl-CH
CH Ph), 36.33 (adamantyl-CH ), 30.91 (adamantyl-CH), 29.44 and
28.35 (2 ꢁ (CH
2
), 38.02 and 37.35 (2 ꢁ
2
2
4
3
)
3
C); HRMS (m/z), calculated for C39
54
H N
3
O :
7
þ
ycarbonyl)
amino)-1-oxo-4-phenylbutan-2-yl-2-((tert-butox-
676.3962, found (M þ H) : 676.3973.
ꢀ
ycarbonyl) amino)-3-phenylpropanoate 33A. M.p. 80e81 C; IR
ꢂ1
v
max (cm ): 3342 (NH), 3029 (CeH), 2977 (CeH), 2909 (CeH),1753
4.3.22.2. (2R)-(2S,3S)-1-(adamantan-1-ylamino)-3-((tert-butox-
1
(
(
C]O),1692 (C]O), 1662 (C]O), 1496 (C]C), 1365 (CeO); H NMR
500 MHz, CDCl 7.41e7.00 (10H, m, Ar-H), 6.42e6.27 (1H, m,
ycarbonyl)amino)-1-oxo-4-
phenylbutan-2-yl
2-((tert-butox-
ꢀ
3
)
d
ycarbonyl)amino)-3-phenylpropanoate 34B. M.p. 102e104 C; IR
ꢂ1
NH), 5.22 (1H, d, J ¼ 9.9 Hz, NH), 5.14e5.02 (1H, m, H-2), 5.02e4.94
1H, m, NH), 4.37e4.25 and 4.25e4.12 (2H, 2 ꢁ m, 2 ꢁ CHNH),
.13e2.95 (2H, m, H-4), 2.61e2.47 and 2.35e2.25 (2H, 2 ꢁ m,
CH and 3 ꢁ adamantyl-
Ph) 2.12e1.94 (9H, m, 3 ꢁ adamantyl-CH
CH), 1.66 (6H, s, 3 ꢁ adamantyl-CH ), 1.49e1.10 (18H, m, 2 ꢁ
171.08 and 166.94 (C]O),
55.50 and 154.74 (Boc C]O), 137.51 (Ar-C), 135.51 (Ar-C), 129.39
Ar-C), 129.15 (Ar-C), 129.09 (Ar-C), 128.96 (Ar-C), 128.26 (Ar-C),
27.51 (Ar-C), 126.37 (Ar-C), 80.55 ((CH C), 79.15 ((CH C), 74.27
C-2), 55.50 and 52.80 (2 ꢁ CHNH), 52.52 (adamantyl-C), 41.17
adamantyl-CH Ph), 36.37 (adamantyl-
), 29.44 (adamantyl-CH), 28.32 and 28.25 (2 ꢁ (CH
m/z), calculated for C39
v
max (cm ): 3342 (NH), 2973 (CeH), 1760 (C]O), 1692 (C]O),
1
(
3
1654 (C]O), 1497 (C]C), 1163, 1056 (CeO); H NMR (300 MHz,
CDCl
3
)
d
7.42e7.03 (10H, m, Ar-H), 6.34 and 6.10 (1H, 2 ꢁ s, NH),
2
2
5.40e5.23 and 5.16e5.01 (2H, 2 ꢁ m, H-2 and NH), 4.57e4.36,
2
d
4.36e4.24 and 4.22e4.06 (3H, 3 ꢁ m, H-3, CHNH and NH),
13
(
CH
3
)
3
C); C NMR (126 MHz, CDCl
3
)
3.22e2.94 and 2.83e2.58 (4H, 2 ꢁ m, H-4 and CH
2
Ph), 2.04e2.00
1
(
(9H, m, 3 ꢁ adamantyl-CH
adamantyl-CH
), 1.49e1.29 (18H, m, 2 ꢁ (CH
(75 MHz, CDCl 171.51 and 166.11 (C]O), 155.77 and 154.99 (Boc
2
and 3 ꢁ adamantyl-CH), 1.67 (6H, s, 3 ꢁ
13
2
3 3
) C); C NMR
1
3
)
3
3
)
3
3
) d
(
(
CH
C]O), 137.60 (Ar-C), 135.79 (Ar-C), 129.39 (Ar-C), 129.14 (Ar-C),
128.96 (Ar-C), 128.44 (Ar-C), 127.48 (Ar-C), 126.44 (Ar-C), 80.53 and
2
), 37.73 and 37.27 (2 ꢁ CH
2
2
3
)
3
C); HRMS
79.40 (2 ꢁ (CH
(adamantyl-C), 41.22 (adamantyl-CH
CH Ph), 36.38 (adamantyl-CH ), 30.91 (adamantyl-CH), 29.46 and
8.26 (2 ꢁ (CH
3
)
3
C), 75.22 (C-2), 55.86 and 53.01 (2 ꢁ CHNH), 52.41
þ
(
54
H N
3
O
7
: 676.3962, found (M þ H) :
2
), 38.01 and 37.76 (2 ꢁ
6
76.3954.
2
2
2
3
)
3
C); HRMS (m/z), calculated for C39
54
H N
3
O :
7
þ
4
.3.21.2. (2S)-(2S,3S)-1-adamantan-1-ylamino-3-[(tert-butox-
676.3962, found (M þ H) : 676.3973.
ycarbonyl)
amino]-1-oxo-4-phenylbutan-2-yl-2-((tert-butox-
ꢀ
ycarbonyl) amino)-3-phenylpropanoate 33B. M.p. 132e133 C; IR
4.3.23. (5S,9S)-5,9-dibenzyl-3,13,13-trimethyl-4,7,11-trioxo-2,12-
dioxa-3,6,10-triazatetradecan-8-yl acetate 35
ꢂ1
v
max (cm ): 3343 (NH), 2908, 2851 (CeH), 1741 (C]O), 1690 (C]
1
O), 1657 (C]O), 1518 (C]C), 1344 (CeO); H NMR (500 MHz,
CDCl 7.39e7.09 (10H, m, Ar-H), 6.45e6.27 (m) and 5.98 (1H, s,
NH), 5.20e5.07 (1H, m, H-2), 5.02e4.76 (2H, m, 2 ꢁ NH), 4.61e4.49
1H, m) and 4.41e4.21 (1H, m, 2 ꢁ CHNH), 3.27e3.16 (1H, m, H-4a),
.16e2.99 (1H, m, H-4b), 2.97e2.85 (1H, m, CHaHbPh), 2.85e2.71
Product 35 was isolated as a white solid (283 mg, 45%) that was
ꢂ1
3
)
d
a 1.52:1 mixture of two diastereomers. IR vmax(cm ): 3354 (NH),
3029 (CeH), 2917 (CeH), 1747 (C]O), 1690 (C]O), 1654 (C]O),
1
(
3
1585 (C]C), 1366 (CeO); H NMR (300 MHz, CDCl
3
)
d
7.40e6.99
(10H, m, Ar-H), 6.92e6.57 (1H, m, NH), 5.43e4.95 (2H, m, NH and
H-2), 4.46e4.15 (2H, m, H-3 and CHNH), 3.83e3.58 (3H, m, CH O),
3.33e3.14 (3H, m, CH N), 3.14e2.39 (4H, m H-4 and CH Ph),
2.22e1.95 (3H, m, CH CO), 1.44e1.20 (9H, m, (CH C); C NMR
(126 MHz, CDCl 171.23, 170.88, 169.35, 168.92, 167.55 and 166.77
(
1H, m, CHaHbPh), 2.14e1.91 (9H, m, 3 ꢁ adamantyl-CH
2
and 3 ꢁ
3
adamantyl-CH), 1.74e1.60 (6H, m, 3 ꢁ adamantyl-CH
2
), 1.47e1.17
3
2
13
13
(
1
18H, m, 2 ꢁ (CH
3
)
3
C); C NMR (126 MHz, CDCl
3
)
d
170.72 and
3
3 3
)
66.07 (C]O), 155.35 (Boc C]O), 137.45 (Ar-C), 135.89 (Ar-C),
29.32 (Ar-C), 129.23 (Ar-C), 128.99 (Ar-C), 128.78 (Ar-C), 128.45
Ar-C), 128.28 (Ar-C), 127.20 (Ar-C), 126.56 (Ar-C), 80.29 and 79.50
2 ꢁ (CH C), 75.74 (C-2), 54.70 and 53.45 (2 ꢁ CHNH), 52.43
adamantyl-C), 41.30 (adamantyl-CH
), 37.50 and 36.64 (2 ꢁ
Ph), 36.31 (adamantyl-CH ), 29.42 (adamantyl-CH), 28.37 and
3
) d
1
(C]O), 155.40 and 154.84 (Boc C]O), 137.28 (Ar-C), 135.82 (Ar-C),
129.54 (Ar-C), 129.49 (Ar-C),129.33 (Ar-C),129.24 (Ar-C), 129.17 (Ar-
C), 128.77 (Ar-C), 128.58 (Ar-C), 128.46 (Ar-C), 128.43 (Ar-C), 128.36
(Ar-C), 127.14 (Ar-C), 127.04 (Ar-C), 126.53 (Ar-C), 126.48 (Ar-C),
(
(
(
3 3
)
2
CH
2
2
79.42 ((CH
52.66, 52.54, 50.08 and 49.83 (2 ꢁ CHNH), 38.69, 38.53, 37.91 and
36.96 (2 ꢁ CH Ph), 32.16 (CH N), 28.44 and 28.25 ((CH C), 20.86
and 20.55 (CH CO); HRMS (m/z), calculated for C28
528.2710, found (M þ H) : 528.2710.
3 3 3
) C), 74.35 and 73.68 (C-2), 61.77 and 61.66 (CH O),
2
6
8.26 (2 ꢁ (CH
3
)
3
C), HRMS (m/z), calculated for C39
H
54
N
3
O :
7
þ
76.3962, found (M þ H) : 676.3962.
2
3
3 3
)
3
38 3 7
H N O :
þ
4.3.22. 1-(Adamantan-1-ylamino)-3-((tert-butoxycarbonyl)
amino)-1- oxo-4-phenylbutan-2-yl 2-((tert-butoxycarbonyl)
amino)-3-phenylpropanoate 34
4.3.24. (5S,9S)-5,9-dibenzyl-3,13,13-trimethyl-4,7,11-trioxo-2,12-
Product 34 was isolated as a white solid (620 mg, 92%) that was
separated into two diastereomers 34A and 34B.
dioxa-3,6,10-triazatetradecan-8-yl propionate 36
Product 36 was isolated as a white solid (544 mg, 100%) that was
a 1.34:1 mixture of two diastereomers. IR vmax(cm ): 3372 (NH),
ꢂ1
4
.3.22.1. (2R)-(2R,3S)-1-(adamantan-1-ylamino)-3-((tert-butox-
3343 (NH), 3064 (CeH), 2979 (CeH),1738 (C]O),1691 (C]O),1656
1
ycarbonyl)amino)-1-oxo-4-
ycarbonyl)amino)-3-phenylpropanoate 34A. M.p. 192e195 C; IR
phenylbutan-2-yl
2-((tert-butox-
(C]O), 1639 (C]O), 1523 (C]C); H NMR (300 MHz, CDCl
3
)
ꢀ
d
7.48e6.69 (11H, m, Ar-H and NH), 5.49e4.98 (3H, m, NH, H-2 and
ꢂ1
vmax (cm ): 3275 (NH), 2967 (CeH),1747 (C]O),1721 (C]O),1689
3
CHNH), 4.58e4.15 (1H, m, H-3), 3.84e3.52 (3H, m, CH O), 3.41e2.10
1
(
C]O), 1644 (C]O), 1538, 1491 (C]C), 1163, 1056 (CeO); H NMR
300 MHz, CDCl 7.43e7.09 (10H, m, Ar-H), 6.10 (1H, s, NH),
.21e4.96 (2H, m, NH and H-2), 4.89e4.74 (1H, m, NH), 4.60e4.43
and 4.39e4.21 (2H, 2 ꢁ m, H-3 and CHNH), 3.27e2.94 and
.87e2.57 (4H, 2 ꢁ m, H-4 and CH Ph), 2.10e1.95 (9H, m, 3 ꢁ
adamantyl-CH
and 3 ꢁ adamantyl-CH), 1.66 (6H, s, 3 ꢁ adamantyl-
CH
), 1.53e1.22 (18H, m, 2 ꢁ (CH
170.26 and 166.59 (C]O), 155.65 and 154.84 (Boc C]O), 137.41
Ar-C), 135.79 (Ar-C), 129.33 (Ar-C), 129.16 (Ar-C), 128.95 (Ar-C),
28.44 (Ar-C), 127.40 (Ar-C), 126.53 (Ar-C), 80.51 and 79.42 (2 ꢁ
CH
C), 74.73 (C-2), 54.73 and 52.82 (2 ꢁ CHNH), 52.54
(9H, m, H-4, CH
2
Ph, CH
3
CH
2
and CH
3
N), 1.60e0.99 (12H, m, (CH
3 3
) C
1
3
(
5
3
)
d
and CH
3
CH
2
); C NMR (75 MHz, CDCl ) d
3
172.67, 172.37, 170.99,
167.75 and 166.95 (C]O), 155.34 and 154.90 (Boc C]O), 137.35 (Ar-
C), 136.30 (Ar-C), 135.86 (Ar-C), 135.27 (Ar-C), 129.52 (Ar-C), 129.48
(Ar-C), 129.31 (Ar-C), 129.26 (Ar-C), 129.19 (Ar-C), 128.74 (Ar-C),
128.54 (Ar-C),128.45 (Ar-C), 128.39 (Ar-C),128.31 (Ar-C),127.09 (Ar-
2
2
2
13
2
3
)
3
C); C NMR (75 MHz, CDCl
3
)
C), 126.96 (Ar-C), 126.48 (Ar-C), 126.43 (Ar-C), 79.36 ((CH
and 73.51 (C-2), 61.60 (CH O), 52.74 and 50.18 (C-3), 49.87 (CHNH),
38.69, 38.50, 37.98, 37.77 and 37.01 (2 ꢁ CH Ph), 32.16 (CH N),
28.23 ((CH C), 27.44 and 27.25 (CH CH ), 8.93 and 8.83 (CH CH );
HRMS (m/z), calculated for C29
: 542.2866, found (M þ H) :
3 3
) C), 74.19
d
3
(
1
(
2
3
3
)
3
3
2
3
2
þ
3
)
3
40 3 7
H N O
Please cite this article in press as: Zimuwandeyi M, et al., PADAM reactions of
a-aminoaldehydes: Identity of major and minor diastereomers
from the Passerini reaction, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.04.065

M. Zimuwandeyi et al. / Tetrahedron xxx (2018) 1e17
11
5
42.2868.
733.3815.
4
3
.3.25. 5,9-Dibenzyl-3,13,13-trimethyl-4,7,11-trioxo-2,12-dioxa-
,6,10-triazatetradecan-8-yl 2-[(tert-butoxycarbonyl)amino]-3-
4.3.26.2. (2R)-(5S,8S,9S)-5,9-dibenzyl-3,13,13-trimethyl-4,7,11-
trioxo-2,12-dioxa-3,6,10-
triazatetradecan-8-yl
2-[(tert-butox-
ꢀ
phenylpropanoate 37
Product 37 was obtained as a white solid (320 mg, 77%) that was
separated into two diastereomers 37A and 37B.
ycarbonyl)amino]-3-phenylpropanoate 38B. M.p. 70e71 C; IR
ꢂ1
v
max(cm ): 3317 (NH), 2973, 2940 (CeH), 1757, 1689 and 1656 (C]
1
3
O), 1497 (C]C), 1164, 1055 (CeO); H NMR (300 MHz, CDCl )
d
7.45e7.02 (15H, m, Ar-H), 5.49e4.77 and 4.61e4.11 (6H, 2 ꢁ m, 2 ꢁ
4
.3.25.1. (2S)-(5S,8R,9S)-5,9-dibenzyl-3,13,13-trimethyl-4,7,11-
NH, H-2, 3 ꢁ CHNH), 3.71e3.58 (3H, m, CH
3
O), 3.23e2.84,
Ph and CH N),
3 3 3
1.54e1.20 (18H, m, (CH ) C)); C NMR (75 MHz, CDCl ) d 171.15,
trioxo-2,12-dioxa-3,6,10-
triazatetradecan-8-yl
2-[(tert-butox-
2.82e2.60 and 2.59e2.40 (10H, 3 ꢁ m, NH, 3 ꢁ CH
2
3
ꢀ
13
ycarbonyl)amino]-3-phenylpropanoate 37A. M.p. 136e139 C; IR
ꢂ1
v
max(cm ): 3358 (NH), 2973, 2938 (CeH), 1755 (C]O), 1691 (C]
170.91 and 166.73 (C]O), 155.37 and 155.15 (Boc C]O), 137.37 (Ar-
C), 136.09 (Ar-C), 135.95 (Ar-C), 129.47 (Ar-C), 129.36 (Ar-C), 129.16
(Ar-C), 128.79 (Ar-C), 128.44 (Ar-C), 128.26 (Ar-C), 127.23 (Ar-C),
1
O), 1660 (C]O), 1527, 1497 (C]C), 1165 (CeO); H NMR (300 MHz,
CDCl 7.39e7.10 (15H, m, Ar-H), 5.32e5.15 (2H, m, H-2 and
CHNH), 5.12e5.00 (1H, m, NH), 4.98e4.90 (1H, m, NH), 4.48e4.35
and 4.29e4.13 (2H, 2 ꢁ m, 2 ꢁ CHNH), 3.62 (3H, s, CH O), 3.23e2.85
and 2.61e2.46 (10H, 2 ꢁ m, NH, 3 ꢁ CH Ph and CH N), 1.47e1.27
C)); C NMR (75 MHz, CDCl 171.20, 170.81
and 167.43 (C]O), 155.45 and 154.78 (Boc C]O), 137.39 (Ar-C),
36.48 (Ar-C),135.61 (Ar-C), 129.44 (Ar-C), 129.39 (Ar-C), 129.14 (Ar-
C), 128.91 (Ar-C), 128.39 (Ar-C), 128.34 (Ar-C), 127.41 (Ar-C), 126.83
Ar-C), 126.43 (Ar-C), 80.63 and 79.27 (2 ꢁ (CH C), 73.97 (C-2),
1.56 (CH
O), 55.22, 52.90 and 50.23 (3 ꢁ CHNH), 37.99, 37.71 and
7.40 (3 ꢁ CH Ph), 32.08 (CH N), 28.32 (2 ꢁ (CH C); HRMS (m/z),
calculated for C40
: 733.3813, found (M þ H) : 733.3802.
3
) d
126.93 (Ar-C), 126.40 (Ar-C), 80.47 and 79.45 (2 ꢁ (CH
3 3
) C), 75.05
3
(C-2), 61.57 (CH
3
O), 55.46, 52.66 and 50.29 (3 ꢁ CHNH), 38.01, 37.86
2
3
and 35.96 (3 ꢁ CH
2
Ph), 32.18 (CH
3
N), 28.32 (2 ꢁ (CH
3
)
3
C); HRMS
1
3
þ
(
18H, m, 2 ꢁ (CH
3
)
3
3
)
d
(m/z), calculated for C40
H
53
N
4
O
9
: 733.3813, found (M þ H) :
733.3815.
1
4.3.27. 5,9-Dibenzyl-3,13,13-trimethyl-4,7,11-trioxo-2,12-dioxa-
3,6,10-triazatetradecan-8-yl 2-[(tert-butoxycarbonyl)amino]-3-
phenylpropanoate 39
Product 39 was obtained as a white solid (170 mg, 50%) that was
separated into two diastereomers 39A and 39B.
(
6
3
3 3
)
3
2
3
3
)
3
þ
53 4 9
H N O
4
.3.25.2. (2S)-(5S,8S,9S)-5,9-dibenzyl-3,13,13-trimethyl-4,7,11-
4.3.27.1. (2S)-(5R,8R,9S)-5,9-dibenzyl-3,13,13-trimethyl-4,7,11-
trioxo-2,12-dioxa-3,6,10-
triazatetradecan-8-yl
2-[(tert-butox-
trioxo-2,12-dioxa-3,6,10-
triazatetradecan-8-yl
2-[(tert-butox-
ꢀ
ꢀ
ycarbonyl)amino]-3-phenylpropanoate 37B. M.p. 119e122 C; IR
ycarbonyl)amino]-3-phenylpropanoate 39A. M.p. 89e90 C; IR
ꢂ1
ꢂ1
v
max(cm ): 3357 (NH), 2971, 2939 (CeH),1756,1692 and 1659 (C]
v
max(cm ): 3349 (NH), 2972, 2940 (CeH), 1755, 1689 and 1656
1
1
O), 1519, 1497 (C]C), 1164 (CeO); H NMR (300 MHz, CDCl
3
)
3
(C]O), 1527, 1497 (C]C), 1164 (CeO); H NMR (300 MHz, CDCl )
d
7.45e6.99 (15H, m, Ar-H), 5.38e4.86 and 4.70e4.13 (6H, 2 ꢁ m, H-
d
7.46e6.99 (15H, m, Ar-H), 5.48e4.89 and 4.69e4.15 (6H, 2 ꢁ m,
2
2
, 2 ꢁ NH, 3 ꢁ CHNH), 3.81e3.55 (3H, m, CH
.75e2.46 (10H, 2 ꢁ m, NH, 3 ꢁ CH Ph and CH
C)); 13C NMR (75 MHz, CDCl
3
O), 3.30e2.76 and
2ꢁ NH, H-2 and 3 ꢁ CHNH), 3.76e3.56 (3H, m, CH
3
O), 3.29e2.83
N), 1.47e1.26
3 3 3
(18H, m, (CH ) C)); C NMR (75 MHz, CDCl ) d 171.15, 170.70 and
2
3
N), 1.50e1.20 (18H,
and 2.75e2.45 (10H, 2 ꢁ m, NH, 3 ꢁ CH
2 3
Ph and CH
13
m, 2 ꢁ (CH
3
)
3
3
)
d
171.15, 170.91 and
1
(
1
(
6
3
66.73 (C]O), 155.37 and 155.15 (Boc C]O), 137.37 (Ar-C), 136.09
Ar-C), 135.95 (Ar-C), 129.47 (Ar-C), 129.36 (Ar-C), 129.16 (Ar-C),
28.79 (Ar-C), 128.44 (Ar-C), 128.26 (Ar-C), 127.23 (Ar-C), 126.93
Ar-C), 126.40 (Ar-C), 80.47 and 79.45 (2 ꢁ (CH C), 75.05 (C-2),
1.57 (CH
5.96 (3 ꢁ CH
calculated for C40
167.00 (C]O), 155.43 and 154.74 (Boc C]O), 137.30 (Ar-C), 136.41
(Ar-C), 135.82 (Ar-C), 129.46 (Ar-C), 129.40 (Ar-C), 129.18 (Ar-C),
128.86 (Ar-C), 128.46 (Ar-C),128.33 (Ar-C), 127.21 (Ar-C),126.89 (Ar-
C), 126.38 (Ar-C), 80.57 and 79.38 (2 ꢁ (CH
(CH
(3 ꢁ CH
calculated for C40
3
)
3
3 3
) C), 74.04 (C-2), 61.58
3
O), 55.46, 52.66 and 50.29 (3 ꢁ CHNH), 38.01, 37.86 and
3
O), 55.15, 52.81 and 50.58 (3 ꢁ CHNH), 38.03, 37.68 and 37.36
2
Ph), 32.18 (CH
3
N), 28.32 (2 ꢁ (CH
3
)
3
C); HRMS (m/z),
2
Ph), 32.10 (CH
3
N), 28.35 (2 ꢁ (CH
3
)
3
C); HRMS (m/z),
þ
þ
53
H N
4
O
9
: 733.3813, found (M þ H) : 733.3802.
53
H N
4
O
9
: 733.3813, found (M þ H) : 733.3814.
4
3
.3.26. 5,9-Dibenzyl-3,13,13-trimethyl-4,7,11-trioxo-2,12-dioxa-
,6,10-triazatetradecan-8-yl 2-[(tert-butoxycarbonyl)amino]-3-
4.3.27.2. (2S)-(5R,8S,9S)-5,9-dibenzyl-3,13,13-trimethyl-4,7,11-
trioxo-2,12-dioxa-3,6,10-
triazatetradecan-8-yl
2-[(tert-butox-
ꢀ
phenylpropanoate 38
Product 38 was obtained as a white solid (410 mg, 98%) that was
separated into two diastereomers 38A and 38B.
ycarbonyl)amino]-3-phenylpropanoate 39B. M.p. 108e109 C; IR
ꢂ1
v
max(cm ): 3358 (NH), 2968, 2937 (CeH), 1755, 1691 and 1656
1
(C]O), 1526, 1497 (C]C), 1166 (CeO); H NMR (300 MHz, CDCl
7.38e7.09 (15H, m, Ar-H), 5.35e5.11 (2H, m, H-2 and CHNH),
5.11e5.00 (1H, m, NH), 4.99e4.87 (1H, m, NH), 4.52e4.32 and
4.30e4.10 (2H, 2 ꢁ m, 2 ꢁ CHNH), 3.62 (3H, s, CH O), 3.25e2.83 and
2.64e2.43 (10H, 2 ꢁ m, NH, 3 ꢁ CH Ph and CH N), 1.52e1.25 (18H,
C)); C NMR (75 MHz, CDCl 171.16, 170.66 and 167.37
3
)
d
4
.3.26.1. (2R)-(5S,8R,9S)-5,9-dibenzyl-3,13,13-trimethyl-4,7,11-
trioxo-2,12-dioxa-3,6,10-
ycarbonyl)amino]-3-phenylpropanoate 38A. M.p. 65e67 C; IR
triazatetradecan-8-yl
2-[(tert-butox-
3
ꢀ
2
3
ꢂ1
13
vmax(cm ): 3318 (NH), 2974, 2938 (CeH), 1746, 1690 and 1654 (C]
m, (CH
3
)
3
3
) d
1
O), 1497 (C]C), 1160 (CeO); H NMR (300 MHz, CDCl
3
)
d
7.43e6.96
(C]O), 155.57 and 154.83 (Boc C]O), 137.40 (Ar-C), 136.42 (Ar-C),
135.69 (Ar-C), 129.46 (Ar-C),129.39 (Ar-C), 129.18 (Ar-C), 128.86 (Ar-
C), 128.46 (Ar-C), 128.33 (Ar-C), 127.30 (Ar-C), 126.93 (Ar-C), 126.41
(
15H, m, Ar-H), 5.31e5.05 (2H, m, H-2 and CHNH), 4.98e4.72 (2H,
m, 2 ꢁ NH), 4.56e4.40 and 4.40e4.21 (2H, 2 ꢁ m, 2 ꢁ CHNH), 3.66
(
3H, s, CH
3
O), 3.21e2.83 and 2.74e2.60 (10H, 2 ꢁ m, NH, 3 ꢁ CH
2
Ph
(Ar-C), 80.56 and 79.39 (2 ꢁ (CH
3 3 3
) C), 74.19 (C-2), 61.56 (CH O),
13
and CH
3
N), 1.53e1.19 (18H, m, (CH
3
)
3
C)); C NMR (75 MHz, CDCl3)
55.14, 52.91 and 50.60 (3 ꢁ CHNH), 37.93, 37.81 and 37.52 (3 ꢁ
d
171.07, 170.41 and 167.40 (C]O), 155.59 and 154.77 (Boc C]O),
37.33 (Ar-C), 136.38 (Ar-C), 135.95 (Ar-C), 129.45 (Ar-C), 129.34 (Ar-
CH
2
Ph), 32.09 (CH
3
N), 28.35 (2 ꢁ (CH
3
)
3
C); HRMS (m/z), calculated
þ
1
for C40H
53
N
4
O
9
: 733.3813, found (M þ H) : 733.3814.
C), 129.18 (Ar-C), 128.86 (Ar-C), 128.44 (Ar-C), 128.39 (Ar-C), 127.24
Ar-C), 126.87 (Ar- C), 126.51 (Ar-C), 80.63 and 79.42 (2 ꢁ (CH C),
4.46 (C-2), 61.52 (CH
7.66 and 37.39 (3 ꢁ CH
m/z), calculated for C40
(
7
3
(
3
)
3
4.4. General procedure for the preparation of PADAM products
40e60
3
O), 54.66, 52.87 and 50.67 (3 ꢁ CHNH), 37.85,
2
Ph), 32.17 (CH
3
N), 28.35 ((CH
3
)
3
C); HRMS
þ
H
53
N
4
O
9
: 733.3813, found (M þ H) :
2 2
Passerini product (1 equivalent) was dissolved in CH Cl and TFA
Please cite this article in press as: Zimuwandeyi M, et al., PADAM reactions of
a-aminoaldehydes: Identity of major and minor diastereomers
from the Passerini reaction, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.04.065

12
M. Zimuwandeyi et al. / Tetrahedron xxx (2018) 1e17
(
10 equivalents) was added. The mixture was stirred at room
temperature for 3 h after which the solvent and most of the TFA
were removed in vacuo. The residue was redissolved in CH Cl and
Et N (10 equivalents) was added and the reaction stirred for 1 h at
CDCl
3
) 7.32e7.26 (3H, m, Ar-H), 7.25e7.10 (5H, m, Ar-H, 2 ꢁ NH and
OH), 4.34e4.25 (1H, m, H-3), 4.25e4.18 (1H, m, H-2), 3.96 (1H, d,
J ¼ 15.0 Hz, CHaHbCl), 3.90 (1H, d, J ¼ 15.0 Hz, CHaHbCl), 3.83e3.71
(1H, m, cyclohexyl-CH), 3.00e2.87 (2H, m, H-4), 1.94e1.83 (2H, m,
2
2
3
room temperature. Excess solvent was removed in vacuo and the
desired product was purified by column chromatography (49:1
cyclohexyl-CH
m, cyclohexyl-CH
(3H, m, cyclohexyl-CH
2
), 1.80e1.68 (2H, m, cyclohexyl-CH
2
), 1.68e1.58 (1H,
2
), 1.44e1.32 (2H, m, cyclohexyl-CH
2
), 1.28e1.14
13
CHCl
3
/MeOH).
2
); C NMR (126 MHz, CDCl
3
)
d
170.12 and
1
67.96 (C]O),137.30 (Ar-C),129.14 (Ar-C),128.67 (Ar-C),126.83 (Ar-
C), 73.32 and 73.23 (C-2), 56.81 and 56.72 (C-3), 48.27 and 48.16
(cyclohexyl-CH), 42.28 and 42.25 (CH Cl), 34.86 and 34.82 (C-4),
33.04, 33.01, 32.88, 32.85, 25.46 and 24.83 (cyclohexyl-CH
4.4.1. (2R,3S)-3-acetamido-N-cyclohexyl-2-hydroxy-4-
phenylbutanamide 40A
2
Product 40A was isolated as a white solid (59 mg, 84%).
2
); HRMS
ꢀ
ꢀ
ꢂ1
þ
M.p. ¼159 C-160 C; IR (solid) vmax(cm ): 3350 (OH), 3249 (NH),
(m/z), calculated for C18
353.1628.
H26ClN
2
O
3
: 353.1632, found, (M þ H) :
3
064 (CeH), 2931 (CeH), 2853 (CeH), 1689 (C]O), 1635 (C]O,
528 (C]C)); H NMR (300 MHz, CDCl ) d 7.40e7.09 (6H, m, Ar-H
3
1
1
and NH), 6.98 (1H, d, J ¼ 8.4 Hz) and 6.48 (1H, d, J ¼ 6.4 Hz, NH
and OH), 4.21e3.98 (2H, m, H-2 and H-3), 3.85e3.63 (1H, m,
cyclohexyl-CH), 3.12 (1H, dd, J ¼ 13.7, 6.0 Hz, H-4a), 3.01e2.75 (1H,
4.4.5. (2R,3S)eN-cyclohexyl-2-hydroxy-4-phenyl-3-
propionamidobutanamide 42A
Product 42A was isolated as a white solid (25 mg, 42%).
ꢀ
ꢂ1
m, H-4b), 1.97e1.78 (2H, m, cyclohexyl-CH
2
), 1.77e1.51 (3H, m,
M.p. ¼130 - 131 C; IR
nmax(cm ): 3347 (OH), 3322 (NH), 3236
1
3
cyclohexyl-CH
2
), 1.46e1.01 (5H, m, cyclohexyl-CH
2
); C NMR
(NH), 3065 (CeH), 2934 (CeH), 2855 (CeH), 1676 (C]O), 1626 (C]
O), 1526 (C]C); H NMR (300 MHz, CDCl ) d 7.34e7.14 (5H, m, Ar-
3
1
(
(
(
75 MHz, CDCl
3
)
d
172.29 and 171.94 (C]O), 138.24 (Ar-C), 129.15
Ar-C), 128.46 (Ar-C), 126.54 (Ar-C), 73.21 (C-2), 56.10 (C-3), 48.04
cyclohexyl-CH), 35.51 (C-4), 33.10, 32.57, 25.46 and 24.77 (cyclo-
H), 7.09e6.92 (2H, m, NH and OH), 6.57 (1H, d, J ¼ 6.7 Hz, NH),
4.18e4.04 (2H, m, H-2 and H-3), 3.80e3.63 (1H, m, cyclohexyl-CH),
3.11 (1H, dd, J ¼ 13.7, 6.0 Hz, H-4a), 3.03e2.88 (1H, m, H-4b), 2.08
hexyl-CH
2
), 22.90 (CH
3
CO); HRMS (m/z), calculated for C18
H N
27 2
O
3
:
þ
319.2022, found (M þ H) : 319.2014.
(2H, q, J ¼ 7.6 Hz, CH
3
CH
2
), 1.92e1.54 (5H, m, cyclohexyl-CH
2
),
);
176.08 and 171.96 (C]O), 138.27 (Ar-C),
1
.46e1.07 (5H, m, cyclohexyl-CH
2
), 1.01 (3H, t, J ¼ 7.6 Hz, CH
3 2
CH
1
3
4.4.2. (2S,3S)-3-acetamido-N-cyclohexyl-2-hydroxy-4-
C NMR (75 MHz, CDCl
3
)
d
phenylbutanamide 40B
129.19 (Ar-C), 128.42 (Ar-C), 126.52 (Ar-C), 73.41 (C-2), 55.92 (C-3),
48.03 (cyclohexyl-CH), 35.45 (C-4), 33.16 (cyclohexyl-CH ), 32.62
), 24.79
Product 40B was isolated as a white solid (36 mg, 95%).
2
ꢀ
ꢂ1
M.p. ¼ 238 - 239 C; IR
n
max(cm ): 3386 (OH), 3277 (NH), 3028
(cyclohexyl-CH
(cyclohexyl-CH
2
), 29.43 (CH
), 9.87 (CH
3
CH
2 2
), 25.44 (cyclohexyl-CH
1
(
(
7
CeH), 2918 (CeH), 2850 (CeH), 1645 (C]O), 1570 (C]C); H NMR
2
3
CH
2
); HRMS (m/z), calculated for
þ
300 MHz, MeOD)
.36e7.14 (5H, m, Ar-H), 4.56e4.43 (1H, m, H-3), 4.17 (1H, d,
J ¼ 3.5 Hz, H-2), 3.84e3.61 (1H, m, cyclohexyl-CH), 2.76 (2H, d,
and cyclohexyl-CH ),
), 1.57e1.11 (6H, m, cyclohexyl-
172.36 and 171.53 (C]O), 138.38
d
8.01 and 7.74 (1H, 2 ꢁ d, J ¼ 8.9, 8.4 Hz, NH),
C
19
H
29
N
2
O
3
: 333.2178, found (M þ H) : 333.2175.
4.4.6. (2S,3S)eN-cyclohexyl-2-hydroxy-4-phenyl-3-
propionamidobutanamide 42B
J ¼ 7.3 Hz, H-4), 1.98e1.73 (6H, m, CH
3
2
1
CH
.73e1.57 (1H, m, cyclohexyl-CH
2
d
Product 42B was isolated as a white solid (24 mg, 56%). M.p.
13
ꢀ
ꢂ1
2
); C NMR (75 MHz, MeOD)
154e155 C; IR vmax(cm ): 3390 (OH), 3297 (NH), 3151 (NH), 3029
(
(
3
Ar-C), 128.70 (Ar-C), 127.76 (Ar-C), 125.81 (Ar-C), (72.99 C-2), 53.93
C-3), ~48 (cyclohexyl-CH obscured by CD OD signal), 33.80 (C-4),
2.19, 25.08 and 24.60 (cyclohexyl-CH ), 20.97 (CH
z), calculated for C18
(CeH), 2978 (CeH), 2850 (CeH), 1657 (C]O), 1634 (C]O), 1518
1
3
(C]C); H NMR (300 MHz, DMSO)
d
7.59 (1H, d, J ¼ 8.8 Hz, NH or
2
3
CO); HRMS (m/
OH), 7.44 (1H, d, J ¼ 8.5 Hz, NH or OH) 7.25e7.01 (5H, m, Ar-H), 5.80
(1H, d, J ¼ 6.0 Hz, NH or OH), 4.28e4.16 (1H, m, H-3), 3.90e3.83 (1H,
m, H-2), 3.54 (1H, s, cyclohexyl-CH), 2.68e2.48 (2H, m, H-4), 1.92
þ
H N
27 2
O
3
: 319.2022, found (M þ H) : 319.2015.
4
.4.3. (2R,3S)-3-(2-chloroacetamido)-N-cyclohexyl-2-hydroxy-4-
phenylbutanamide 41A
Product 41A was isolated as a white solid (35 mg, 88%). M.p.
(2H, q, J ¼ 7.5 Hz, CH
1.55e1.36 (2H, m, cyclohexyl-CH
CH CH
), 0.79 (3H, t, J ¼ 7.6 Hz, CH
172.50 and 170.59 (C]O), 139.20 (Ar-C), 128.95 (Ar-C), 127.88 (Ar-
C), 125.77 (Ar-C), 73.24 (C-2), 53.05 (C-3), 47.16 (cyclohexyl-CH),
33.94 (C-4), 32.30 and 32.07 (cyclohexyl-CH ), 28.41 (CH CH ),
25.08 and 24.64 (cyclohexyl-CH ), 9.83 (CH CH ); HRMS (m/z),
calculated for C19
: 333.2178, found, (M þ H) : 333.2173.
3
CH
2
), 1.72e1.55 (3H, m, cyclohexyl-CH
2
),
2
), 1.31e1.13 (5H, m, cyclohexyl-
2
); C NMR (75 MHz, DMSO)
13
2
3
ꢀ
ꢂ1
169e170 C; IR (solid) vmax (cm ): 3404 (OH), 3298 (NH), 3032
d
1
(
(
CeH), 1661 (C]O), 1614 (C]O), 1529 (C]C), 892 (CeCl); H NMR
500 MHz, CDCl
3
)
d
7.69 (1H, d, J ¼ 9.0 Hz, NH), 7.31e7.23 (2H, m, Ar-
2
3
2
H), 7.23e7.15 (3H, m, Ar-H), 6.84 (1H, d, J ¼ 9.2 Hz, NH), 5.59 (1H, d,
J ¼ 6.0 Hz, OH), 4.39e4.24 (1H, m, H-3), 4.16e4.07 (1H, m, H-2),
2
3
2
þ
29 2 3
H N O
3
2
.83 (2H, s, CH Cl), 3.79e3.69 (1H, m, cyclohexyl-CH), 3.09 (1H, dd,
J ¼ 13.7, 5.8 Hz, H-4a), 2.84 (1H, dd, J ¼ 13.7, 9.3 Hz, H-4b), 1.91e1.80
2H, m, cyclohexyl-CH ), 1.77e1.66 (2H, m, cyclohexyl-CH ),
), 1.44e1.27 (2H, m, cyclohexyl-
4.4.7. (3S)-3-butyramido-N-cyclohexyl-2-hydroxy-4-phenyl
butanamide 43
(
1
2
2
.66e1.56 (1H, m, cyclohexyl-CH
2
Product 43 was isolated as a white solid (65 mg, 36%) that was a
13
ꢂ1
CH
CDCl
1
2
), 1.24e1.07 (3H, m, cyclohexyl-CH
171.25 and 167.23 (C]O), 137.60 (Ar-C), 129.19 (Ar-C),
28.50 (Ar-C), 126.69 (Ar-C), 72.21 (C-2), 55.38 (C-3), 48.10 (cyclo-
hexyl-CH), 42.30 (CH Cl), 35.63 (C-4), 33.11, 32.68, 25.39 and 24.78
2
); C NMR (126 MHz,
2.01:1 mixture of diastereomers. IR vmax(cm ): 3278 (OH), 2930
1
3
)
d
(CeH), 1642 (C]O), 1538 (C]C), 1124; H NMR (300 MHz, CDCl
3
)
d
7.34e7.15 (5H, m, Ar-H), 7.01 and 6.93 (1H, 2 ꢁ d, J ¼ 8.5, 8.4 Hz,
2
NH), 6.74 and 6.47 (1H, 2 ꢁ d, J ¼ 8.0, 6.9 Hz, NH), 6.24 and 6.07 (1H,
2 ꢁ d, J ¼ 6.7, 5.1 Hz, OH), 4.30e4.04 (2H, m, H-2 and H-3),
3.85e3.62 (1H, m, cyclohexyl-CH), 3.21e2.94 (2H, m, H-4),
(
3
cyclohexyl-CH
53.1632, found, (M þ H) : 353.1624.
2
); HRMS (m/z), calculated for
C
18
H26ClN
2
O
3
:
þ
2
CH
CH
.15e2.00 (2H, m, CH
2
CO), 1.98e1.44 (7H, m, cyclohexyl-CH
), 1.44e1.08 (5H, m, cyclohexyl-CH ), 0.94e0.78 (3H, m,
176.11, 175.28, 171.80 and
2
and
4.4.4. (2S,3S)-3-(2-chloroacetamido)-N-cyclohexyl-2-hydroxy-4-
3
CH
2
2
13
phenylbutanamide 41B
Product 41B was isolated as a white solid (20 mg, 90%). M.p.
3
CH
2
); C NMR (75 MHz, CDCl
3
)
d
170.86 (C]O), 138.19 (Ar-C), 137.86 (Ar-C), 129.20 (Ar-C), 128.62
(Ar-C), 128.47 (Ar-C), 126.71 (Ar-C), 126.57 (Ar-C), 74.93 and 73.55
(C-2), 57.72 and 56.06 (C-3), 48.04 and 47.96 (cyclohexyl-CH), 38.29
ꢀ
ꢂ1
2
(
10 C; IR vmax(cm ): 3399 (OH), 3280 (NH), 3028 (CeH), 1658
1
C]O), 1618 (C]O), 1540 (C]C), 893 (CeCl); H NMR (500 MHz,
Please cite this article in press as: Zimuwandeyi M, et al., PADAM reactions of
a-aminoaldehydes: Identity of major and minor diastereomers
from the Passerini reaction, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.04.065

M. Zimuwandeyi et al. / Tetrahedron xxx (2018) 1e17
13
1
and 38.13 (C-4), 35.72 and 35.57 (CH
5.46 and 24.80 (cyclohexyl-CH ), 19.07 (CH
CH CH ); HRMS (m/z), calculated for C20
M þ H) : 347.2330.
2
CO), 33.21, 33.15, 32.80, 32.69,
CH ), 13.63 and 13.56
: 347.2335, found
2859 (CeH), 1636 (C]O), 1535 (C]C); H NMR (500 MHz, DMSO)
d
2
(
(
2
3
2
7.59 (1H, d, J ¼ 8.7 Hz, NH), 7.50 (1H, d, J ¼ 8.4 Hz, NH), 7.25e7.19
3
2
H
31
N
2
O
3
(2H, m, Ar-H), 7.18e7.10 (3H, m, Ar-H), 5.83 (1H, d, J ¼ 5.8 Hz, OH),
4.40e4.31 (1H, m, H-3), 3.98e3.91 (1H, m, H-2), 3.61 (1H, s,
cyclohexyl-CH), 2.70e2.62 (1H, m, H-4a), 2.59e2.54 (1H, m, H-4b),
þ
4
.4.8. (2R,3S)eN-cyclohexyl-2-hydroxy-4-phenyl-3-
1.93e1.85 (2H, m, H-10), 1.78e1.61 (5H, m, cyclohexyl-CH
2
),
C); C NMR
171.16 and 170.94 (C]O), 139.68 (Ar-C), 129.47
(Ar-C), 128.37 (Ar-C), 126.27 (Ar-C), 73.86 (C-2), 53.50 (C-3), 49.15
(CH CO), 47.69 (cyclohexyl-CH), 34.28 (C-4), 32.81 and 32.59
13
pivalamidobutanamide 44A
2 3 3
1.35e1.06 (5H, m, cyclohexyl-CH ), 0.79 (9H, s, (CH )
Product 44A was isolated as a white solid (37 mg, 93%). M.p.
(126 MHz, DMSO)
d
ꢀ
ꢂ1
182e183 C; IR vmax(cm ): 3341 (OH), 3264 (NH), 3030 (CeH),
1
1
653 (C]O), 1619 (C]O), 1529 (C]C); H NMR (500 MHz, CDCl
7.36e7.21 (2H, m, Ar-H), 7.21e7.11 (3H, m, Ar-H), 6.97 (1H, d,
J ¼ 8.5 Hz, NH), 6.78 (1H, d, J ¼ 8.1 Hz, NH), 6.56 (1H, br s, OH),
.32e4.20 (1H, m, H-3), 4.09 (1H, s, H-2), 3.84e3.65 (1H, m,
cyclohexyl-CH), 3.10 (1H, dd, J ¼ 13.8, 5.7 Hz, H-4a), 3.02e2.93 (1H,
m, H-4b), 1.94e1.78 (2H, m, cyclohexyl-CH ), 1.77e1.65 (2H, m,
cyclohexyl-CH ), 1.65e1.52 (1H, m, cyclohexyl-CH ), 1.44e1.28 (3H,
m, cyclohexyl-CH ), 1.25e1.09 (2H, m, cyclohexyl-CH ), 1.08e0.92
180.65 and 171.82
C]O), 138.27 (Ar-C), 129.26 (Ar-C), 128.35 (Ar-C), 126.47 (Ar-C),
3
)
2
d
(cyclohexyl-CH
(cyclohexyl-CH
375.2648, found, (M þ H) : 375.2644.
2
3 3 3 3
), 30.74 ((CH ) C), 30.06 ((CH ) C), 25.59 and 25.22
2
); HRMS (m/z), calculated for
22 35 2 3
C H N O :
þ
4
2
4.4.12. (3S)-3-((S)-2-amino-3-phenylpropanamido)-N-cyclohexyl-
2-hydroxy-4-phenylbutanamide 46
Product 46 was isolated as a white solid (92 mg, 68%) that was a
mixture of diastereomers. IR (solid): 3381 (NH), 3297 (NH), 3269
2
2
2
2
13
(
3 3 3
9H, m, (CH ) C)); C NMR (126 MHz, CDCl ) d
(
7
(OH), 3027 (CeH), 2930 (CeH), 1671 (C]O), 1641 (C]O), 1629 (C]
1
3.62 (C-2), 55.49 (C-3), 47.96 (cyclohexyl-CH), 38.63 ((CH
3
)
3
C)),
O), 1523 (C]C), 1198 (CeO); H NMR (500 MHz, DMSO)
d
8.64
3
5.28 (C-4), 33.32 and 32.77 (cyclohexyl-CH ), 27.39 C-11, 27.18
2
(0.6H, d, J ¼ 8.8 Hz, NH) and 8.48 (0.4H, d, J ¼ 8.8 Hz, NH), 7.63
(0.6H, d, J ¼ 8.4 Hz, NH) and 7.49 (0.4H, d, J ¼ 8.3 Hz, NH), 7.35e7.09
(10H, m, Ar-H), 6.37 (0.4H, d, J ¼ 5.7 Hz, OH) and 6.24 (0.6H, d,
J ¼ 5.8 Hz, OH), 4.45e4.35 (0.6H, m, H-3) and 4.32e4.21 (0.4H, m,
(
(CH
3
)
3
C)), 25.45 and 24.84 (cyclohexyl-CH
2
); HRMS (m/z), calcu-
þ
lated for C21
H N
33 2
O
3
: 361.2491, found, (M þ H) : 361.2488.
4
.4.9. (2S,3S)eN-cyclohexyl-2-hydroxy-4-phenyl-3-pivalamido
butanamide 44B
Product 44B was isolated as a white solid (26 mg, 65%). M.p.
H-3), 4.08 (0.6H, dd, J ¼ 8.9, 4.0 Hz, CHNH
3.85e3.80 (0.4H, m, CHNH
(1H, m, cyclohexyl-CH), 2.97e2.57 (2H, m, CH
2
), 3.98e3.90 (1H, m, H-2),
), 3.67e3.31 (2H, m, H-4), 3.19e3.12
Ph), 2.51 (2H, s, NH ),
2
2
2
ꢀ
ꢂ1
123e125 C; IR vmax(cm ): 3303 (OH), 3029 (CeH), 2926 (CeH),
1.79e1.46 (5H, m, cyclohexyl-CH
2
), 1.37e1.01 (5H, m, cyclohexyl-
171.14,170.90,168.62 and 168.41
1
13
1644 (C]O), 1527 (C]C), 1152; H NMR (500 MHz, CDCl
3
)
CH
2
); C NMR (126 MHz, DMSO)
d
d
7.40e7.26 (2H, m, Ar-H), 7.24e7.13 (3H, m, Ar-H), 6.94 (1H, d,
(C]O), 139.35 (Ar-C), 138.98 (Ar-C), 135.68 (Ar-C), 135.66 (Ar-C),
130.00 (Ar-C), 129.95 (Ar-C), 129.70 (Ar-C), 129.45 (Ar-C), 128.93
(Ar-C), 128.90 (Ar-C), 128.83 (Ar-C), 128.62 (Ar-C), 127.48 (Ar-C),
126.73 (Ar-C), 126.48 (Ar-C), 73.40 and 70.45 (C-2), 54.23 and 54.12
J ¼ 8.5 Hz, NH), 6.14 (1H, br s, OH), 5.97 (1H, d, J ¼ 6.3 Hz, NH),
4
3
4
.26e4.18 (2H, m, H-2 and H-3), 3.84e3.69 (1H, m, cyclohexyl-CH),
.21 (1H, dd, J ¼ 14.1, 10.5 Hz, H-4a), 3.05 (1H, dd, J ¼ 14.0, 5.3 Hz, H-
b), 1.98e1.80 (2H, m, cyclohexyl-CH
2
), 1.77e1.65 (2H, m, cyclo-
(C-3), 53.83 (CHNH
37.82 (C-4), 37.34 and 34.40 (CH
25.21, 25.16 and 24.97 (cyclohexyl-CH
2
), 47.80 and 47.76 (cyclohexyl-CH), 37.93 and
hexyl-CH
cyclohexyl-CH
181.77 and 170.74 (C]O), 137.81 (Ar-C), 129.16 (Ar-C), 128.66 (Ar-
C), 126.78 (Ar-C), 75.20 (C-2), 57.58 (C-3), 47.91 (cyclohexyl-CH),
8.61 (CH C), 35.81 (C-4), 33.35 and 32.85 (cyclohexyl-CH ), 27.35
(CH C), 25.47 and 24.84 (cyclohexyl-CH
lated for C21
2
), 1.65e1.52 (1H, m, cyclohexyl-CH
2
), 1.44e1.09 (5H, m,
2
Ph), 32.77, 32.69, 32.49, 25.56,
13
2
), 1.03 (9H, s, (CH
3
)
3
C); C NMR (126 MHz, CDCl
3
)
2
); HRMS (m/z), calculated for
þ
d
C
25
H
34
N
3
O
3
: 424.2600 found, (M þ H) : 424.2597.
3
(
3
)
3
2
4.4.13. (2R,3S)-3-acetamido-N-(2,6-dimethylphenyl)-2-hydroxy-4-
phenylbutanamide 47A
3
)
3
2
); HRMS (m/z), calcu-
: 361.2491, found, (M þ H) : 361.2487.
þ
H N
33 2
O
3
Product 47A was isolated as a white solid (63 mg, 81%). M.p.
ꢀ
ꢂ1
2
38e248 C; IR vmax(cm ): 3064 (NH), 2924 (CeH), 2854 (CeH),
1
4
.4.10. (2R,3S)eN-cyclohexyl-3-(3,3-dimethylbutanamido)-2-
1658 (C]O), 1617 (C]O); H NMR (500 MHz, MeOD) d 7.25e7.17
hydroxy-4-phenylbutanamide 45A
(4H, m, Ar-H), 7.13e7.08 (1H, m, Ar-H), 7.00e6.93 (3H, m, Ar-H),
4.52e4.46 (2H, m, NH and H-3), 4.06 (1H, d, J ¼ 2.2 Hz, H-2), 2.89
Product 45A was isolated as a white solid (51 mg, 86%). M.p.
ꢀ
ꢂ1
1
29e130 C; IR vmax(cm ): 3274 (OH), 3088 (CeH), 2926 (CeH),
(1H, dd, J ¼ 13.4, 8.1 Hz, H-4a), 2.82 (1H, dd, J ¼ 13.3, 7.4 Hz, H-4b),
1
13
1
729 (C]O), 1643 (C]O), 1539 (C]C), 1256 (CeO); H NMR
500 MHz, CDCl
7.32e7.17 (5H, m, Ar-H), 6.89 (1H, d, J ¼ 8.3 Hz,
NH), 6.47 (1H, d, J ¼ 7.8 Hz, NH), 6.39 (1H, d, J ¼ 7.1 Hz, OH),
.27e4.13 (1H, m, H-3), 4.09e4.02 (1H, m, H-2), 3.77e3.64 (1H, m,
cyclohexyl-CH), 3.21e3.12 (1H, m, H-4a), 3.05 (1H, dd, J ¼ 13.8,
.1 Hz, H-4b), 1.98 (1H, d, J ¼ 13.0 Hz, CHaHbCO), 1.93 (1H, d,
),
), 1.47e1.00 (5H, m, cyclohexyl-
C); C NMR (126 MHz, CDCl 174.26 and
2.06 (6H, s, 2 ꢁ ArCH
3
), 1.80 (3H, s, CH
3
CO); C NMR (126 MHz,
(
3
)
d
MeOD)
133.65 (Ar-C), 129.13 (Ar-C), 128.07 (Ar-C), 127.63 (Ar-C), 127.01 (Ar-
C),126.14 (Ar-C), 71.31 (C-2), 53.74 (C-3), 37.64 (C-4), 21.39 (CH CO),
d 172.74 and 171.44 (C]O), 138.12 (Ar-C), 135.45 (Ar-C),
4
3
17.09 (2 ꢁ ArCH
3
); HRMS (m/z), calculated for C20
341.1865, found, (M þ H) : 341.1854.
25
H N
2
O
3
:
þ
9
J ¼ 13.0 Hz, CHaHbCO), 1.91e1.77 (1H, m, cyclohexyl-CH
2
1
CH
.76e1.64 (4H, m, cyclohexyl-CH
2
4.4.14. (2S,3S)-3-acetamido-N-(2,6-dimethylphenyl)-2-hydroxy-4-
phenylbutanamide 47B
13
2
), 0.92 (9H, s, (CH
3
)
3
3
)
d
1
(
71.78 (C]O), 138.05 (Ar-C), 129.22 (Ar-C), 128.54 (Ar-C), 126.63
Ar-C), 73.68 (C-2), 56.17 (C-3), 50.18 (CH CO), 48.13 (cyclohexyl-
CH), 35.64 (C-4), 33.03 and 32.75 (cyclohexyl-CH ), 30.71 ((CH C),
9.67 ((CH C), 25.44 and 24.77 (cyclohexyl-CH ); HRMS (m/z),
calculated for C22
: 375.2648, found, (M þ H) : 375.2640.
Product 47B was isolated as a white solid (21 mg, 70%). M.p.
ꢀ
ꢂ1
2
223e224 C; IR vmax(cm ): 3316 (OH), 2909 (CeH), 2851 (CeH),
1
2
3
)
3
1745 (C]O), 1694 (C]O), 1665 (C]O), 1524 (C]C); H NMR
2
3
)
3
2
(500 MHz, MeOD) d 7.34e7.15 (5H, m, Ar-H), 7.13e7.03 (3H, m, Ar-
þ
35
H N
2
O
3
H), 4.64e4.56 (2H, m, NH and H-3), 4.39 (1H, d, J ¼ 3.5 Hz, H-2),
3
.02e2.88 (2H, m, H-4), 2.25 and 2.17e2.15 (6H, 1 ꢁ s, 1 ꢁ m, 2 ꢁ
13
4.4.11. (2S,3S)eN-cyclohexyl-3-(3,3-dimethylbutanamido)-2-
ArCH
3
), 1.90 and 1.84 (3H, 2 ꢁ s, CH
3
CO); C NMR (126 MHz,
hydroxy-4-phenylbutanamide 45B
MeOD) d 172.74, 172.11, 171.76 and 171.44 (C]O), 138.44 (Ar-C),
Product 45B was isolated as a white solid (30 mg, 73%). M.p.
30e132 C; IR vmax(cm ): 3279 (OH), 3092 (NH), 2930 (CeH),
138.12 (Ar-C), 135.45 (Ar-C), 135.41 (Ar-C), 133.66 (Ar-C), 129.13 (Ar-
C), 128.80 (Ar-C), 128.07 (Ar-C), 127.91 (Ar-C), 127.74 (Ar-C), 127.63
ꢀ
ꢂ1
1
Please cite this article in press as: Zimuwandeyi M, et al., PADAM reactions of
a-aminoaldehydes: Identity of major and minor diastereomers
from the Passerini reaction, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.04.065

14
M. Zimuwandeyi et al. / Tetrahedron xxx (2018) 1e17
(
(
1
Ar-C), 127.04 (Ar-C), 126.14 (Ar-C), 125.97 (Ar-C), 73.58 and 71.31
C-2), 54.11 and 53.75 (C-3), 34.17 (C-4), 21.39 and 21.09 (CH CO),
7.29 and 17.09 (2 ArCH ); HRMS (m/z), calculated for
: 341.1865 found, (M þ H) : 341.1856.
ArCH
3
), 14.10 and 13.94 (CH
3
CH
2
); HRMS (m/z), calculated for
þ
3
C
22
H
29
N
2
O
3
: 369.2178, found (M þ H) : 369.2171.
ꢁ
3
þ
C
H
20 25
N
2
O
5
4.4.18. (3S)eN-(2,6-dimethylphenyl)-2-hydroxy-4-phenyl-3-
pivalamidobutanamide 51
4
.4.15. (3S)-3-(2-Chloroacetamido)-N-(2,6-dimethylphenyl)-2-
Product 51 was isolated as a cream solid (114 mg, 96%) which
was a 1.88:1 mixture of diastereomers. IR vmax(cm ): 3352 (OH),
ꢂ1
hydroxy-4-phenylbutanamide 48
Product 48 was isolated as a white solid (78 mg, 76%) that was a
.72:1 mixture of diastereomers. IR vmax(cm ): 3333 (OH), 3212
3238 (NH), 3028 (C]CeH), 2968 (CeH), 1654 (C]O), 1637 (C]O),
ꢂ1
1
1
1593 (C]C); H NMR (500 MHz, CDCl
3
)
d
8.54 (0.47H, s, NH), 8.49
(
NH), 3068 (CeH), 2973 (CeH), 1657 (C]O), 1648 (C]O), 1443 (C]
(0.53H, s, NH), 7.45e7.15 (5H, m, Ar-H), 7.15e6.87 (3H, m, Ar-H),
6.70e6.50, 6.35e6.20 and 5.53e5.02 (2H, 3 ꢁ m, NH and OH),
4.56e4.22 (2H, m, H-2 and H-3), 3.38e3.13 (1H, m, H-4a),
1
C), 768 (CeCl); H NMR (500 MHz, DMSO)
0.46H, s, NH), 8.23e8.17 (0.10H, m, NH) and 7.94 (0.31H, d,
J ¼ 9.3 Hz, NH), 7.31e7.07 (5H, m, Ar-H), 7.05e6.91 (3H, m, Ar-H),
.40 (0.48H, d, J ¼ 6.0 Hz, NH) and 6.24 (0.21H, d, J ¼ 6.1 Hz, NH)
NH, 4.38e4.29 (1H, m, H-3), 4.18e4.13 and 4.01e3.88 (3H, 2 ꢁ m, H-
and CH
d 9.31 (0.21H, s, NH), 9.08
(
3.12e2.81 (1H, m, H-4b), 2.30e2.03 (6H, m, 2 ꢁ ArCH
3
), 1.09e0.73
13
6
(9H, m, (CH ) C); C NMR (126 MHz, CDCl ) d 181.86, 180.97, 171.48
3 3 3
and 170.31 (C]O),138.10 (Ar-C), 137.92 (Ar-C), 134.98 (Ar-C), 134.96
(Ar-C), 133.23 (Ar-C), 133.18 (Ar-C), 129.34 (Ar-C), 129.28 (Ar-C),
129.16 (Ar-C),128.60 (Ar-C),128.58 (Ar-C),128.40 (Ar-C),128.23 (Ar-
C), 128.21 (Ar-C), 128.18 (Ar-C), 128.16 (Ar-C), 128.10 (Ar-C), 127.57
(Ar-C), 126.74 (Ar-C), 126.71 (Ar-C), 75.54 and 73.84 (C-2), 57.58 and
2
2
Cl), 2.85 (0.70H, dd, J ¼ 13.2, 7.8 Hz, H-4a), 2.78e2.74
(
2
d
0.54H, m, H-4b), 2.69 (0.66H, dd, J ¼ 13.2, 7.1 Hz, H-4a and H-4b),
1
3
.10 and 2.02 (6H, 2 ꢁ s, 2 ꢁ ArCH
3
); C NMR (126 MHz, DMSO)
170.94, 170.91, 170.87, 165.78, 165.61 and 165.54 (C]O), 139.27
(
1
Ar-C), 138.79 (Ar-C), 135.81 (Ar-C), 135.74 (Ar-C), 129.77 (Ar-C),
29.39 (Ar-C), 128.78 (Ar-C), 128.63 (Ar-C), 128.11 (Ar-C), 128.01 (Ar-
C), 126.95 (Ar-C), 126.92 (Ar-C), 126.76 (Ar-C), 126.56 (Ar-C), 73.72,
1.21 and 71.12 (C-2), 54.20, 54.09 and 54.06 (C-3), 43.13 and 43.09
55.57 (C-3), 38.68 and 38.66 ((CH
and 27.31 ((CH
C), 18.62 and 18.58 (2 ꢁ ArCH
calculated for C23
3 3
) C), 35.42 and 34.90 (C-4), 27.36
3
)
3
3
); HRMS (m/z),
þ
H
31
N
2
O
3
: 383.2335, found, (M þ H) : 383.2331.
7
(
CH
2
Cl), 37.87 and 34.53 (C-4), 18.73 and 18.58 (2 ꢁ ArCH
3
); HRMS
: 375.1475, found (M þ H) :
4.4.19. (3S)-3-(3,3-Dimethylbutanamido)-N-(2,6-dimethylphenyl)-
2-hydroxy-4-phenyl-butanamide 52
þ
(
m/z), calculated for C20ClH24
N
2
O
3
3
75.1469.
Product 52 was isolated as a white solid (325 mg, 91%) that was a
ꢂ1
2
.21:1 mixture of diastereomers. IR vmax(cm ): 3376 (OH), 3256
4
.4.16. (3S)eN-(2,6-dimethylphenyl)-2-hydroxy-4-phenyl-3-
(NH), 3062 (C]CeH), 2954 (CeH), 1660 (C]O), 1640 (C]O), 1520
(C]C), 1365 (CeO); H NMR (300 MHz, CDCl ) d 8.45 (0.72H, s, NH),
3
1
propionamidobutanamide 49
Product 49 was isolated as a cream solid (351 mg, 98%) which
8.25 (0.28H, s, NH), 7.47e7.15 (5H, m, Ar-H), 7.14e6.94 (3H, m, Ar-
H), 4.29e4.10 (1.4H, m) and 3.68e3.50 (0.30H, m, H-2 and H-3),
3.38 (0.74H, dd, J ¼ 13.7, 7.8 Hz) and 3.23e3.08 (0.46H, m) and 2.96
(0.76H, dd, J ¼ 13.8, 7.8 Hz) and 2.62 (0.29H, dd, J ¼ 13.6, 10.1 Hz, H-
ꢂ1
was a 1.83:1 mixture of diastereomers. IR vmax(cm ): 3318 (OH),
1
3
245 (NH), 3027 (CeH), 1664 (C]O), 1619 (C]O); H NMR
(
(
(
500 MHz, DMSO) d 9.29 (0.24H, s, NH), 9.10 (0.66H, s, NH), 7.77
0.23H, d, J ¼ 8.7 Hz, NH), 7.55 (0.71H, d, J ¼ 8.9 Hz, NH), 7.38e7.14
4), 2.29e2.08 (6H, m, 2 ꢁ ArCH ), 1.84 (1H, d, J ¼ 12.8 Hz,
3
5H, m, Ar-H), 7.13e6.98 (3H, m, Ar-H), 6.29 (0.66H, br s, OH),
CHaHbCO),1.76 (1H, d, J ¼ 12.8 Hz, CHaHbCO),1.10 and 0.85 (9H, 2 ꢁ
13
6
.24e6.14 (0.29H, m, OH), 4.45e4.30 (1H, m, H-3), 4.23e4.17
3 3 3
s, (CH ) C); C NMR (75 MHz, CDCl ) d 174.89, 171.91 and 171.28
(
2
CH
1
0.27H, m, H-2), 4.07e3.97 (0.74H, m, H-2), 2.96e2.74 (2H, m, H-4),
(C]O), 137.96 (Ar-C), 135.25 (Ar-C), 135.13 (Ar-C), 133.24 (Ar-C),
129.34 (Ar-C), 129.26 (Ar-C), 128.75 (Ar-C), 128.58 (Ar-C), 128.25
(Ar-C), 128.16 (Ar-C), 127.43 (Ar-C), 127.28 (Ar-C), 126.76 (Ar-C),
126.67 (Ar-C), 75.87 and 73.67 (C-2), 56.59 and 53.86 (C-3), 49.82
.12e1.99 (8H, m, CH
3
CH
2
and 2 ꢁ ArCH
3
), 0.96e0.84 (3H, m,
173.18, 173.02, 171.21 and
13
3
CH
2
); C NMR (126 MHz, DMSO) d
71.10 (C]O),139.79 (Ar-C),139.29 (Ar-C),135.77 (Ar-C),135.73 (Ar-
C), 129.77 (Ar-C), 129.46 (Ar-C), 128.65 (Ar-C), 128.46 (Ar-C), 128.07
and 47.80 (CH
((CH C), 29.69, 29.64 and 29.52 ((CH
(2 ꢁ ArCH ); HRMS (m/z), calculated for C24
found, (M þ H) : 399.2486.
2
CO), 39.71 and 35.57 (C-4), 30.99 and 30.80
C), 18.74, 18.53 and 18.41
: 399.2491,
(
(
Ar-C), 127.98 (Ar-C), 126.84 (Ar-C), 126.57 (Ar-C), 74.30 and 71.94
C-2), 53.70 (C-3), 46.23 (C-10), 37.96 and 34.68 (C-4), 28.96 and
3
)
3
3 3
)
3
33 2 3
H N O
þ
2
8.93 (CH
3
CH
2
), 18.71 and 18.52 (2 ꢁ ArCH
3
), 10.35 and 10.14
: 355.2022,
(CH
3
CH
2
); HRMS (m/z), calculated for C21
H
27
N
2
O
3
þ
found, (M þ H) : 355.2019.
4.4.20. (3S)-3-((S)-2-amino-3-phenylpropanamido)-N-(2,6-
dimethylphenyl)-2-hydroxy-4-phenylbutanamide 53
4
.4.17. (3S)-3-Butyramido-N-(2,6-dimethylphenyl)-2-hydroxy-4-
Product 53 was isolated as a white solid (320 mg, 92%) that was
ꢂ1
phenylbutanamide 50
a 1.75:1 mixture of diastereomers. IR vmax(cm ): 3308 (OH), 3031
1
Product 50 was isolated as a white solid (58 mg, 74%) that was a
(CeH), 2906 (CeH), 1654 (C]O), 1518 (C]C), 1359 (CeO); H NMR
ꢂ1
2
.06:1 mixture of diastereomers. IR vmax(cm ): 3264 (NH), 3028
(300 MHz, DMSO) d 9.37 (0.55H, s, NH), 9.20 (0.49H, s, NH), 8.03
1
(
(
(
(
(
CeH), 2960 (NH), 1662 (C]O), 1649 (C]O), 1375 (CeO); H NMR
500 MHz, DMSO) 9.30 (0.79H, s, NH), 9.11 (0.26H, s, NH), 7.79
0.72H, d, J ¼ 8.8 Hz, NH), 7.56 (0.26H, d, J ¼ 8.9 Hz, NH), 7.36e7.13
5H, m, Ar-H), 7.12e7.00 (3H, m, Ar-H), 6.25 (1H, s, OH), 4.49e4.32
1H, m, H-3), 4.20 (0.72H, d, J ¼ 3.3 Hz, H-2), 4.03 (0.26H, d,
(0.39H, d, J ¼ 9.4 Hz, NH), 7.94 (0.56H, d, J ¼ 9.2 Hz, NH), 7.43e7.11
(10H, m, Ar-H), 7.10e6.98 (3H, m, Ar-H), 6.47 (0.48H, d, J ¼ 5.6 Hz,
OH), 6.27 (0.57H, d, J ¼ 5.8 Hz, OH), 4.57e4.32 (1H, m, H-3),
4.27e4.13 and 4.09e3.99 (1H, 2 ꢁ m, H-2), 3.01e2.66 and
d
2.48e2.30 (4H, 2 ꢁ m, H-4 and CH
2
Ph), 2.18 and 2.08 (6H, 2 ꢁ s,
13
J ¼ 2.5 Hz, H-2), 2.96e2.75 (2H, m, H-4), 2.18 and 2.10 (6H, 2 ꢁ s, 2 ꢁ
ArCH
3
), 1.63 (2H, br s, NH
2
); C NMR (75 MHz, DMSO) 173.83,
d
ArCH
and 0.72 (3H, 2 ꢁ t, J ¼ 7.4 Hz, CH
172.22, 172.18, 171.20 and 171.12 (C]O), 139.78 (Ar-C), 139.28 (Ar-
C), 135.76 (Ar-C), 135.73 (Ar-C), 135.50 (Ar-C), 135.35 (Ar-C), 129.75
Ar-C), 129.44 (Ar-C), 128.64 (Ar-C), 128.44 (Ar-C), 128.07 (Ar-C),
27.98 (Ar-C),126.84 (Ar-C),126.82 (Ar-C),126.55 (Ar-C),126.33 (Ar-
C), 74.46 and 71.96 (C-2), 53.72 and 53.67 (C-3), 37.92 and 37.80 (C-
), 34.60 (CH CO), 19.07 and 18.96 (CH CH
), 18.71 and 18.55 (2 ꢁ
3
), 2.08e1.96 (2H, m, CH
2
CO), 1.50e1.35 (2H, m, CH
3
CH
2
), 0.79
173.31, 170.68 and 170.43 (C]O), 138.75 (Ar-C), 138.51 (Ar-C),
135.30 (Ar-C), 135.22 (Ar-C), 134.89 (Ar-C), 129.34 (Ar-C), 129.29
(Ar-C), 129.17 (Ar-C), 129.09 (Ar-C), 128.22 (Ar-C), 128.12 (Ar-C),
128.08 (Ar-C), 128.04 (Ar-C), 127.59 (Ar-C),127.44 (Ar-C), 126.39 (Ar-
C), 126.00 (Ar-C), 73.46 and 70.72 (C-2), 56.21, 55.99 and 52.64 (C-3
13
3
CH ); C NMR (126 MHz, DMSO)
2
d
(
1
and CHNH
2
), 37.61 and 34.48 (C-4 and CH
2
Ph), 18.21 and 18.04 (2 ꢁ
ArCH
3
); HRMS (m/z), calculated for C27
H
32
N
3
O
3
: 446.2444, found
þ
4
2
3
2
(M þ H) : 446.2441.
Please cite this article in press as: Zimuwandeyi M, et al., PADAM reactions of
a-aminoaldehydes: Identity of major and minor diastereomers
from the Passerini reaction, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.04.065

M. Zimuwandeyi et al. / Tetrahedron xxx (2018) 1e17
15
4
.4.21. (2R,3S)-3-acetamido-N-adamantan-1-yl-2-hydroxy-4-
126.82 (Ar-C), 73.97 (C-2), 57.41 (C-3), 51.94 (3 ꢁ adamantyl-C),
42.29 (CH
phenyl butanamide 54A
2
Cl), 41.51 (3 ꢁ adamantyl-CH ), 36.27 (3 ꢁ adamantyl-
2
Product 54A was obtained as a white solid (51 mg, 93%). M.p.
CH
2
), 35.40 (C-4), 29.39 (3 ꢁ adamantyl-CH); HRMS (m/z), calcu-
ꢀ
ꢂ1
þ
196e197 C; IR vmax(cm ): 3345 (OH), 3314 (NH), 3031 (CeH),
lated for C22
H30ClN
2
O
3
: 405.1945, found (M þ H) : 405.1945.
1
2
904 (CeH), 2849 (CeH), 1641 (C]O), 1540 (C]C), 1312 (CeO); H
NMR (300 MHz, CDCl 7.34e7.15 (5H, m, Ar-H), 7.05 (1H, d,
J ¼ 8.2 Hz, NH), 6.72 (1H, s, OH), 6.34 (1H, d, J ¼ 6.8 Hz, NH),
.14e4.01 (1H, m, H-3), 3.97 (1H, dd, J ¼ 6.8, 3.4 Hz, H-2), 3.10 (1H,
dd, J ¼ 13.7, 6.2 Hz, H-4a), 2.92 (1H, dd, J ¼ 13.7, 9.2 Hz, H-4b), 2.07
),
); C NMR
172.08 and 171.87 (C]O),138.26 (Ar-C), 129.15
3
)
d
4.4.25. (2R,3S)eN-adamantan-1-yl-2-hydroxy-4-phenyl-3-
propionamidobutanamide 56A
4
Product 56A was isolated as a white solid (47 mg, 99%). M.p.
ꢀ
ꢂ1
185e186 C; IR vmax(cm ): 3342 (OH), 3292 (NH), 3028 (CeH),
1
(
1
3H, s, 3 ꢁ adamantyl-CH), 2.02e1.95 (6H, m, 3 ꢁ adamantyl-CH
2
2906 (CeH), 1646 (C]O), 1526 (C]C); H NMR (500 MHz, CDCl
3
)
13
.87 (3H, s, CH
3
)
CO), 1.67 (6H, s, 3 ꢁ adamantyl-CH
2
d
7.28e7.22 (2H, m, Ar-H), 7.21e7.16 (3H, m, Ar-H), 6.74 (1H, d,
(
(
(
75 MHz, CDCl
3
d
J ¼ 8.1 Hz), 6.65 (1H, s) and 6.22 (1H, s, 2 ꢁ NH and OH), 4.19e4.09
(1H, m, H-3), 4.01e3.92 (1H, m, H-2), 3.08 (1H, dd, J ¼ 13.8, 6.2 Hz,
H-4a), 2.97 (1H, dd, J ¼ 13.8, 9.3 Hz, H-4b), 2.15e2.03 (5H, m, 3 ꢁ
Ar-C), 128.44 (Ar-C), 126.52 (Ar-C), 73.22 (C-2), 55.91 (C-3), 51.76
adamantyl-C), 41.42 (3 ꢁ adamantyl-CH
), 29.38 (3 ꢁ adamantyl-CH), 23.00 (CH
m/z), calculated for C22
2
), 36.29 (C-4), 35.58 (3 ꢁ
adamantyl-CH
(
2
3
CO); HRMS
adamantyl-CH and CH
(6H, s, 3 ꢁ adamantyl-CH
NMR (126 MHz, CDCl 175.82 and 171.84 (C]O), 138.35 (Ar-C),
29.23 (Ar-C), 128.44 (Ar-C), 126.53 (Ar-C), 73.52 (C-2), 55.74 (C-3),
51.81 (adamantyl-C), 41.57 (3 ꢁ adamantyl-CH ), 36.38 (3 ꢁ ada-
mantyl-CH ), 35.76 (C-4), 29.54 (CH CH
CH), 9.91 (CH
3
CH
2
), 1.98 (6H, s, 3 ꢁ adamantyl-CH
2
), 1.67
þ
13
H
31
N
2
O
3
: 371.2335, found (M þ H) :
2
), 1.02 (3H, t, J ¼ 7.6 Hz, CH CH
3
2
);
C
371.2331.
3
) d
1
4.4.22. (2S,3S)-3-acetamido-N-adamantan-1-yl-2-hydroxy-4-
2
phenyl butanamide 54B
2
3
2
), 29.49 (3 ꢁ adamantyl-
Product 54B was isolated as a white solid (47 mg, 99%). M.p.
3
CH
2
); HRMS (m/z), calculated for C23
33
H N
2
O
3
:
ꢀ
ꢂ1
þ
217e218 C; IR vmax(cm ): 3357 (OH), 3324 (NH), 3103 (NH), 2902
385.2491, found (M þ H) : 385.2487.
1
(
3
CeH), 1642 (C]O), 1559 (C]C); H NMR (500 MHz, CDCl )
d
7.34e7.15 (6H, m, Ar-H and NH), 6.73, 6.61 and 5.91e5.82 (2H, 2 ꢁ
4.4.26. (2S,3S)eN-adamantan-1-yl-2-hydroxy-4-phenyl-3-
propionamidobutanamide 56B
s, 1 ꢁ m, NH and OH), 4.26e4.13 (1H, m, H-3), 4.13e4.06 (1H, m, H-
), 3.10e2.99 (1H, m, H-4a), 2.99e2.88 (1H, m, H-4b), 2.13e1.96
), 1.93e1.86 (3H,
); C NMR (126 MHz,
172.59, 172.51,170.75 and 170.69 (C]O), 138.36 (Ar-C),
29.28 (Ar-C), 128.51 and 128.41 (Ar-C), 126.52 (Ar-C), 74.78 and
4.68 (C-2), 57.39, 57.29 and 57.24 (C-3), 51.62 and 51.40 (ada-
mantyl-C), 41.64 and 41.61 (3 ꢁ adamantyl-CH ), 36.39 (3 ꢁ ada-
mantyl-CH
CH), 22.88 and 22.83 (CH
2
Product 56B was isolated as a white solid (28 mg, 88%). M.p.
ꢀ
ꢂ1
(
9H, m, 3 ꢁ adamantyl-CH and 3 ꢁ adamantyl-CH
2
214e215 C; IR vmax(cm ): 3362 (OH), 3264 (NH), 3028 (CeH),
13
1
m, CH
3
)
CO), 1.70 (6H, s, 3 ꢁ adamantyl-CH
2
2908 (CeH), 1639 (C]O), 1527 (C]C); H NMR (500 MHz, CDCl
3
)
CDCl
1
7
3
d
d
7.31e7.24 (2H, m, Ar-H), 7.24e7.16 (3H, m, Ar-H), 6.71 (1H, s), 5.95
(1H, d, J ¼ 6.8 Hz) and 5.86 (1H, d, J ¼ 5.2 Hz, 2 ꢁ NH and OH),
4.21e4.14 (1H, m, H-3), 4.14e4.09 (1H, m, H-2), 3.11 (1H, dd,
J ¼ 14.1, 10.0 Hz, H-4a), 2.99 (1H, dd, J ¼ 14.1, 5.6 Hz, H-4b),
2
2
), 35.33 35.29 and 35.24 (C-4), 29.46 (3 ꢁ adamantyl-
2.18e1.94 (11H, m, CH
3
CH
2
, 3 ꢁ adamantyl-CH
2
and 3 ꢁ adamantyl-
), 1.06 (3H, t, J ¼ 7.6 Hz,
176.66 and 170.78 (C]O),
38.01 (Ar-C), 129.19 (Ar-C), 128.66 (Ar-C), 126.73 (Ar-C), 75.13 (C-
2), 57.91 (C-3), 51.75 (adamantyl-C), 41.68 (3 ꢁ adamantyl-CH ),
3
CO); HRMS (m/z), calculated for
CH), 1.69 (6H, s, 3 ꢁ adamantyl-CH
2
þ
13
C
22 31
H N
2
O
3
: 371.2335, found (M þ H) : 371.2331.
3 2 3
CH CH ); C NMR (126 MHz, CDCl ) d
1
4
.4.23. (2R,3S)eN-adamantan-1-yl-3-(2-chloroacetamido)-2-
2
hydroxy-4-phenyl-butanamide 55A
36.41 (3 ꢁ adamantyl-CH
2
), 35.72 (C-4), 29.52 (3 ꢁ adamantyl-CH),
Product 55A was isolated as a white solid (42 mg, 88%). IR
29.46 (CH CH ), 9.76 (CH
3
2
3
CH
2
); HRMS (m/z), calculated for
ꢂ1
þ
v
max(cm ): 3320 (OH), 3280 (NH), 3064 (C]CeH), 2907 (CeH),
C
23
33
H N
2
O
3
: 385.2491, found (M þ H) : 385.2486.
1
1
649 (C]O), 1528 (C]C), 1360 (CeO), 749 (CeCl); H NMR
500 MHz, CDCl
7.51 (1H, d, J ¼ 8.7 Hz, NH), 7.31e7.24 (2H, m, Ar-
H), 7.24e7.17 (3H, m, Ar-H), 6.50 (1H, s, NH), 5.37 (1H, s, OH),
.36e4.24 (1H, m, H-3), 4.01 (1H, s, H-2), 3.86 (2H, s, CH Cl), 3.08
(
3
)
d
4.4.27. (2R,3S)eN-adamantan-1-yl-3-butyramido-2-hydroxy-4-
phenylbutanamide 57A
4
2
Product 57A was isolated as a white solid (60 mg, 94%). M.p.
ꢀ
ꢂ1
(
2
1H, dd, J ¼ 13.7, 6.1 Hz, H-4a), 2.87 (1H, dd, J ¼ 13.5, 8.9 Hz, H-4b),
109e110 C; IR vmax(cm ): 3374 (OH), 3284 (NH), 3064 (C]CeH),
1
.13e2.05 (3H, m, 3 ꢁ adamantyl-CH), 1.99 (6H, s, 3 ꢁ adamantyl-
2907 (CeH), 1645 (C]O), 1528 (C]C); H NMR (500 MHz, CDCl
3
)
13
CH
2
), 1.68 (6H, s, 3 ꢁ adamantyl-CH
2
); C NMR (126 MHz, CDCl
3
)
d
7.28e7.21 (2H, m, Ar-H), 7.21e7.15 (3H, m, Ar-H), 6.95 (1H, s, OH),
d
171.06 and 167.15 (C]O), 137.61 (Ar-C), 129.22 (Ar-C), 128.52 (Ar-
C), 126.69 (Ar-C), 72.26 (C-2), 55.35 (C-3), 52.00 (3 ꢁ adamantyl-C),
2.34 (CH
6.78e6.70 (1H, m, NH), 6.50e6.38 (1H, m, NH), 4.20e4.09 (1H, m,
H-3), 4.01e3.93 (1H, m, H-2), 3.11 (1H, dd, J ¼ 13.8, 6.2 Hz, H-4a),
4
CH
2
Cl), 41.40 (3 ꢁ adamantyl-CH
2
), 36.23 (3 ꢁ adamantyl-
2.99e2.90 (1H, m, H-4b), 2.14e2.02 (5H, m, CH
2
CO and 3 ꢁ
), 1.67 (6H, s, 3 ꢁ
), 0.84 (3H, t, J ¼ 7.3 Hz,
175.06 and 171.89 (C]O),
138.29 (Ar-C), 129.17 (Ar-C), 128.40 (Ar-C), 126.47 (Ar-C), 73.49 (C-
2), 55.73 (C-3), 51.71 (adamantyl-C), 41.44 (3 ꢁ adamantyl-CH ),
), 35.53 (CH
), 13.69 (CH CH
2
), 35.87 (C-4), 29.36 (3 ꢁ adamantyl-CH); HRMS (m/z), calcu-
adamantyl-CH), 1.99 (6H, s, 3 ꢁ adamantyl-CH
adamantyl-CH ), 1.58e1.45 (2H, m, CH CH
); C NMR (126 MHz, CDCl
2
þ
lated for C22
H30ClN
2
O
3
: 405.1945, found (M þ H) : 405.1945.
2
3
2
13
CH
3
CH
2
3
) d
4
.4.24. (2S,3S)eN-adamantan-1-yl-3-(2-chloroacetamido)-2-
hydroxy-4-phenyl-butanamide 55B
2
Product 55B was isolated as a white solid (25 mg, 77%). M.p.
38.24 (C-4), 36.30 (3 ꢁ adamantyl-CH
adamantyl-CH), 19.08 (CH CH
calculated for C24
2
2
CO), 29.38 (3 ꢁ
ꢀ
ꢂ1
2
23e224 C; IR (solid) vmax(cm ): 3313 (OH), 2906 (CeH), 1648
3
2
3
2
); HRMS (m/z),
1
þ
(
C]O), 1521 (C]C), 1361 (CeO), 794 (CeCl); H NMR (500 MHz,
H
35
N
2
O
3
: 399.2648, found (M þ H) : 399.2645.
CDCl 7.32e7.25 (2H, m, Ar-H), 7.25e7.17 (3H, m, Ar-H), 6.97 (1H,
3
) d
d, J ¼ 7.5 Hz), 6.64 (1H, s) and 5.07 (1H, d, J ¼ 5.2 Hz, 2 ꢁ NH and
4.4.28. (2S,3S)eN-adamantan-1-yl-3-butyramido-2-hydroxy-4-
phenylbutanamide 57B
OH), 4.34e4.24 (1H, m, H-3), 4.21e4.14 (1H, m, H-2), 3.98e3.88
(
2H, m, CH
2
Cl), 3.09e2.95 (2H, m, H-4), 2.13e2.06 (3H, m, 3 ꢁ
), 1.77e1.66
); C NMR (126 MHz, CDCl 170.07
and 168.05 (C]O), 137.39 (Ar-C), 129.18 (Ar-C), 128.67 (Ar-C),
Product 57B was isolated as a white solid (57 mg, 100%). M.p.
ꢀ
ꢂ1
adamantyl-CH), 2.06e1.98 (6H, m, 3 ꢁ adamantyl-CH
2
151e152 C; IR vmax(cm ): 3360 (OH), 3266 (NH), 3064 (CeH),
13
1
(
6H, m, 3 ꢁ adamantyl-CH
2
3
)
d
2924 (CeH), 1660 (C]O), 1529 (C]C), 1370 (CeO); H NMR
3
(500 MHz, CDCl ) d 7.32e7.25 (2H, m, Ar-H), 7.21e7.13 (3H, m, Ar-
Please cite this article in press as: Zimuwandeyi M, et al., PADAM reactions of
a-aminoaldehydes: Identity of major and minor diastereomers
from the Passerini reaction, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.04.065

16
M. Zimuwandeyi et al. / Tetrahedron xxx (2018) 1e17
H), 5.73 (1H, s, NH), 4.96 (1H, d, J ¼ 3.9 Hz, NH), 4.26e4.15 (1H, m,
4.4.32. (2S,3S)eN-adamantan-1-yl-3-(3,3-dimethylbutanamido)-
2-hydroxy-4-phenyl-butanamide 59B
H-3), 3.99 (1H, d, J ¼ 6.5 Hz, H-2),
d
3.13 (1H, dd, J ¼ 13.8, 6.2 Hz, H-
a), 2.98e1.97 (1H,m, H-4b), 2.36 (2H, t, J ¼ 7.4 Hz, CH CO),
.12e2.05 (3H, m, 3 ꢁ adamantyl-CH), 2.01 (6H, m, 3 ꢁ adamantyl-
), 1.71e1.68 (8H, m, 3 ꢁ adamantyl-CH and CH CH ), 0.97 (3H,
); C NMR (126 MHz, CDCl 172.42 and
66.70 (C]O), 137.45 (Ar-C), 129.19 (Ar-C), 128.49 (Ar-C), 126.60
Ar-C), 74.24 (C-2), 56.48 (C-3), 52.32 (adamantyl-C), 41.44 (3 ꢁ
adamantyl-CH ), 36.03
), 13.65
: 399.2648, found
4
2
2
Product 59B was isolated as a white solid (27 mg, 100%). M.p.
ꢀ
ꢂ1
195e196 C; IR vmax(cm ): 3301 (OH), 3285 (NH), 3029 (CeH),
CH
q, J ¼ 7.1 Hz, CH
2
2
3
2
2906 (CeH), 2851 (CeH), 1654 (C]O), 1638 (C]O), 1522 (C]C),
13
1
3
CH
2
3
)
d
1360 (CeO); H NMR (500 MHz, CDCl
3
)
d
7.32e7.14 (5H, m, Ar-H),
1
6.76 (1H, s) and 6.07e5.95 (2H, m, 2 ꢁ NH and OH), 4.27e4.15
(1H, m, H-3), 4.15e4.08 (1H, m, H-2), 3.14 (1H, dd, J ¼ 14.3, 10.3 Hz.
H-4a), 3.04 (1H, dd, J ¼ 14.2, 5.3 Hz, H-4b), 2.04 (3H, m, 3 ꢁ
(
2
), 37.49 (C-4), 36.26 (3 ꢁ adamantyl-CH
CO), 29.70 (3 adamantyl-CH), 18.32 (CH CH
CH ); HRMS (m/z), calculated for C24
2
(
(
(
CH
CH
2
3
ꢁ
3
2
adamantyl-CH), 2.04e1.89 (8H, m, CH
2
CO and 3 ꢁ adamantyl-CH
2
),
C
1
3
2
35
H N
2
O
3
1.73e1.63 (6H, m, 3 ꢁ adamantyl-CH
NMR (126 MHz, CDCl
29.11 (Ar-C), 128.67 (Ar-C), 126.71 (Ar-C), 75.36 (C-2), 57.77 (C-3),
51.68 (adamantyl-C), 50.07 (CH ),
CO), 41.53 (3 ꢁ adamantyl-CH
), 35.94 (C-4), 30.81 ((CH C), 29.63
2
), 0.88 (9H, s, (CH
3
)
3
C);
þ
M þ H) : 399.2643.
3
) d 174.87 and 170.82 (C]O), 137.91 (Ar-C),
1
4.4.29. (2R,3S)eN-adamantan-1-yl-2-hydroxy-4-phenyl-3-
2
2
pivalamidobutanamide 58A
36.32 (3 ꢁ adamantyl-CH
2
3 3
)
Product 58A was isolated as a white solid (51 mg, 70%). M.p.
3
((CH )
3
C), 29.40 (3 ꢁ adamantyl-CH); HRMS (m/z), calculated for
ꢀ
ꢂ1
þ
2
1
39e240 C; IR vmax(cm ): 3301 (OH), 2907 (CeH), 1651 (C]O),
C
26
39
H N
2
O
3
: 427.2961, found (M þ H) : 427.2962.
1
520 (C]C), 1345 (CeO); H NMR (500 MHz, CDCl
3
) d 7.28e7.22
(
6
4
2H, m, Ar-H), 7.21e7.15 (3H, m, Ar-H), 6.75e6.67 (1H, m),
.67e6.54 (1H, m) and 6.48e6.39 (1H, m, 2 ꢁ NH and OH),
.27e4.16 (1H, m, H-3), 4.02e3.95 (1H, m, H-2), 3.12e2.96 (2H, m,
4.4.33. (2R,3S)eN-adamantan-1-yl-3-((S)-2-amino-3-
phenylpropanamido)-2-hydroxy-4-phenylbutanamide 60A
Product 60A was isolated as a white solid (59 mg, 84%). M.p.
ꢀ
ꢂ1
H-4), 2.07 (3H, s, 3 ꢁ adamantyl-CH), 1.99 (6H, s, 3 ꢁ adamantyl-
65e66 C; IR vmax(cm ): 3311 (OH), 3028 (CeH), 2907 (CeH),1648
1
3
1
CH
NMR (126 MHz, CDCl
29.25 (Ar-C), 128.37 (Ar-C), 126.49 (Ar-C), 73.85 (C-2), 55.46 (C-3),
1.69 (adamantyl-C), 41.52 (3 ꢁ adamantyl-CH ), 38.65 ((CH C)
2
), 1.67 (6H, s, 3 ꢁ adamantyl-CH
2
), 1.05 (9H, s, (CH
3
)
3
C);
C
3
(C]O), 1517 (C]C), 1345 (CeO); H NMR (500 MHz, CDCl ) d 7.96
3
)
d
180.67 and 171.73 (C]O), 138.26 (Ar-C),
(0.83H, d, J ¼ 8.3 Hz, NH), 7.67 (0.13H, d, J ¼ 8.9 Hz, NH), 7.34e7.11
(10H, m, Ar-H), 6.60 (0.89H, s, NH), 6.53 (0.13H, s, NH), 6.10 (1H, br s,
OH), 4.34e4.23 (1H, m, H-3), 4.05e3.99 (0.89H, m, H-2), 3.94e3.90
(0.13H, m, H-2), 3.49 (1H, dd, J ¼ 10.4, 3.7 Hz, H-6), 3.24e3.04 (2H,
m, H-4a and CHaHbPh), 3.04e2.91 (1H, m, H-4b), 2.36 (1H, dd,
J ¼ 13.8, 10.3 Hz, CHaHbPh), 2.11e2.03 (3H, m, 3 ꢁ adamantyl-CH),
1
5
3
2
2
3 3
)
6.30 (3 ꢁ adamantyl-CH ), 35.52 (C-4), 29.38 (3 ꢁ adamantyl-CH),
2
7.48 ((CH
3
)
3
C); HRMS (m/z), calculated for C25
H
37
N
2
O
3
: 413.2804,
þ
found (M þ H) : 413.2798.
2
.03e1.93 (6H, m, 3 ꢁ adamantyl-CH
2
), 1.71e1.61 (6H, m, 3 ꢁ
13
4
.4.30. (2S,3S)eN-adamantan-1-yl-2-hydroxy-4-phenyl-3-
adamantyl-CH
2
); C NMR (126 MHz, CDCl 176.31 and 171.40
3
) d
pivalamidobutanamide 58B
(C]O), 138.19 (Ar-C), 137.75 (Ar-C), 129.35 (Ar-C), 129.29 (Ar-C),
129.10 (Ar-C),128.77 (Ar-C),128.66 (Ar-C),128.44 (Ar-C),128.40 (Ar-
C), 126.89 (Ar-C), 126.86 (Ar-C), 126.57 (Ar-C), 126.54 (Ar-C), 73.38
Product 58B was isolated as a white solid (26 mg, 70%). M.p.
ꢀ
ꢂ1
6
1e63 C; IR vmax(cm ): 3318 (OH), 3248 (NH), 2961 (CeH), 1664
1
(
C]O), 1636 (C]O), 1540 (C]C), 1358 (CeO); H NMR (500 MHz,
CDCl 7.34e7.17 (5H, m, Ar-H), 6.75 (1H, s, NH), 5.97 (1H, d,
J ¼ 6.6 Hz, NH), 4.24e4.15 (1H, m, H-3), 4.14e4.09 (1H, m, H-2), 3.18
1H, dd, J ¼ 14.2, 10.5 Hz, H-4a), 3.05 (1H, dd, J ¼ 14.1, 5.4 Hz, H-4b),
.13e2.05 (3H, m, 3 ꢁ adamantyl-CH), 2.05e1.91 (6H, m, 3 ꢁ ada-
mantyl-CH ), 1.05 (9H, s,
), 1.73e1.60 (6H, m, 3 ꢁ adamantyl-CH
181.67 and 170.79 (C]O),
37.89 (Ar-C), 129.36 (Ar-C), 128.65 (Ar-C), 126.75 (Ar-C), 75.28 (C-
(C-2), 56.51 and 55.20 (C-3 and CHNH
), 41.01 (CH
2
), 51.79 (adamantyl-C), 41.50
),
3
)
d
(3 ꢁ adamantyl-CH
2
2
Ph), 36.29 (3 ꢁ adamantyl-CH
2
35.95 (C-4), 29.39 (3 ꢁ adamantyl-CH); HRMS (m/z), calculated for
þ
(
2
C
29
38
H N
3
O
3
: 476.2913, found (M þ H) : 476.2918.
2
2
4.4.34. (2S,3S)eN-adamantan-1-yl-3-((S)-2-amino-3-
phenylpropanamido)-2-hydroxy-4-phenylbutanamide 60B
Product 60B was isolated as a white solid (25 mg, 89%). M.p.
13
(
3 3 3
CH ) C); C NMR (126 MHz, CDCl ) d
1
2
3
ꢀ
ꢂ1
), 57.59 (C-3), 51.65 (adamantyl-C), 41.62 (3 ꢁ adamantyl-CH
2
),
60e62 C; IR vmax(cm ): 3313 (OH), 3028 (C]CeH), 2906 (CeH),
1
8.62 ((CH
3
)
3
C), 36.27 (3 ꢁ adamantyl-CH
2
), 35.97 (C-4), 29.41 (3 ꢁ
1654 (C]O), 1636 (C]O), 1518 (C]C), 1360 (CeO); H NMR
adamantyl-CH), 27.40 ((CH
3
)
3
C); HRMS (m/z), calculated for
(500 MHz, CDCl
Ar-H), 6.74 (1H, s, NH), 4.24e4.13 (2H, m, H-2 and H-3), 3.57e3.49
1H, m, CH NH ), 3.14e3.05 (2H, m, H-4a and CHaHbPh), 2.97 (1H,
dd, J ¼ 14.0, 5.1 Hz, H-4b), 2.49 (1H, dd, J ¼ 13.8, 9.2 Hz, CHaHbPh),
2.12e1.96 (9H, m, 3 ꢁ adamantyl-CH and 3 ꢁ adamantyl-CH),
1.75e1.63 (6H, m, 3 ꢁ adamantyl-CH
CDCl 176.95 and 170.48 (C]O), 138.17 (Ar-C), 137.22 (Ar-C),
129.22 (Ar-C),129.18 (Ar-C),128.77 (Ar-C),128.53 (Ar-C),126.99 (Ar-
C), 126.60 (Ar-C), 74.93 (C-2), 57.51 (C-3), 56.08 (CH NH ), 51.63
(adamantyl-C), 41.56 (3 ꢁ adamantyl-CH ), 40.77 (CH Ph) 36.32
3
)
d
7.74 (1H, d, J ¼ 7.1 Hz, NH), 7.33e7.09 (10H, m,
þ
C
25 37
H N
2
O
3
: 413.2804, found (M þ H) : 413.2802.
(
2
2
4
2
.4.31. (2R,3S)eN-adamantan-1-yl-3-(3,3-dimethylbutanamido)-
-hydroxy-4-phenyl-butanamide 59A
2
13
Product 59A was isolated as a white solid (50 mg, 82%). M.p.
2
); C NMR (126 MHz,
ꢀ
ꢂ1
1
72e173 C; IR vmax(cm ): 3346 (OH), 3290 (NH), 3088 (CeH),
3
) d
1
2
906 (CeH), 1668 (C]O), 1643 (C]O), 1535 (C]C), 1360 (CeO); H
NMR (500 MHz, CDCl 7.28e7.13 (5H, m, Ar-H), 6.97 (1H, d,
J ¼ 8.2 Hz), 6.77 (1H, s) and 6.57 (1H, d, J ¼ 6.5 Hz, 2 ꢁ NH and OH),
.24e4.15 (1H, m, H-3), 4.00e3.92 (1H, m, H-2), 3.16 (1H, dd,
3
)
d
2
2
2
2
4
(3 ꢁ adamantyl-CH ), 35.03 (C-4), 29.42 (3 ꢁ adamantyl-CH);
2
J ¼ 13.8, 6.4 Hz, H-4a), 2.92 (1H, dd, J ¼ 13.8, 9.3 Hz, H-4b),
HRMS (m/z), calculated for
(M þ H) : 476.2917.
C
H
29 38
N
3
O
3
:
476.2913, found
þ
2
3
.11e2.04 (3H, m, 3 ꢁ adamantyl-CH), 2.04e1.91 (8H, m, CH
2
CO and
), 0.90
173.84 and 171.96
C]O), 138.25 (Ar-C), 129.19 (Ar-C), 128.41 (Ar-C), 126.45 (Ar-C),
3.43 (C-2), 55.59 (C-3), 51.73 (adamantyl-C), 50.02 (CH CO), 41.47
), 35.49 (C-4),
ꢁ adamantyl-CH ), 1.70e1.63 (6H, m, 3 ꢁ adamantyl-CH
2
2
13
(
(
9H, s, (CH
3
)
3
C)), C NMR (126 MHz, CDCl
3
)
d
4.5. HPLC separation of diastereomers and determination of
diastereomeric ratio
7
2
(
3
3 ꢁ adamantyl-CH
2
), 36.30 (3 ꢁ adamantyl-CH
2
The compound of interest (150 mg) was dissolved in HPLC grade
0.74 ((CH
3
)
3
C), 29.73 ((CH
3
)
3
C), 29.38 (3 ꢁ adamantyl-CH); HRMS
acetonitrile (5 ml) and 250
10
m Agilent semi-preparative C-18 column (21.2 ꢁ 250 mm)
attached to an Agilent 1260 infinity preparative HPLC fitted with a
ml of this solution was injected onto a
þ
(
m/z), calculated for C26
H
39
N
2
O
3
: 427.2961, found (M þ H) :
m
4
27.2955.
Please cite this article in press as: Zimuwandeyi M, et al., PADAM reactions of
a-aminoaldehydes: Identity of major and minor diastereomers
from the Passerini reaction, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.04.065

M. Zimuwandeyi et al. / Tetrahedron xxx (2018) 1e17
17
PDA detector. Diastereomers were separated using gradient elution
5:5e8:2 acetonitrile/H O; flow-rate 20 ml/min) and after collec-
Acknowledgements
(
2
tion solvent was removed in vacuo. Determination of diastereo-
meric ratio was performed on an analytical column (Phenomenex
The authors would like to thank the DST biocatalysis initiative
and the University of the Witwatersrand for funding.
Luna 5
instrument using the solvent system described above (flow-rate
ml/min), and peak areas of the diastereomers were compared
directly. Elution of compounds was detected by UV at 217 nm.
m
m C-18, 4.6 ꢁ 150 mm) attached to a Dionex Ultimate 3000
Appendix A. Supplementary data
1
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.2018.04.065.
4.6. Crystal structure determination
References
The Bruker D8 VENTURE PHOTON CMOS area detector diffrac-
1. Bode ML, Gravestock D, Rousseau AL. Org Prep Proced Int. 2016;48:89.
2
. a) Banfi L, Guanti G, Riva R. Chem Commun. 2000:985;
b) Owens TD, Araldi G-L, Nutt RF, Semple JE. Tetrahedron Lett. 2001;42:6271;
c) Shaw AY, Medda F, Hulme C. Tetrahedron Lett. 2012;53:1313;
d) Banfi L, Guanti G, Riva R, Basso A, Calcagno E. Tetrahedron Lett. 2002;43:
4067;
tometer, equipped with a graphite monochromated Mo Ka1 radi-
ation (50 kV, 30 mA), was used to collect all the intensity data.
Crystal structures were collected at 173 K and to achieve satisfac-
14
tory thermal ellipsoids. The program SAINTþ, vers. 6.02 was used
e) Morana F, Basso A, Riva R, Rocca V, Banfi L. Chem Eur J. 2013;19:4563;
f) Banfi L, Basso A, Guanti G, Riva R. Mol Divers. 2003;6:227.
15
to integrate the data and the program SADABS was used to make
empirical absorption corrections. Space group assignments were
3. Maeda S, Komagawa S, Uchiyama M, Morokuma K. Angew Chem Int Ed.
2011;50:644.
made using XPREP12 on all compounds. In all cases, the structures
4
5
. Ramozzi R, Morokuma K. J Org Chem. 2015;80:5652.
. a) de Graaff C, Ruijter E, Orru RVA. Chem Soc Rev. 2012;41:3969;
b) van Berkel SS, B o€ gels BGM, Wijdeven MA, Westermann B, Rutjes FPJT. Eur J
16
were solved in the WinGX suite of programs by direct methods
using SHELXS-9717 and refined using full-matrix least-squares/dif-
2
15
Org Chem. 2012:3543.
ference Fourier techniques on F using SHELXL-97. All non-
hydrogen atoms were refined anisotropically. After that, all C-
bound hydrogen atoms were placed at idealized positions and
refined as riding atoms with Uiso parameter 1.2 or 1.5 times those of
their parent atoms. Thereafter, the N-bound and O-bound hydrogen
atoms were located in the difference Fourier map and their co-
ordinates and isotropic displacement parameters refined freely for
compound 56A. The hydroxyl H on the methanol solvent molecule
of 40B was placed at an idealized position and refined as a riding
atom with Uiso parameter 1.5 times of the parent atoms. Further
crystallographic data are summarised in the supplementary
information. Diagrams and publication material were generated
using ORTEP-3,18 PLATON. Crystallographic data has been depos-
ited at the Cambridge Crystallographic Data Centre: compound 40B
has the CCDC code 1837530 and compound 56A has the CCDC code
6
. a) Basso A, Banfi L, Ganti G, Riva R, Tosatti P. Synlett. 2011:2009;
b) Owens TD, Semple JE. Org Lett. 2001;3:3301;
(c) Faure S, Hjelmgaard T, Roche SP, Aitken DJ. Org Lett. 2009;11:1167.
. Gravestock D, Rousseau AL, Lourens ACU, Hoppe HC, Nkabinde LA, Bode ML.
Tetrahedron Lett. 2012;53:3225.
7
8
9
. Reynolds C, de Koning CB, Pelly SC, van Otterlo WAL, Bode ML. Chem Soc Rev.
2012;41:4657.
. Clare M. Perspect Drug Discov Des. 1993;1:49.
1
1
0. Fehrentz J-A, Castro B. Synthesis. 1983:676.
1. Barreto AFS, Vercillo OE, Andrade CKZ. J Braz Chem Soc. 2011;22:462.
12. Hili RM. PhD thesis, University of Toronto, 2010.
13. Moni L, Banfi L, Basso A, et al. Molecules. 2016;21:1153.
1
4. Bruker. SAINTþ (Including XPREP). Madison, WI, USA: Bruker AXS Inc.; 1999.
.02. .
5. Sheldrick GM. SADABS. University of Gottingen; 1997.
6
1
€
19
16. Farrugia L. J Appl Crystallogr. 2012;45:849.
17. Sheldrick GM. SHELX, Release 97-2 (Includes SHELXS and SHELXL). University of
G o€ ttingen; 1997.
18. Farrugia L. J Appl Crystallogr. 1997;30:565.
1837529.
19. Spek A. J Appl Crystallogr. 2003;36:7.
Please cite this article in press as: Zimuwandeyi M, et al., PADAM reactions of
a-aminoaldehydes: Identity of major and minor diastereomers
from the Passerini reaction, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.04.065