Syntheses of Enantiopure 1,2-Ethylenediamines with Tethered Secondary Amines of the Formula H 2NCH 2CH[(CH 2) nNHMe]NH 2(n = 1-4) from α-Amino Acids: New Agents for Asymmetric Catalysis

Article abstract of DOI:10.1055/s-0040-1707146

Tris(hydrochloride) adducts of the title compounds-are prepared from the inexpensive α-amino acids H 2 N(C=O)CH 2 CH(NH 2)CO 2 H, HO(C=O)(CH 2) n ′ CH(NH 2)CO 2 H (n ′ = 1, 2), and H2 N(CH 2) 4 CH(NH 2)CO 2 H, respectively (steps/overall yield = 5/32, 7/30, 7/33, 5/38). The NH 2 group that is remote from the secondary amine is installed via BH 3 reduction of an amide [-(C=O)NR 2[ derived?-from an α-amino carboxylic acid. The MeNHCH 2 units are introduced by BH 3 reductions of alkyl carbamate [RO(C=O)NHCH 2-; R = Et, t-Bu] or amide [MeHN(C=O)-] moieties.

Full text of DOI:10.1055/s-0040-1707146

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–I
special topic
A
en
C. Q. Kabes et al.
Special Topic
Synthesis
Syntheses of Enantiopure 1,2-Ethylenediamines with Tethered
Secondary Amines of the Formula H2NCH2CH[(CH2)nNHMe]NH2
(n = 1–4) from -Amino Acids: New Agents for Asymmetric Catalysis
Connor Q. Kabes
Jack H. Gunn
0
0
0
0-0
0
0
1-
8
3
8
3-5
7
1
3
Maximilian A. Selbst
Reagan F. Lucas
John A. Gladysz*
0
0
0
0-0
0
0
2-7
0
1
2-
4
8
7
2
Department of Chemistry, Texas A&M University, P.O.
Box 30012, College Station, Texas 77842-3012, USA
gladysz@mail.chem.tamu.edu
Published as part of the Special Topic Recent Advances in
Amide Bond Formation
Received: 04.05.2020
Accepted after revision: 18.05.2020
Published online: 16.06.2020
have employed one or more lipophilic tetraarylborate coun-
teranions, BAr4 , to solubilize these salts in organic solvents
–
and remove water as a competitor for the substrate-binding
NH2 groups.
DOI: 10.1055/s-0040-1707146; Art ID: ss-2020-c0235-st
Abstract Tris(hydrochloride) adducts of the title compounds are pre-
pared from the inexpensive -amino acids H2N(C=O)CH2CH(NH2)CO2H,
HO(C=O)(CH2)n′CH(NH2)CO2H (n′ = 1, 2), and H2N(CH2)4CH(NH2)CO2H,
respectively (steps/overall yield = 5/32%, 7/30%, 7/33%, 5/38%). The
NH2 group that is remote from the secondary amine is installed via BH3
reduction of an amide [–(C=O)NR2] derived from an -amino carboxylic
acid. The MeNHCH2 units are introduced by BH3 reductions of alkyl
carbamate [RO(C=O)NHCH2–; R = Et, t-Bu] or amide [MeHN(C=O)–]
moieties.
Ar
Ar
(S)
NH2
NH2
NH2
(S)
H2
N
H2
N
H2
N
H2N
H2N
H2N
Ar
Ar
H2N
H2N
3+
3+
3+
Co
n
NMe2
(S)
(S)
Co
Co
(S)
N
H2N
N
n = 1–4
3X–
N
H2
H2
H2
(S)
(S)
NH2
NH2
NH2
3X–
3X–
Ar
Ar
Co,S6C-II
ΛCo-I
Λ
Λ
Co,SC-III
(other diastereomers
also prepared)
(other diastereomers
also prepared)
Key words 1,2-diamines, triamines, -amino acids, chiral ligands, BH3
reduction, amides, carbamates
O
OH
N
NH2
X
n
n
Transition-metal complexes play a central role in enan-
tioselective catalysis,1 and in the absence of a metal-based
stereocenter, chiral ligands are normally required. Also, cer-
tain types of heteroatom donor ligands can themselves
serve as Lewis base or nucleophilic catalysts, and these are
frequently classified as ‘organocatalysts’.2 Despite the ex-
tensive history of chiral ligands,3 there are many rather
simple structures that remain to be synthesized.
n = 1–4
H
NH2
NH2
V
IV
X =
HO
n'
H2N
H2N
O
n' = 1,2
O
Scheme 1 Some enantioselective cobalt(III) hydrogen bond donor cat-
alysts based upon chelating 1,2-diamines, and a new type of functional-
ized 1,2-diamine
We have been interested in exploiting cobalt(III)
tris(1,2-diamine) complexes as hydrogen bond donor cata-
lysts,4–6 and other cobalt(III) systems have been analogously
investigated by Belokon.7 The unsubstituted tris(1,2-eth-
ylenediamine) adduct [Co(en)3]3+·3X– (I) (Scheme 1), a ‘chi-
ral at metal’ species, was among the first inorganic com-
plexes to be isolated in enantiomerically pure form, as re-
ported by Werner some 108 years ago.8 In our studies, we
All catalysts of the type I have given rather modest
enantioselectivities.4 However, excellent results have been
obtained with the corresponding 1,2-diaryl-substituted
species II (Scheme 1),5 as well as with related bifunctional
systems containing an appended tertiary amine, such as
III.6 The NMe2 moiety, which can be tethered with varying
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
C. Q. Kabes et al.
Special Topic
Synthesis
(CH2)n spacer lengths (n = 1–4),9 obviates the need for an
external Brønsted base, as is commonly required for many
Michael-type addition reactions.
O
O
Boc2O, NaHCO3
dioxane/H2O (1:1)
H2N
H2N
OH
OH
O
NH2
O
NHBoc
1
Chiral secondary amines—in particular a large family of
proline derivatives—have played a key role in the develop-
ment of organocatalysis.10 This has evolved into a subfield
termed ‘iminium ion catalysis’ in reference to intermediates
generated by the secondary amine and appropriate carbon-
yl compounds. We were curious whether this family of chi-
ral cobalt(III) complexes, which could furthermore bring
hydrogen bonding interactions into play, might provide a
viable (or even superior) platform for such transformations.
Surprisingly, the most obvious type of secondary-
amine-containing ethylenediamine derivative, H2NCH2CH-
[(CH2)nNHMe]NH2 (IV) (Scheme 1), has not been reported
in the literature, either in racemic or enantiopure form, and
for any value of n. Accordingly, we set out to develop practi-
cal syntheses from the inexpensive, commercially available
-amino acids V. As described below, tris(hydrochloride)
adducts of the target molecules with n = 1–4 are easily pre-
pared in 5–7 steps and 30–38% overall yields. Apropos to
the themed collection of articles in this issue, in each case
amide and carbamate functionalities are introduced that
serve not merely as protecting groups, but rather as precur-
sors to methylene or methyl units in the products.
O
O
O
PhI(OAc)2
ClCOOEt, NaHCO3
dioxane/H2O (1:1)
H2N
OH
NHBoc
EtO
N
OH
NHBoc
EtOAc/MeCN/H2O
(2:1:1)
H
2
3
1. ClCOOiBu, NMM
2. NH4OH
O
O
O
O
TFA
EtO
N
NH2
EtO
N
NH2
CH2Cl2
THF
H
H
NH2
NHBoc
4
5
1. BH3•SMe2
2. HCl
N
H
NH2
NH2
toluene
•3HCl
6•3HCl
Scheme 2 Synthesis of triamine IV with n = 1 (6)
ride adducts described below were hygroscopic and stored
in desiccators. The overall yield for the five steps in Scheme
2 (or six if 5 is counted) is 32%.
2. Triamine IV with n = 2, 3
The availability of both L-aspartic and L-glutamic acid
allowed these two syntheses to be developed in parallel, as
summarized in Scheme 3. The methyl ester of the former, 7,
was prepared by a literature procedure (96%),16 and the
same method was applied to the higher homolog 14 (73%),
which had previously been accessed by another route.17 The
amino groups were then protected with Cbz under stan-
dard conditions, but the products 8 and 15 were isolated as
viscous oils that retained solvent (85% and 99%), and rigor-
ous purifications were not attempted.
The carboxylic acid moieties in 8 and 15 were then con-
verted into di(benzyl) amides by a route analogous to that
used to access the amide 4 in Scheme 1. Work-ups gave 9
and 16 as waxy solids in 61% and 87% yields. Subsequent re-
actions with aqueous methylamine transformed the methyl
ester moieties into methyl amides, completing the installa-
tion of the nitrogen atoms and giving 10 and 17 (>99%
each). When analogous sequences were attempted with
simple amide (CONH2) derivatives of 8 and 15, products
corresponding to 10 and 17 were not obtained, possibly due
to intramolecular condensations or alternative modes of
methylamine attack.
1. Triamine IV with n = 1
As shown in Scheme 2, commercial L-asparagine was
converted into the known Boc derivative 1 in 79% yield.11
The conditions were adapted from those used for similar
transformations in the literature.12 As for all ‘new steps’ in
this study, the product was characterized by NMR (1H,
13C{1H}) and microanalysis. Per an earlier report,13 a mod-
ern version of the Hofmann rearrangement that uses an io-
dine(III) oxidant was employed to convert 1 into the prima-
ry amine 2 in 85% yield. The amine was subsequently treat-
ed with ethyl chloroformate to give the ethyl carbamate 3, a
new compound. Although it could be isolated in 96% yield,
it (and similar species below) remained an oil and was used
without exhaustive purification.
In a standard sequence,14 carbamate 3 and isobutyl
chloroformate were combined to generate a mixed anhy-
dride that upon treatment with NH4OH gave the amide 4 in
55% yield. This completed the installation of the nitrogen
atoms needed in the target molecule. Subsequent reaction
with trifluoroacetic acid removed the Boc protecting group.
However, the -amino amide 5 was not isolated, but treated
further with BH3·SMe2 in toluene. This reagent is also com-
mercially available as a THF solution, but the higher boiling
solvent was used as optimal rates and yields required ele-
vated temperatures.15 Reductions of both carbonyl func-
tionalities to methyl or methylene groups were effected,
and addition of HCl afforded the tris(hydrochloride) salt
6·3HCl in 89% yield from 4. This and the other hydrochlo-
The remaining steps required manipulation of the pro-
tecting groups and carbonyl functionalities. First, mild hy-
drogenolysis (Pd/C, 75 psig H2) removed the Cbz groups to
give the -amino amides 11 and 18 (99% and 83%). Next, a
BH3 reduction analogous to that in Scheme 2 gave the tri-
amines 12 and 19 (67% and 84%). Finally, a hydrogenolysis
was carried out with the synergistically acting mixed
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

C
C. Q. Kabes et al.
Special Topic
Synthesis
O
O
O
Cbz-OSu, base
n'
n'
AcCl
n'
O
O
HO
OH
NH2 • HCl
n' = 1, 7
2, 14
OH
NHCbz
n' = 1, 8
2, 15
OH
MeOH
7: base = K2CO3
H2O/acetone
14: base = NaHCO3
H2O/THF
O
O
O
NH2
n' = 1, 2
1. ClCOOiBu, NMM
2. NHBn2
O
O
H
N
NH2Me
THF
n'
n'
O
NBn2
NHCbz
n' = 1, 9
2, 16
NBn2
NHCbz
n' = 1, 10
THF
O
O
2, 17
1. BH3•SMe2
2. HCl
O
H
N
H
H2, Pd/C
n'
n'
N
NBn2
NBn2
toluene
MeOH/CH2Cl2
NH2
O
NH2
n' = 1, 11
2, 18
n' = 1, 12
2, 19
H
n'
H2, Pd/C, Pd(OH)2/C
MeOH/HCl
N
NH2
NH2
•3 HCl
n' = 1, 13•3HCl
2, 20•3HCl
Scheme 3 Synthesis of triamine IV with n = 2 and 3 (13, 20)
heterogeneous catalyst18 Pd/C and Pd(OH)2/C (75 psig H2) in
the presence of HCl. This removed the N-benzyl groups and
gave the target tris(hydrochloride) salts 13·3HCl and
20·3HCl in 91% and 76% yields, respectively. The overall
yields for the two sequences in Scheme 3 (7 steps) are 30%
and 33%.
yield. The overall yield for the entire sequence in Scheme 4
(5 steps) is 38%.
4. Additional Analyses
The reactions used to access the title molecules in
Schemes 2–4 are for the most part familiar to amino acid
and peptide chemistry. As depicted in Scheme 1 (structure
V), the starting materials for the sequences differ in the ter-
minal functional group opposite to the -amino acid moi-
ety [H2N(C=O)–, HO(C=O)–, H2N–]. That in Scheme 2 re-
quires that a carbon atom be excised, and this is effected via
a variant of a Hofmann rearrangement. In all cases, the pri-
mary amine that is most remote from the secondary amine
is installed via a BH3 reduction of an amide [–(C=O)NR2] de-
rived from the terminal carboxylic acid. The N-methyl or
MeHNCH2 units are introduced by BH3 reductions of alkyl
carbamate [RO(C=O)NHCH2–; R = Et, t-Bu] or amide
[MeHN(C=O)–] moieties.
3. Triamine IV with n = 4
As shown in Scheme 4, L-lysine was converted into its
Boc-protected form 21 by a literature procedure (74%).19
The next step, protecting the remaining amino group with
Cbz to give 22 (79%), was taken from a recent patent.20 The
carboxylic acid was then converted into the amide 23 (86%)
by the same protocol employed for the comparable step in
Scheme 2. The Cbz group was removed using the same hy-
drogenolysis conditions as in Scheme 3, affording 24 in 91%
yield. Reduction with BH3 reduced the two carbonyl func-
tionalities to methyl and methylene groups, and addition of
HCl delivered the tris(hydrochloride) salt 25·3HCl in 83%
1. CuSO4, NaHCO3, (Boc)2O
2. 8-quinolinol
O
O
H2N
BocHN
OH
OH
H2O
21
NH2
NH2
1. ClCOOiBu, NMM
2. NH4OH
O
O
Cbz-OSu, NaHCO3
THF/H2O (1:1)
BocHN
BocHN
OH
NH2
NHCbz
THF
22
23
NHCbz
1. BH3•SMe2
2. HCl
O
H
H2, Pd/C
MeOH
N
BocHN
NH2
NH2
toluene
NH2
NH2
24
25•3HCl
•3HCl
Scheme 4 Synthesis of triamine IV with n = 4 (25)
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

D
C. Q. Kabes et al.
Special Topic
Synthesis
The triamine tris(hydrochloride) end products 6·3HCl,
13·3HCl, 20·3HCl, and 25·3HCl have shelf lives of at least
months. However, they are deliquescent and best kept in a
desiccator. Nonetheless, the hydrated forms remain perfect-
ly usable, although they have ‘goo-like’ morphologies. We
have no experience with the shelf lives of the correspond-
ing free bases or triamines, but the series of triamines used
to prepare III (Scheme 1) slowly degrade, presumably due
to oxidation. Furthermore, tris(hydrochloride) adducts of
such triamines can be directly used in methods for prepar-
ing cobalt(III) complexes, as basic leaving groups (e.g., car-
bonate) can serve as ‘deprotecting’ agents.6
The -amino acid starting materials in Schemes 2–4 are
currently priced at $12.80/mol, $7.10/mol, $10.06/mol, and
$16.64/mol, respectively.21 Since the overall yields of
6·3HCl, 13·3HCl, 20·3HCl, and 25·3HCl are 32%, 30%, 33%,
and 38%, these ligands can be expected to be economically
competitive with many others commonly used in enantio-
selective catalysis, despite the costs associated with the in-
tervening steps. Surprisingly, we have been unable to locate
any other derivatives of 1,2-ethylenediamine that incorpo-
rate a secondary amine on the carbon backbone, regardless
of the tether or NHR (or NHAr) substituent. However, there
are a number of related triamines or derivatives,22 some of
which have been employed as tris(hydrochloride) salts and
serve as precursors to tridentate ligands.22a
N-Boc-L-Asparagine (1)24
L-Asparagine (3.00 g, 22.7 mmol, 1.0 equiv) was suspended in a mix-
ture of water (45 mL) and dioxane (45 mL), and K2CO3 (2.41 g, 22.7
mmol, 1.0 equiv) was added. Next, di-tert-butyl dicarbonate (5.95 g,
27.3 mmol, 1.2 equiv) was added in one portion with stirring. After 16
h, the solution was concentrated (to ca. 45 mL) by rotary evaporation
and water (ca. 50 mL) was added. The solution was washed with pe-
troleum ether (3 × 50 mL) and carefully acidified with 12.0 N HCl un-
til no additional white precipitate formed. The precipitate was col-
lected by filtration, washed with water, and dried by passive evapora-
tion (fume hood) for several days to give 1 as a white solid (4.14 g,
17.8 mmol, 79%).
Mp 165.0–165.9 °C (open capillary).25,26
1H NMR (400 MHz, DMSO-d6):  = 12.52 (s, 1 H), 7.32 (s, 1 H), 6.92 (s,
3
1 H), 6.88 (d, JH–H = 8.4 Hz, 1 H), 4.32–4.15 (m, 1 H), 2.49 (partially
obscured dd, 3JH–H = 5.4 Hz, 1 H), 2.41 (dd, 2JH–H = 15.4, 3JH–H = 7.5 Hz, 1
H), 1.38 (s, 9 H).
13C{1H} NMR (100 MHz, DMSO-d6):  = 173.4, 171.4, 155.2, 78.1, 50.2,
36.7, 28.2 (7 × s).
Anal. Calcd for C9H16N2O5 (232.24): C, 46.55; H, 6.94; N, 12.06. Found:
C, 46.65; H, 6.98; N, 12.11.
3-Amino-N-Boc-L-alanine (2)
This compound was prepared from 1 by a literature procedure.13
3-(Ethoxycarbonyl)amino-N-Boc-L-alanine (3)
A suspension of 2 (1.00 g, 4.90 mmol, 1.0 equiv) and NaHCO3 (0.905 g,
10.8 mmol, 2.2 equiv) in a mixture of dioxane (8 mL) and water (8 mL)
was cooled to 0 °C. Ethyl chloroformate (0.56 mL, 5.9 mmol, 1.2 equiv)
was added dropwise with stirring. After the mixture became clear, it
was allowed to warm to room temperature. After 16 h total, water (20
mL) was added. The solution was washed with petroleum ether
(2 × 30 mL), acidified with 12.0 N HCl (monitored with pH paper), and
extracted with EtOAc (3 × 30 mL). The combined extracts were
washed with brine and dried (MgSO4). The solvent was removed by
rotary evaporation to give 3 as a viscous colorless oil (1.294 g, 4.685
mmol, 96%) that was used without further purification.
In summary, this work has shown that a portfolio of en-
antiopure 1,2-ethylenediamines with tethered secondary
amines [(CH2)nNHCH3] are easily accessed from inexpensive
commercially available -amino acids via amide and carba-
mate intermediates. Their application in enantioselective
catalysis will be described in upcoming reports.
All operations were carried out under ambient (air) atmospheres un-
less noted. Capillary thermolyses were monitored with an Optimelt
MPA 100 instrument. NMR spectra were recorded on standard FT
spectrometers at ambient probe temperatures (500 MHz) or 298 K
(400 MHz). Chemical shifts (/ppm) were generally referenced to
solvent signals (1H: CHCl3, 7.26 ppm; HDO, 4.79 ppm;23 DMSO-d5,
2.50 ppm; 13C: CDCl3, 77.16 ppm; D2O, added dioxane at 67.2 ppm;
DMSO-d6, 39.5 ppm). Microanalyses were conducted by Atlantic
Microlab (Georgia, USA).
1H NMR (500 MHz, CDCl3, 40 °C):  = 5.77 (br s, 1 H), 5.38 (br s, 1 H),
4.43–4.24 (m, 1 H), 4.15–4.10 (m, 2 H), 3.69–3.53 (m, 2 H), 1.45 (s, 9
H), 1.31–1.20 (m, 3 H).
13C{1H} (125 MHz, CDCl3, 40 °C):  = 173.4, 157.9, 156.4, 80.8, 61.3,
54.6, 42.7, 28.4, 14.6 (9 × s).
Anal. Calcd for C11H20N2O6 (276.29): C, 47.82; H, 7.30; N, 10.14.
Found: C, 47.93; H, 7.61; N, 9.57.
3-(Ethoxycarbonyl)amino-N-Boc-L-alaninamide (4)
Chemicals were treated as follows: N-methylmorpholine (Alfa Aesar,
99%) and trifluoroacetic acid (EMD, 99.5%), distilled before use; L-as-
paragine (Alfa Aesar, 98+%), L-glutamic acid (multiple sources), diben-
zylamine (Beantown, 98%), methylamine (Beantown, 40 wt% in H2O),
BH3·SMe2 (Alfa Aesar, 2.0 M in toluene), di-tert-butyl dicarbonate
(Chem-Impex International Inc., 99.4%), ethyl chloroformate (Alfa Ae-
sar, 97%), isobutyl chloroformate (Alfa Aesar, 98%), N-(benzyloxycar-
bonyloxy)succinimide (Alfa Aesar, ≥95%), acetyl chloride (TCI, 98%),
Pd/C (Sigma-Aldrich, 10 wt% Pd, dry), and Pd(OH)2/C (Beantown, 20
wt% Pd, ca. 50% H2O), used as received. Routine chemicals not noted
above were used as received from common commercial sources.
A solution of 3 (0.730 g, 2.64 mmol, 1.0 equiv) in anhydrous THF (9
mL) was cooled to –15 °C in a flame-dried flask. Then N-methylmor-
pholine (0.35 mL, 3.2 mmol, 1.2 equiv) was added in one portion un-
der an inert atmosphere with stirring, followed by the dropwise addi-
tion of isobutyl chloroformate (0.41 mL, 3.2 mmol, 1.2 equiv). After
30 min, NH4OH (2 mL) was added and the solution allowed to warm
to room temperature. After 16 h total, the solvent was removed by ro-
tary evaporation and the obtained white residue was dissolved in
EtOAc (50 mL). The solution was washed with water (30 mL), sat.
NaHCO3 (30 mL), and brine (30 mL), and then dried (MgSO4). The sol-
vent was removed by rotary evaporation. The residue was dry loaded
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

E
C. Q. Kabes et al.
Special Topic
Synthesis
onto a silica gel column that was packed and eluted with EtOAc (Rf =
0.3).27 The solvent was removed from the product-containing frac-
tions by rotary evaporation to give 4 as a white solid (0.402 g, 1.46
mmol, 55%).
13C{1H} (100 MHz, CDCl3):  = 175.2, 171.6, 156.3, 136.0, 128.6, 128.3,
128.2, 67.4, 52.3, 50.2, 36.4 (11 × s).
N-Cbz-L-aspartic Acid 1-Dibenzyl Amide 4-Methyl Ester (9)
Mp 168.1–170.0 °C (open capillary).
A round-bottom flask was charged with 8 (3.39 g, 12.0 mmol, 1.0
equiv; in a common embodiment, this represented the product flask
from the previous synthesis) and anhydrous THF (27 mL). The solu-
tion was transferred via cannula to a flame-dried three-neck flask un-
der an inert atmosphere. Then N-methylmorpholine (1.6 mL, 14
mmol, 1.2 equiv) was added in one portion with stirring. The flask
was placed in a –15 °C NaCl/ice bath. Isobutyl chloroformate (1.9 mL,
14 mmol, 1.2 equiv) was slowly added dropwise to give a white slur-
ry. After 30 min, dibenzylamine (3.2 mL, 17 mmol, 1.4 equiv) was
added in one portion and the cold bath removed. After 16 h, the mix-
ture was filtered and the filter cake washed with THF. The solvent was
removed from the combined filtrate/washings by rotary evaporation
and the obtained oily residue was dissolved in EtOAc. The resulting
solution was washed with aqueous citric acid (10% w/v), saturated
NaHCO3, and brine, dried (MgSO4), and taken to dryness by rotary
evaporation. The residue was column chromatographed on silica gel
(30:70 v/v EtOAc/hexanes, Rf = 0.4).27 The solvent was removed from
the product-containing fractions by rotary evaporation and oil pump
vacuum (rt) to give 9 as a colorless oil that slowly became a waxy col-
orless solid (3.4 g, 7.4 mmol, 61%).
1H NMR (500 MHz, DMSO-d6):  = 7.28 (s, 1 H), 7.05 (s, 1 H), 7.03–
3
6.98 (m, 1 H), 6.66 (d, JH–H = 8.3 Hz, 1 H), 4.01–3.89 (m, 3 H), 3.26–
3.15 (m, 1 H), 1.37 (s, 9 H), 1.14 (t, 3JH–H = 7.1 Hz, 3 H).
13C{1H} (100 MHz, DMSO-d6):  = 172.1, 156.4, 155.1, 78.2, 59.8, 54.6,
42.2, 28.2, 14.6 (9 × s).
Anal. Calcd for C11H21N3O5 (275.31): C, 47.99; H, 7.69; N, 15.26.
Found: C, 48.25; H, 7.71; N, 15.02.
(R)-N1-Methyl-1,2,3-triaminopropane Tris(hydrochloride)
(6·3HCl)
A flask was charged with 4 (0.299 g, 1.09 mmol, 1.0 equiv) and CH2Cl2
(2 mL) and cooled to 0 °C. Then trifluoroacetic acid (2 mL) was slowly
added. The solution was stirred for 1 h, and the cold bath removed.
After an additional 2 h, the solvent was removed by rotary evapora-
tion. The residue was dried, first azeotropically with MeOH/toluene
(1:1 v/v, 3 × 10 mL), and then by oil pump vacuum (overnight). The
obtained sticky white residue 528 (see Scheme 2) and BH3·SMe2 (3.8
mL, 2.0 M in toluene, 7.61 mmol, 7.0 equiv) were separately cooled to
0 °C, and slowly combined with stirring. The cold bath was removed,
and after 1 h the solution was refluxed.15 After 36 h, the mixture was
cooled to 0 °C and MeOH (3 mL) was added with stirring. After 1 h, the
solvent was removed by rotary evaporation and 4.0 N HCl (6 mL) was
added. The solution was refluxed for 14 h, cooled to room tempera-
ture, and taken to dryness by rotary evaporation. Then 12.0 N HCl (3
mL) was added, and the solution was cooled to 0 °C. The resulting pre-
cipitate was removed by filtration. The filtrate was taken to dryness
by rotary evaporation. The oily residue was dissolved in water (10
mL), washed with diethyl ether (10 mL), and dried by rotary evapora-
tion and oil pump vacuum (rt, 20 h) to give 6·3HCl as a hygroscopic
white solid (0.206 g, 0.967 mmol, 89%) that was stored in a desiccator
to retard the formation of a goo.29
Mp 60.1–76.8 °C (open capillary).
1H NMR (400 MHz, CDCl3):  = 7.35–7.02 (m, 15 H), 5.76 (d, 3JH–H = 9.3
2
Hz, 1 H), 5.14–5.05 (m, 1 H), 4.92 (q, JH–H = 12.2 Hz, 2 H), 4.70 (d,
2JH–H = 14.8 Hz, 1 H), 4.60 (d, 2JH–H = 16.8 Hz, 1 H), 4.42 (d, 2JH–H = 16.7
2
2
Hz, 1 H), 4.27 (d, JH–H = 14.8 Hz, 1 H), 3.58 (s, 3 H), 2.76 (dd, JH–H
=
15.8, 3JH–H = 6.8 Hz, 1 H), 2.62 (dd, 2JH–H = 15.8, 3JH–H =5.7 Hz, 1 H).
13C{1H} (100 MHz, CDCl3):  = 171.1 (double intensity), 155.5, 136.7,
136.2, 136.0, 129.0, 128.8, 128.6 (double intensity), 128.3, 128.1,
127.9, 127.6, 127.1, 67.2, 52.1, 50.0, 48.4, 48.3, 37.7 (19 × s).
Anal. Calcd for C27H28N2O5 (460.53): C, 70.42; H, 6.13; N, 6.08. Found:
C, 70.28; H, 6.13; N, 6.04.
(S)-2-(Benzyloxycarbonyl)amino-N1,N1-dibenzyl-N4-methyl-
1H NMR (500 MHz, D2O):  = 4.08–3.92 (m, 1 H), 3.57–3.32 (m, 4 H),
butanediamide (10)
2.82 (s, 3 H).
13C{1H} (125 MHz, D2O):  = 48.9, 47.2, 40.0, 34.5 (4 × s)
A round-bottom flask was charged with 9 (2.00 g, 4.34 mmol, 1.0
equiv) and THF (14.5 mL). The resulting suspension was treated with
aqueous methylamine (40 wt%, 3.8 mL, 43 mmol, 10 equiv) with stir-
ring.30 After 16 h, the mixture was taken to dryness by rotary evapo-
ration to give 10 as a fluffy white solid (1.99 g, 4.34 mmol, 100%).
L-Aspartic Acid 4-Methyl Ester Hydrochloride (7)
This compound was prepared from L-aspartic acid by a literature pro-
cedure.16
Mp 166.7–172.8 °C (open capillary).
1H NMR (500 MHz, CDCl3):  = 7.38–7.19 (m, 11 H), 7.22–7.03 (m, 4
H), 6.07 (d, 3JH–H = 8.9 Hz, 1 H), 6.01 (s, 1 H), 5.20–5.10 (m, 1 H), 5.03
(q, J = 12.2 Hz, 2 H), 4.87 (d, 2JH–H = 16.4 Hz, 1 H), 4.80 (d, 2JH–H = 15.1
N-Cbz-L-aspartic Acid 4-Methyl Ester (8)
A round-bottom flask was charged with a suspension of 7 (10.00 g,
54.47 mmol, 1.0 equiv) and K2CO3 (18.82 g, 136.2 mmol, 2.5 equiv) in
acetone (52 mL) and water (69 mL). Then N-(benzyloxycarbonyl-
oxy)succinimide (14.93 g, 59.92 mmol, 1.1 equiv) was added in one
portion with stirring. After 16 h, the solution was washed with dieth-
yl ether (2 × 25 mL) and carefully acidified to pH 4 with 12.0 N HCl
(monitored by pH paper). The milky sample was extracted with EtO-
Ac (3 × 50 mL). The extract was washed with brine and dried (MgSO4).
The solvent was removed by rotary evaporation to give 8 as a viscous
colorless oil (13.07 g, 46.47 mmol, 85%).
2
2
Hz, 1 H), 4.53 (d, JH–H = 16.4 Hz, 1 H), 4.27 (d, JH–H = 15.1 Hz, 1 H),
2.71 (d, 3JH–H = 3.6 Hz, 3 H), 2.68–2.54 (m, 2 H).
13C{1H} (100 MHz, CDCl3):  = 172.5, 170.0, 155.8, 136.5, 136.4, 135.9,
129.0, 128.8, 128.6, 128.21, 128.13, 127.9, 127.7, 127.6, 127.4, 67.1,
50.7, 48.7, 48.5, 39.6, 26.3 (21 × s).
Anal. Calcd for C27H29N3O4 (459.55): C, 70.57; H, 6.36; N, 9.14. Found:
C, 70.36; H, 6.36; N, 9.10.
1H NMR (500 MHz, CDCl3):  = 9.40 (br s, 1 H), 7.45–7.30 (m, 5 H),
(S)-2-Amino-N1,N1-dibenzyl-N4-methylbutanediamide (11)
5.85 (d, 2JH–H = 8.5 Hz, 1 H), 5.14 (s, 2 H), 4.72–4.62 (m, 1 H), 3.71 (s, 3
A Fischer-Porter bottle that had been purged with N2 was charged
with 10 (1.00 g, 2.18 mmol), CH2Cl2 (4 mL), and MeOH (4 mL). Then
Pd/C (10 wt% Pd, 0.050 g, 5 wt% of 10) was added to the solution. The
2
3
2
H), 3.09 (dd, JH–H = 17.4, JH–H = 4.4 Hz, 1 H), 2.89 (dd, JH–H = 17.3,
3JH–H = 4.6 Hz, 1 H).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

F
C. Q. Kabes et al.
Special Topic
Synthesis
bottle was pressurized with 50 psig of H2 and after a few minutes
vented. This step was repeated three times. The bottle was then pres-
surized with 75 psig of H2, and the mixture stirred overnight. The
sample was vented and filtered through Celite. The filter cake was
washed with MeOH (ca. 50 mL) and the solvent was removed from
the filtrate/washings by rotary evaporation. The obtained viscous col-
orless residue was passed through a silica gel column (8:92 v/v
MeOH/CH2Cl2).27 The solvent was removed from the product-contain-
ing fractions by oil pump vacuum (rt, 16 h) to give 11 as a viscous col-
orless oil (0.703 g, 2.16 mmol, 99%).
a 55 °C oil bath. The mixture was stirred. After 48 h, the bath was re-
moved and the bottle vented. The contents were filtered through
Celite. The filter cake was washed with MeOH, and the solvent re-
moved from the filtrate/washings by rotary evaporation. The yellow
residue was dissolved in water (10 mL) and washed with diethyl ether
(10 mL). The aqueous layer was taken to dryness by rotary evapora-
tion and oil pump vacuum (rt) to give 13·3HCl as a viscous yellow oil
(0.540 g, 2.47 mmol, 91%) that was stored in a desiccator.29
1H NMR (500 MHz, D2O):  = 3.78 (quin, 3JH–H = 6.6 Hz, 1 H), 3.46–3.33
(m, 2 H), 3.30–3.14 (m, 2 H), 2.76 (s, 3 H), 2.26–2.11 (m, 2 H).
13C{1H} (100 MHz, D2O):  = 47.8, 45.3, 41.3, 33.6, 27.5 (5 × s).
1H NMR (400 MHz, CDCl3):  = 7.42–7.21 (m, 7 H), 7.20–7.10 (m, 4 H),
2
2
4.98 (d, JH–H = 14.9 Hz, 1 H), 4.68 (d, JH–H = 17.0 Hz, 1 H), 4.43–4.26
(m, 2 H), 4.11 (d, 2JH–H = 14.9 Hz, 1 H), 3.69 (s, 2 H), 2.71 (d, 3JH–H = 4.8
Hz, 3 H), 2.68–2.54 (m, 2 H).
L-Glutamic Acid 5-Methyl Ester Hydrochloride (14)
A round-bottom flask was charged with MeOH (25 mL) and cooled to
0 °C. Acetyl chloride (6.8 mL, 95 mmol, 1.4 equiv) was added drop-
wise and the solution stirred for 30 min. In a separate flask, a slurry of
L-glutamic acid (10.00 g, 67.97 mmol, 1.0 equiv) in MeOH (25 mL) was
cooled to 0 °C. The solution was then added dropwise to the slurry at
0 °C. The mixture was stirred at 4 °C (20 h) and then concentrated to
ca. one third the original volume by rotary evaporation while main-
taining a temperature below 10 °C. Diethyl ether was added until the
product precipitated (ca. 125 mL). The precipitate was collected by fil-
tration and dried by oil pump vacuum (rt) to give 14 as a white solid
(9.800 g, 49.59 mmol, 73%) that was used without further purifica-
tion.
13C{1H} (100 MHz, CDCl3):  = 173.4, 170.5, 136.5, 135.9, 129.2, 128.9,
128.1 128.0, 127.7, 126.8, 49.9, 49.0, 48.7, 40.4, 26.3 (15 × s).
Anal. Calcd for C19H23N3O2 (325.41): C, 70.13; H, 7.12; N, 12.91.
Found: C, 68.94; H, 7.28; N, 12.55.31
(S)-1-(Dibenzyl)amino-2-amino-4-(methylamino)butane (12)
A flame-dried three-neck flask was charged with 11 (1.20 g, 3.70
mmol, 1.0 equiv) and anhydrous toluene (3 mL) under an inert atmo-
sphere, and was cooled to 0 °C. Then BH3·SMe2 (9.25 mL, 2.0 M in tol-
uene, 18.5 mmol, 5.0 equiv) was added to the slurry with stirring, and
the cold bath removed. After 30 min, the resulting solution was slowly
heated to reflux.15 After 20 h, the sample was cooled to room tem-
perature, and 10% HCl was slowly added dropwise with vigorous stir-
ring until no further foaming occurred. The solution was neutralized
with 2.0 N aqueous NaOH, and solid KOH (7.5 g) was added (Caution!
Exothermic). The mixture was again refluxed (16 h), and after cooling
the cloudy aqueous phase was separated. Water was added until the
phase became clear (ca. 10 mL). It was then extracted with EtOAc
(2 × 40 mL). The extracts were washed with water and brine (2 × 30
mL), dried (Na2SO4), and taken to dryness by rotary evaporation. The
resulting oil was dissolved in THF (5 mL) and 12.0 N HCl (1.0 mL) add-
ed. The obtained milky sample was taken to dryness by rotary evapo-
ration and the residue dissolved in water (25 mL). The aqueous phase
was washed with diethyl ether (2 × 30 mL) and made basic with 2.0 N
aqueous NaOH. The oily white suspension was extracted with EtOAc
(3 × 30 mL). The combined extracts were washed with brine, dried
(Na2SO4), and taken to dryness by rotary evaporation and oil pump
vacuum (rt) to give 12 as a clear oil (0.738 g, 2.48 mmol, 67%).
Mp 143.4–148.1 °C (open capillary).
1H NMR (400 MHz, D2O):  = 4.11 (t, 3JH–H = 6.7 Hz, 1 H), 3.71 (s, 3 H),
2.74–2.53 (m, 2 H), 2.44–2.09 (m, 2 H).
13C{1H} (100 MHz, D2O):  = 175.6, 172.4, 53.0, 52.9, 30.0, 25.5 (6 × s).
N-Cbz-glutamic Acid 5-Methyl Ester (15)
A round-bottom flask was charged with a suspension of 14 (5.00 g,
25.3 mmol, 1.0 equiv) and NaHCO3 (4.46 g, 53.1 mmol, 2.1 equiv) in
water (28 mL) and THF (56 mL). Then N-(benzyloxycarbonyloxy)suc-
cinimide (6.94 g, 27.8 mmol, 1.1 equiv) was added in one portion
with stirring. After 15 h, the mixture was concentrated by rotary
evaporation (removing THF), and water (20 mL) was added. The solu-
tion was washed with petroleum ether (50 mL) and carefully acidified
to pH 4 with 12.0 N HCl (ca. 7 mL, monitored by pH paper). The milky
sample was extracted with EtOAc (3 × 50 mL). The extract was
washed with brine (30 mL) and dried (MgSO4). The solvent was re-
moved by rotary evaporation to give 15 as a colorless oil (7.36 g, 24.9
mmol, 99%).
1H NMR (400 MHz, CDCl3):  = 7.38–7.28 (m, 8 H), 7.27–7.20 (m, 2 H)
2
2
3.74 (d, JH–H = 13.5 Hz, 2 H), 3.40 (d, JH–H = 13.5 Hz, 2 H), 3.01–2.93
(m, 1 H), 2.62 (t, J = 7.0 Hz, 2 H), 2.39 (s, 3 H), 2.35 (dd, 2JH–H = 12.5,
3JH–H = 4.3 Hz, 1 H), 2.29 (dd, 2JH–H = 12.5, 3JH–H = 9.2 Hz, 1 H), 1.62–1.53
(m, 1 H), 1.49 (br s, 1 H), 1.34–1.22 (m, 1 H).
1H NMR (400 MHz, CDCl3):  = 10.00 (s, 1 H), 7.44–7.25 (m, 5 H), 5.59
(d, 3JH–H = 8.1 Hz, 1 H), 5.17–5.04 (m, 2 H), 4.50–4.38 (m, 1 H), 3.65 (s,
3 H), 2.56–2.34 (m, 2 H), 2.29–2.17 (m, 1 H), 2.09–1.92 (m, 1 H).
13C{1H} (100 MHz, CDCl3):  = 139.4, 129.1, 128.4, 127.1, 61.7, 59.1,
13C{1H} (100 MHz, CDCl3):  = 175.6, 173.8, 156.5, 136.1, 128.7, 128.4,
49.5, 47.7, 36.4, 35.1 (10 × s).
128.2, 67.4, 53.3, 52.1, 30.2, 27.3 (12 × s).
Anal. Calcd for C19H27N3 (297.45): C, 76.72; H, 9.15; N, 14.13. Found:
C, 72.78; H, 8.93; N, 13.01.31
Anal. Calcd for C14H17NO6 (295.29): C, 56.95; H, 5.80; N, 4.74. Found:
C, 55.38; H, 5.75; N, 4.80.31
(S)-1,2-Diamino-4-(methylamino)butane Tris(hydrochloride)
N-Cbz-Glutamic Acid 1-Dibenzyl Amide 5-Methyl Ester (16)
(13·3HCl)
A flame-dried flask was charged with a solution of 15 (5.16 g, 17.5
mmol, 1.0 equiv) in anhydrous THF (58 mL) under an inert atmo-
sphere and cooled to –15 °C (NaCl/ice bath). Then N-methylmorpho-
line (2.3 mL, 21 mmol, 1.2 equiv) was added in one portion with stir-
ring. Next isobutyl chloroformate (2.7 mL, 21 mmol, 1.2 equiv) was
added dropwise to give a white slurry. After 45 min, dibenzylamine
(4.7 mL, 24 mmol, 1.4 equiv) was added in one portion and the cold
A Fischer-Porter bottle that had been purged with N2 was sequential-
ly charged with a solution of 12 (0.810 g, 2.72 mmol) in MeOH (9 mL),
12.0 N HCl (1.0 mL), Pd/C (10 wt%, 0.121 g), and Pd(OH)2/C (20 wt%,
0.121 g). The bottle was pressurized with 50 psig of H2 and after a few
minutes vented. This step was repeated three times. The bottle was
then pressurized with 75 psig of H2, and the bottom portion placed in
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

G
C. Q. Kabes et al.
Special Topic
Synthesis
bath removed. After 16 h, the mixture was filtered and the filter cake
washed with THF. The solvent was removed from the combined fil-
trate/washings by rotary evaporation and the obtained oily residue
was dissolved in EtOAc. The resulting solution was washed with aque-
ous citric acid (10% w/v), saturated NaHCO3, and brine, dried (MgSO4),
and taken to dryness by rotary evaporation. The residue was column
chromatographed on silica gel (30:70 v/v EtOAc/hexanes, Rf = 0.4).27
The solvent was removed from the product-containing fractions by
oil pump vacuum to give 16 as a colorless oil that slowly became a
waxy colorless solid (7.20 g, 15.2 mmol, 87%).
1H NMR (400 MHz, CDCl3):  = 7.60–7.22 (m, 6 H), 7.24–7.08 (m, 4 H),
5.92 (s, 1 H), 5.18 (d, 2JH–H = 14.8 Hz, 1 H), 4.81 (d, 2JH–H = 17.2 Hz, 1 H),
4.34 (d, 2JH–H = 17.2 Hz, 1 H), 4.08 (d, 2JH–H = 14.8 Hz, 1 H), 3.67 (dd, J =
9.6, 3.3 Hz, 1 H), 2.72 (d, 3JH–H = 4.8 Hz, 3 H), 2.52–2.39 (m, 1 H), 2.35–
2.23 (m, 1 H), 2.18–2.03 (m, 1 H), 1.80 (s, 2 H), 1.73–1.59 (m, 1 H).
13C{1H} (100 MHz, CDCl3):  = 176.6, 173.1, 137.2, 136.9, 129.1, 128.8,
128.1, 127.7, 127.6, 126.5, 50.9, 49.5, 48.9, 32.2, 30.9, 26.3 (16 × s).
Anal. Calcd for C20H25N3O2 (339.44): C, 70.77; H, 7.42; N, 12.38.
Found: C, 69.60; H, 7.62; N, 12.05.31
Mp 73.8–76.7 °C (open capillary).
(S)-1-(Dibenzyl)amino-2-amino-5-(methylamino)pentane (19)
1H NMR (500 MHz, CDCl3):  = 7.40–7.27 (m, 11 H), 7.23–7.13 (m, 4
A flame-dried three-neck flask was charged with 18 (1.05 g, 3.09
mmol, 1.0 equiv) and anhydrous toluene (3 mL) under an inert atmo-
sphere, and was cooled to 0 °C. Then BH3·SMe2 (7.7 mL, 2.0 M in tolu-
ene, 15 mmol, 5.0 equiv) was added to the slurry with stirring, and
the cold bath removed. After 30 min, the resulting solution was slowly
heated to reflux.15 After 20 h, the sample was cooled to room tem-
perature, and 10% HCl was slowly added dropwise with vigorous stir-
ring until no further foaming occurred. The solution was neutralized
with 2.0 N aqueous NaOH, and solid KOH (7.5 g) was added (Caution!
Exothermic). The mixture was again refluxed (16 h), and after cooling
the cloudy aqueous phase was separated. Water was added until it be-
came clear (ca. 10 mL). It was then extracted with EtOAc (2 × 40 mL).
The extracts were washed with water and brine (2 × 30 mL), dried
(Na2SO4), and taken to dryness by rotary evaporation. The resulting
oil was dissolved with THF (5 mL) and 12.0 N HCl (1.0 mL) added. The
obtained milky sample was taken to dryness by rotary evaporation
and the residue dissolved in water (25 mL). The aqueous phase was
washed with diethyl ether (2 × 30 mL) and made basic with 2.0 N
aqueous NaOH. The oily white suspension was extracted with EtOAc
(3 × 30 mL). The combined extracts were washed with brine, dried
(Na2SO4), and taken to dryness by rotary evaporation and oil pump
vacuum (rt) to give 19 as a clear oil (0.805 g, 2.59 mmol, 84%).
H), 5.75 (d, 3JH–H = 8.6 Hz, 1 H), 5.20–5.03 (m, 2 H), 4.92 (d, 2JH–H = 14.7
2
Hz, 1 H), 4.90–4.85 (m, 1 H), 4.79 (d, JH–H = 16.5 Hz, 1 H), 4.41 (d,
2JH–H = 16.5 Hz, 1 H), 4.20 (d, 2JH–H = 14.8 Hz, 1 H), 3.63 (s, 3 H), 2.47
(dt, 2JH–H = 15.6, 3JH–H = 7.7 Hz, 1 H), 2.39 (dt, 2JH–H = 17.1, 3JH–H = 6.2 Hz,
1 H), 2.20–2.07 (m, 1 H), 1.93–1.77 (m, 1 H).
13C{1H} (100 MHz, CDCl3):  = 173.4, 172.3, 156.3, 136.8, 136.4, 135.9,
129.1, 128.9, 128.7, 128.28, 128.25, 128.1, 128.0, 127.7, 127.2, 67.1,
51.9, 50.6, 49.8, 48.0, 29.6, 28.9 (22 × s).
Anal. Calcd for C28H30N2O5 (474.56): C, 70.87; H, 6.37; N, 5.90. Found:
C, 70.81; H, 6.44; N, 5.89.
(S)-2-(Benzyloxycarbonyl)amino-N1,N1-dibenzyl-N5-methyl-
pentanediamide (17)
A round-bottom flask was charged with 16 (3.00 g, 6.32 mmol, 1.0
equiv) and THF (31 mL). The suspension was treated with aqueous
methylamine (40 wt%, 5.5 mL, 63 mmol, 10 equiv) with stirring.30 Af-
ter 36 h, the sample was taken to dryness by rotary evaporation to
give 17 as a fluffy white solid (2.97 g, 6.28 mmol, 99%).
Mp 135.2–138.5 °C (open capillary).
1H NMR (400 MHz, CDCl3):  = 7.45–7.23 (m, 11 H), 7.21–7.10 (m, 4
H), 6.17 (s, 1 H), 6.01 (d, 3JH–H = 8.4 Hz, 1 H), 5.17–5.03 (m, 3 H), 4.74–
1H NMR (500 MHz, CDCl3):  = 7.41–7.28 (m, 8 H), 7.25–7.19 (m, 2 H),
2
2
2
2
4.62 (m, 2 H), 4.29 (d, JH–H = 16.8 Hz, 1 H), 4.00 (d, JH–H = 14.8 Hz, 1
H), 2.66 (d, 3JH–H = 4.8 Hz, 3 H), 2.29–2.22 (m, 2 H), 2.22–2.14 (m, 1 H),
1.89–1.79 (m, 1 H).
3.75 (d, JH–H = 13.5 Hz, 2 H), 3.36 (d, JH–H = 13.5 Hz, 2 H), 2.98–2.79
(m, 1 H), 2.57–2.48 (m, 2 H), 2.40 (s, 3 H), 2.36 (dd, 2JH–H = 12.6, 3JH–H
=
3.8 Hz, 1 H), 2.27 (dd, 2JH–H = 12.6, 3JH–H = 9.6 Hz, 1 H), 1.62–1.30 (m, 6
13C{1H} (100 MHz, CDCl3):  = 172.8, 172.1, 156.8, 136.6, 136.3, 135.8,
129.1, 128.9, 128.7, 128.3, 128.2, 128.1, 128.0, 127.8, 126.9, 67.1, 50.7,
49.7, 48.2, 32.4, 31.0, 26.4 (22 × s).
H), 1.21–1.10 (m, 1 H).
13C{1H} (125 MHz, CDCl3):  = 139.4, 129.0, 128.3, 127.1, 61.6, 59.1,
52.3, 48.6, 36.5, 33.4, 26.6 (11 × s).
Anal. Calcd for C28H31N3O4 (473.57): C, 71.02; H, 6.60; N, 8.87. Found:
C, 71.25; H, 6.65; N, 8.77.
Anal. Calcd for C20H29N3 (311.47): C, 77.12; H, 9.39; N, 13.49. Found:
C, 75.22; H, 9.48; N, 12.85.31
(S)-2-Amino-N1,N1-dibenzyl-N5-methylpentanediamide (18)
(S)-1,2-Diamino-5-(methylamino)pentane Tris(hydrochloride)
(20·3HCl)
A Fischer-Porter bottle that had been purged with N2 was charged
with 17 (4.00 g, 8.45 mmol), CH2Cl2 (12 mL), and MeOH (12 mL). Then
Pd/C (10 wt% Pd, 0.200 g, 5 wt% of 17) was added to the solution. The
bottle was pressurized with 50 psig of H2 and after a few minutes
vented. This step was repeated three times. The bottle was then pres-
surized with 75 psig of H2, and the mixture stirred overnight. The
sample was vented and filtered through Celite. The filter cake was
washed with MeOH (ca. 50 mL) and the solvent was removed from
the filtrate/washings by rotary evaporation. The viscous colorless res-
A Fischer-Porter bottle that had been purged with N2 was sequential-
ly charged with a solution of 19 (0.735 g, 2.36 mmol) in MeOH (8 mL),
12.0 N HCl (1 mL), Pd/C (10 wt%, 0.075 g), and Pd(OH)2/C (20 wt%,
0.075 g).18 The bottle was pressurized with 50 psig of H2 and after a
few minutes vented. This step was repeated three times. The bottle
was then pressurized with 75 psig of H2 and the mixture was stirred.
After 4 d, the bottom portion of the bottle was placed in a 55 °C bath.
After 3 d, the bath was removed and the bottle vented. The contents
were filtered through Celite. The filter cake was washed with MeOH,
and the solvent removed from the filtrate/washings by rotary evapo-
ration. The yellow residue was dissolved in water (10 mL) and washed
with diethyl ether (10 mL). The aqueous layer was taken to dryness by
rotary evaporation and oil pump vacuum (rt) to give 20·3HCl as a vis-
cous yellow oil (0.434 g, 1.80 mmol, 76%) that was stored in a desicca-
tor.29
idue was passed through
a short silica gel column (8:92 v/v
MeOH/CH2Cl2).27 The solvent was removed from the product-contain-
ing fractions by oil pump vacuum (rt, 16 h) to give 18 as an amor-
phous white solid (2.37 g, 6.97 mmol, 83%).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

H
C. Q. Kabes et al.
Special Topic
Synthesis
1H NMR (500 MHz, D2O):  = 3.72–3.60 (m, 1 H), 3.38–3.28 (m, 2 H),
(S)-1,2-Diamino-6-(methylamino)hexane Tris(hydrochloride)
3.13–3.01 (m, 2 H), 2.71 (s, 3 H), 1.91–1.71 (m, 4 H).
(25·3HCl)
13C{1H} (100 MHz, D2O):  = 49.7, 48.7, 41.2, 33.4, 27.8, 22.0 (6 × s).
A flame-dried three-neck flask was charged with 24 (0.440 g, 1.79
mmol, 1.0 equiv) and cooled to 0 °C. A sample of BH3·SMe2 (5.4 mL,
2.0 M in toluene, 10.76 mmol, 6.0 equiv) was cooled to 0 °C and added
dropwise with stirring under an inert atmosphere. The cold bath was
removed. After 1 h, the solution was refluxed.15 After 36 h, the mix-
ture was worked up exactly as described for 6·3HCl. This gave 25·3HCl
as a hygroscopic white solid (0.381 g, 1.50 mmol, 83%) that was
stored in a desiccator to retard the formation of a goo.29
N6-Boc-L-lysine (21)
This compound was prepared from L-lysine by a literature proce-
dure.19
N2-Cbz-N6-Boc-L-lysine (22)
This compound was prepared from 21 according to a patent.20
1H NMR (500 MHz, D2O):  = 3.69–3.57 (m, 1 H), 3.40–3.24 (m, 2 H),
3.09–2.99 (m, 2 H), 2.69 (s, 3 H), 1.90–1.63 (m, 4 H), 1.61–1.36 (m, 2
H).
N2-Cbz-N6-Boc-L-lysinamide (23)
A flame-dried three-neck flask was charged with 22 (2.44 g, 6.42
mmol, 1.0 equiv) and anhydrous THF (8 mL) under an inert atmo-
sphere and placed in a –15 °C NaCl/ice bath. Then N-methylmorpho-
line (0.85 mL, 7.7 mmol, 1.2 equiv) was added in one portion with
stirring, followed by the dropwise addition of isobutyl chloroformate
(1.0 mL, 7.7 mmol, 1.2 equiv). A white solid formed. After 30 min,
NH4OH (5 mL) was added and the cold bath removed. After 3 h, the
solvent was removed by rotary evaporation and the residue dissolved
in EtOAc (100 mL). The solution was washed with sat. NaHCO3 and
brine (50 mL), and then dried (MgSO4). The solvent was removed by
rotary evaporation. The residue was column chromatographed on sil-
ica gel (4:96 v/v MeOH/CH2Cl2, Rf = 0.3).27 The solvent was removed
from the product-containing fractions by rotary evaporation to give
23 as a white solid (2.09 g, 5.50 mmol, 86%).
13C{1H} (125 MHz, D2O):  = 49.9, 49.2, 41.3, 33.4, 30.2, 25.7, 22.0
(7 × s).
Funding Information
The authors thank the Welch Foundation (Grant A-1656) for support.Welch
F
o
u
n
d
ati
o
n
(A-1
6
5
6)
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707146.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orit
n
gInformati
o
n
Mp 138.1–141.5 °C (open capillary).
1H NMR (500 MHz, DMSO-d6):  = 7.44–7.28 (m, 6 H), 7.26 (d, 3JH–H
=
References
8.2 Hz, 1 H), 7.05–6.90 (m, 1 H), 6.77 (t, 3JH–H = 5.8 Hz, 1 H), 5.01 (s, 2
H), 3.91–3.84 (m, 1 H), 2.96–2.77 (m, 2 H), 1.65–1.54 (m, 1 H), 1.54–
1.43 (m, 1 H), 1.41–1.16 (m, 13 H).
(1) Noyori, R.; Kitamura, M. Enantioselective Catalysis with Metal
Complexes. An Overview, In Modern Synthetic Methods, Vol. 5;
Springer: Berlin, 1989, 115–198.
13C{1H} (125 MHz, DMSO-d6):  = 174.0, 156.0, 155.6, 137.1, 128.3,
(2) (a) Denmark, S. E.; Beutner, G. L. Angew. Chem. Int. Ed. 2008, 47,
1560; Angew. Chem. 2008, 120, 1584. (b) Fu, G. C. Acc. Chem. Res.
2000, 33, 412. (c) Taylor, J. E.; Bull, S. D.; Williams, J. M. J. Chem.
Soc. Rev. 2012, 41, 2109.
127.8, 127.7, 77.4, 65.4, 54.5, 31.6, 29.2, 28.3, 22.9 (14 × s).
Anal. Calcd for C19H29N3O5 (379.46): C, 60.14; H, 7.70; N, 11.07.
Found: C, 60.25; H, 7.86; N, 11.00.
(3) Kizirian, J.-C. Chem. Rev. 2008, 108, 140.
N6-Boc-L-lysinamide (24)
(4) (a) Ganzmann, C.; Gladysz, J. A. Chem. Eur. J. 2008, 14, 5397.
(b) Maximuck, W. J.; Ganzmann, C.; Alvi, S.; Hooda, K. R.;
Gladysz, J. A. Dalton Trans. 2020, 49, 3680.
A Fischer-Porter bottle that had been purged with N2 was charged
with 23 (2.08 g, 5.48 mmol) and MeOH (18 mL). Then Pd/C (10 wt%
Pd, 0.200 g, 10 wt% of 23) was added to the solution. The bottle was
pressurized with 50 psig of H2 and after a few minutes vented. This
step was repeated three times. The bottle was then pressurized with
75 psig of H2, and the mixture stirred overnight. The sample was
vented and filtered through Celite. The filter cake was washed with
MeOH (ca. 50 mL). The solvent was removed from the filtrate/wash-
ings by rotary evaporation. The residue was column chromato-
graphed on silica gel (15:82:3 v/v/v MeOH/EtOAc/NH4OH, Rf = 0.4).27
The solvent was removed from the product-containing fractions by
rotary evaporation to give 24 as a white solid (1.22 g, 4.97 mmol,
91%).
(5) (a) Lewis, K. G.; Ghosh, S. K.; Bhuvanesh, N.; Gladysz, J. A. ACS
Cent. Sci. 2015, 1, 50. (b) Kumar, A.; Ghosh, S. K.; Gladysz, J. A.
Org. Lett. 2016, 18, 760. (c) Joshi, H.; Ghosh, S. K.; Gladysz, J. A.
Synthesis 2017, 49, 3905. (d) Maximuck, W. J.; Gladysz, J. A. Mol.
Catal. 2019, 473, 110360. (e) Kabes, C. Q.; Maximuck, W. J.;
Ghosh, S. K.; Kumar, A.; Bhuvanesh, N.; Gladysz, J. A. ACS Catal.
2020, 10, 3249. (f) Luu, Q. H.; Gladysz, J. A. Chem. Eur. J. 2020, 26,
in press; DOI: 10.1002/chem.202001639.
(6) Ghosh, S. K.; Ganzmann, C.; Bhuvanesh, N.; Gladysz, J. A. Angew.
Chem. Int. Ed. 2016, 55, 4356; Angew. Chem. 2016, 128, 4429.
(7) (a) Belokon, Y. N.; Maleev, V. I.; North, M.; Larionov, V. A.;
Savel’yeva, T. F.; Nijland, A.; Nelyubina, Y. V. ACS Catal. 2013, 3,
1951. (b) Maleev, V. I.; North, M.; Larionov, V. A.; Fedyanin, I. V.;
Savel’yeva, T. F.; Moscalenko, M. A.; Smolyakov, A. F.; Belokon, Y.
N. Adv. Synth. Catal. 2014, 356, 1803. (c) Larionov, V. A.;
Markelova, E. P.; Smol’yakov, A. F.; Savel’yeva, T. F.; Maleev, V. I.;
Belokon, Y. N. RSC Adv. 2015, 5, 72764. (d) Rulev, Y. A.; Larionov,
V. A.; Lokutova, A. V.; Moskalenko, M. A.; Lependina, O. L.;
Maleev, V. I.; North, M.; Belokon, Y. N. ChemSusChem 2016, 9,
216.
Mp 102.2–104.0 °C (open capillary).
1H NMR (500 MHz, CDCl3):  = 7.10 (s, 1 H), 5.85 (s, 1 H), 4.66 (s, 1 H),
3.34 (dd, 3JH–H = 8.0, 3JH–H = 4.5 Hz, 1 H), 3.15–3.02 (m, 2 H), 1.89–1.72
(m, 1 H), 1.61–1.44 (m, 5 H), 1.44–1.32 (m, 11 H).
13C{1H} (125 MHz, CDCl3):  = 178.3, 156.2, 79.2, 55.1, 40.2, 34.7, 30.0,
28.5, 22.9 (9 × s).
Anal. Calcd for C11H23N3O3 (245.32): C, 53.86; H, 9.45; N, 17.13.
Found: C, 54.06; H, 9.57; N, 16.93.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

I
C. Q. Kabes et al.
Special Topic
Synthesis
(8) Werner, A. V. Ber. Dtsch. Chem. Ges. 1912, 45, 121.
(9) Ghosh, S. K.; Ganzmann, C.; Gladysz, J. A. Tetrahedron: Asymme-
try 2015, 26, 1273.
(10) (a) Erkkilä, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107,
5416. (b) Brazier, J. B.; Tomkinson, N. C. O. Secondary and
Primary Amine Catalysts for Iminium Catalysis, In Asymmetric
Organocatalysis. Topics in Current Chemistry, Vol. 291; List, B.,
Ed.; Springer: Berlin, 2010, 281–347. (c) Melchiorre, P.; Marigo,
M.; Carlone, A.; Bartoli, G. Angew. Chem. Int. Ed. 2008, 47, 6138;
Angew. Chem. 2008, 120, 6232.
(22) (a) Comba, P.; Maeder, M.; Zipper, L. Helv. Chim. Acta 1989, 72,
1029. (b) Cox, J. P. L.; Craig, A. S.; Helps, I. M.; Jankowski, K. J.;
Parker, D.; Eaton, M. A. W.; Millican, A. T.; Millar, K.; Beeley, N.
R. A.; Boyce, B. A. J. Chem. Soc., Perkin. Trans. 1 1990, 2567.
(c) Treder, A. P.; Andruszkiewicz, R.; Zgoda, W.; Ford, C.;
Hudson, A. Bioorg. Med. Chem. Lett. 2009, 19, 1009.
(23) Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem. 1997, 62,
7512.
(24) Vizcaino, M. L.; Engel, P.; Trautman, E.; Crawford, J. M. J. Am.
Chem. Soc. 2014, 136, 9244.
(11) The configurations of the products derived from the L-amino
acid starting materials in Schemes 2–4 are not specified in their
numerical abbreviations in the main text but can be inferred
from the Schemes and are provided in the bold headers in the
experimental section. All reactions occur with retention of rela-
tive configuration.
(25) This melting point is somewhat lower than those reported in
the literature, see ref 26.
(26) (a) Azuse, I.; Tamura, M.; Kinomura, K.; Okai, H.; Kouge, K.;
Hamatsu, F.; Koizumi, T. Bull. Chem. Soc. Jpn. 1989, 62, 3103.
(b) Pícha, J.; Buděšínský, M.; Macháčková, K.; Collinsová, M.;
Jiráček, J. J. Peptide Sci. 2017, 23, 202.
(12) Mittapalli, G. K.; Reddy, K. R.; Xiong, H.; Munoz, O.; Han, B.; De
Riccardis, F.; Krishnamurthy, R.; Eschenmoser, A. Angew. Chem.
Int. Ed. 2007, 46, 2470; Angew. Chem. 2007, 119, 2522.
(13) Stojković, M. R.; Piotrowski, P.; Schmuck, C.; Piantandia, I. Org.
Biomol. Chem. 2015, 13, 1629.
(27) For purifications involving column chromatography, ca. 20
grams of silica gel (Silicycle 230–400 mesh) were used for each
gram of sample. Any attendant Rf values were obtained on
Merck 60 silica gel TLC plates (F254).
(28) In a separate experiment, compound 5 was further purified via
(14) Patel, B. A.; Abel, B.; Barbuti, A. M.; Velagapudi, U. K.; Chen, Z.;
Ambudkar, S. V.; Talele, T. T. J. Med. Chem. 2018, 61, 834.
(15) Bonnat, M.; Heercouet, A.; Le Corre, M. Synth. Commun. 1991,
21, 1579.
silica
gel
column
chromatography
(15:82:3
v/v/v
MeOH/EtOAc/NH4OH). 1H NMR (500 MHz, DMSO-d6):  = 7.55
3
(s, 1 H), 7.27 (s, 1 H), 7.09 (s, 1 H), 3.98 (q, JH–H = 7.1 Hz, 2 H),
3.17–3.07 (m, 1 H), 1.16 (t, JH–H = 7.1 Hz, 3 H). 13C{1H} (125
3
(16) Wojciechowski, F.; Suchy, M.; Li, A. X.; Azab, H. A.; Bartha, R.;
Hudson, R. H. E. Bioconjugate Chem. 2007, 18, 1625.
(17) (a) Wang, S.; Zhang, Y.; Li, Q.; Sun, R.; Ma, L.; Li, L. Aust. J. Chem.
2017, 70, 52. (b) More, S. S.; Vince, R. J. Med. Chem. 2009, 52,
4650. (c) Lammnes, T. M.; Le Nôtre, J.; Franssen, M. C. R.; Scott,
E. L.; Sanders, J. P. M. ChemSusChem 2011, 4, 785.
MHz, DMSO-d6):  = 173.1, 156.5, 59.9, 54.1, 43.7, 14.7 (6 × s).
(29) Appropriate microanalyses could not be obtained for the
tris(hydrochloride) salts of the title compounds, presumably
due to their hygroscopic nature, as detailed in the text. The data
were always a better but still imperfect fit to mono- or dihy-
drates (low C, low N).
(18) Li, Y.; Manickam, G.; Ghoshal, A.; Subramaniam, P. Synth.
Commun. 2006, 36, 925.
(30) Caution! Septa appeared to degrade and contaminate the
sample, and were therefore avoided.
(19) Bindman, N. A.; Bobeica, S. C.; Liu, W. R.; van der Donk, W. A.
J. Am. Chem. Soc. 2015, 137, 6975.
(20) Zheng, G. (Stealth BioTherapeutics Corp., Monaco)
WO2019/099481, Chem. Abstr. 2019, 171, 26404
(21) The prices quoted for the amino acids are derived from one kg
quantities available from the supplier VWR Life Science at
us.vwr.com/store (accessed April 27, 2020).
(31) (a) This sample cannot be represented as analytically pure, but
the microanalytical data are nonetheless presented to illustrate
the best results obtained to date. (b) Gabbaï, F. P.; Chirik, P. J.;
Fogg, D. E.; Meyer, K.; Mindiola, D. J.; Schafer, L. L.; You, S.-L.
Organometallics 2016, 35, 3255.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I