Synthesis of enantioenriched 1,2-trans-diamines using the borono-Mannich reaction with N-protected α-amino aldehydes

Article abstract of DOI:10.1039/c5cc01716e

The three-component Petasis borono-Mannich reaction starting with easily accessible N-protected α-amino aldehydes produces efficiently and diastereoselectively 1,2-trans-diamines with an enantiomeric excess of up to 98%.

Full text of DOI:10.1039/c5cc01716e

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Synthesis of enantioenriched 1,2-trans-diamines
using the borono-Mannich reaction with
N-protected a-amino aldehydes†
Cite this:DOI: 10.1039/c5cc01716e
Received 26th February 2015,
Accepted 8th May 2015
Stephanie Norsikian,*a Margaux Beretta,a Alexandre Cannillo,a Amelie Martin,a
´
´
Pascal Retailleaua and Jean-Marie Beau*ab
DOI: 10.1039/c5cc01716e
www.rsc.org/chemcomm
The three-component Petasis borono-Mannich reaction starting
with easily accessible N-protected a-amino aldehydes produces
efficiently and diastereoselectively 1,2-trans-diamines with an
enantiomeric excess of up to 98%.
The Petasis borono-Mannich (PBM) process is a one-pot coupling of
an aryl or a vinylic boronic acid with an amine and a carbonyl
compound.1 This powerful reaction constitutes one of the most
direct and mild methods for preparing geometrically pure
allylamines. Usually, the Petasis reaction relies on the presence
of a hydroxyl or a carboxylic acid group proximate to the
reacting carbonyl group. This allows the activation of the
organoboronic acid as an ‘‘ate’’ complex followed by intramolecular
organyl ligand transfer to a transient iminium species.2 By taking
Scheme 1 Three-component coupling between boronic acid 1a, N,N-
diallylamine 2a and N-tosyl amino aldehyde 3a. X-ray structure of diamine
5. For conditions see Table 1.
advantage of the directing effect of the a-hydroxyl group of chiral aldehydes is particularly challenging since it is known to be
aldehydes,3 this reaction leads to the corresponding enantiopure unstable and prone to racemization.11
b-amino alcohols with an exclusive anti-diastereoselectivity.4,5 This
We initially focused on the three-component coupling
approach has been beneficially applied to the synthesis of many between commercially available (E)-phenyl vinyl boronic acid 1a,
bioactive molecules and complex natural products.6,7 The N,N-diallylamine 2a, and N-tosylated amino aldehyde 3a derived
possibility of using a nitrogen atom to activate the boronic from L-phenylalanine (Scheme 1 and Table 1). The latter compound
acid was also investigated using 2-pyridinecarbaldehyde8 and was obtained after oxidation12 of the corresponding amino alcohol
2-sulfamidobenzaldehyde,9 which successfully reacted in the 4a using NaOCl solution in the presence of KBr with a catalytic
PBM reaction. Very recently, aziridine-containing vicinal diamines amount of TEMPO and buffering with NaHCO3. It was used directly
were synthesized in a high syn-selective fashion using the PBM after the oxidation workup in the next Petasis condensation.13
reaction employing amphoteric aziridine aldehyde dimers.10 We
According to our previous work with a-hydroxyaldehydes,7,14
report herein the direct use of N-protected a-amino aldehydes the reaction was first carried out with an excess of 3a and 2a
as substrates for the Petasis reaction to produce enantioenriched (2 equiv. each) in CH2Cl2 at 120 1C for 30 min under microwave
1,2-diamines with pure trans-selectivity. The use of this class of radiation (entry 1). The reaction proceeded with a high degree
of diastereocontrol leading exclusively to anti-adduct 515 in 85%
yield, however, in low 30% ee.16 Upon conventional heating, the
reaction required 36 h at 50 1C to obtain the desired compound
in 52% yield with a slight increase of the ee to 42% (entry 2).
Using a mixture of CH2Cl2/HFIP (9/1) increased the reaction
rates17 but had a detrimental effect on the enantiomeric purity and
when the reaction was carried out at 50 1C for 12 h, PBM adduct 5
was obtained in 70% yield and 8% ee (entry 3). Performing the
reaction with this mixture of solvents was also possible at 0 1C but
led, after 48 h, to racemic 5 in 76% yield (entry 5).18 The use of
a ICSN-CNRS, Centre de Recherche de Gif, Institut de Chimie des Substances
Naturelles du CNRS, CNRS UPR 2301, 1 Avenue de la Terrasse,
F-91198 Gif-sur-Yvette, France. E-mail: stephanie.norsikian@cnrs.fr,
jean-marie.beau@u-psud.fr; Fax: +33 1 69 07 72 47
b
´
`
´
Universite Paris-Sud and CNRS, Laboratoire de Synthese de Biomolecules,
´
´
Institut de Chimie Moleculaire et des Materiaux d’Orsay, F-91405 Orsay, France
† Electronic supplementary information (ESI) available. CCDC 1044004. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c5cc01716e
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Table 1 Optimization of the Petasis borono-Mannich process with boronic
acid 1a, N,N-diallylamine 2a and N-tosylated amino aldehyde 3a
The influence of the reactants’ stoichiometry was then
investigated (entries 14 to 16). Both the amount of aldehyde
and amine could be reduced (1.3 equiv. of 3a and 1.25 equiv. of 2a),
which provided 5 in a similar yield with a minimal decrease of
the ee (93%, entry 14). Using stoichiometric amounts of all the
reactants (entry 15) or an excess of the boronic acid (entry 16)
had a negative effect on the enantiomeric purity and afforded 5
with ees between 74 and 86%.
Equiv.
3a/2a/1a Solvent
Yieldb
T (1C)
Time (h) Additive (%) eec (%)
1
2
3
2/2/1
2/2/1
2/2/1
CH2Cl2
CH2Cl2
CH2Cl2–
HFIPa
120 (MW) 0.5
—
—
—
85
52
70
30
42
8
50
50
36
12
4
5
6
7
8
8
9
2/2/1
2/2/1
2/2/1
2/2/1
2/2/1
2/2/1
2/2/1
CH2Cl2–TFEa 50
CH2Cl2–HFIP 0
12
48
36
36
36
36
36
36
36
36
36
36
—
42
29
0
50
4 Å MSd 76
The protecting group of the amino aldehyde had a decisive
influence on both the yield and the enantiomeric purity of the
condensation products. Taking as a model study the reaction of
vinyl boronic acid 1a and N,N-diallylamine 2a with N-protected
aldehydes 3 derived from L-phenylalanine, we found that the
lower the pKa of the corresponding NH-groups, the higher the
chemical yields and ees of the diamine products (Table 2 and Fig. 1).
Thus, acetamide 3e (pKa 15)22–24 and tert-butyl carbamate 3f
(pKa 11.4) gave ineffective results (diamines 11, 23% yield, 3% ee
and 12, 21% yield, 15% ee, respectively) while N-tosylated
(pKa 9.5) and N-nosylated (pKa 8.2) substrates 3a and 3b provided
good solutions (diamines 5, 54% yield, 93% ee and 8, 71% yield,
94% ee,25 respectively), with the N-nosylated group being the
best option.‡ The other sulfonamide derivatives (4-methoxy-
2,3,6-trimethylphenylsulfonamide 3c and 2-(trimethylsilyl)ethane-
sulfonamide 3d, pKa around 10) gave unsatisfactory results in terms
of yields and ees. These trends are illustrated in Fig. 1. It is also
worth noting that no reaction occurred with N-methyl N-tosyl
amino aldehyde 3g. These findings suggest that the protecting
group on nitrogen is important for modulating the coordination to
boron as well as the racemization of the asymmetric center.
The scope and limitations of the three-component Petasis
reaction were further surveyed using a variety of reaction
partners, and the results are shown in Table 2. The data were
obtained using the best reaction conditions for the preparation
of 5 from boronic acid 1a (1.3 equiv. of aldehyde, 1.25 equiv. of
amine at rt in PhCF3 with 4 Å MS) and the yields were not
optimized. With N-nosylated amino aldehyde 3b and boronic
acid 1a, the reaction can be performed with other secondary
amines such as N-allyl-N-benzyl amine 2b or N,N-dibenzyl
amine 2c and led to 13 and 14 in 64 and 72% yield, respectively,
and good enantiomeric purity (98% and 96% ee). The reaction
carried out using N-methyl-N-benzyl amine 2c was less efficient
affording 15 in 48% yield and a lower 71% ee. Using primary
N-benzylamine 2e, however, did not provide the desired product.
For the boronic acid component, (E)-(2-cyclohexylvinyl)boronic
acid 1b, 2,4,6-trivinylcyclotriboroxane pyridine complex 1c and
4-anisylboronic acid 1e were used in combination with N,N-diallyl-
amine 2a and N-nosylated amino aldehyde 3b. The reaction provided
the expected products 16, 17 and 19 in 48, 51 and 38% yield,
respectively, with some erosion of the enantiomeric purity (82, 86%
and 82.5% ee). 2-Furanboronic acid 1d was a good reaction partner
with N,N-dibenzyl amine 2c and aldehyde 3b, providing the corre-
sponding PBM adduct 18 in 63% yield and 93% ee.
CH2Cl2
CH2Cl2
CHCl3
CH3CN
MTBE
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
—
19
4 Å MS 46–85 37–84
4 Å MS 21
4 Å MS 18
4 Å MS 51
4 Å MS
4 Å MS 40
4 Å MS 14
31
54
42
65
97
86
10 2/2/1
11 2/2/1
12 2/2/1
13 2/2/1
14 1.3/1.25/ PhCF3
1
THF
4
PhCH3
Mesitylene
PhCF3
4 Å MS 50–53 95–98
4 Å MS 54
93
15 1/1/1
16 1/1/1.5
PhCF3
PhCF3
rt
rt
36
36
4 Å MS 45
4 Å MS 57
86
74
a
b
9 : 1 CH2Cl2/HFIP or 9 : 1 CH2Cl2/TFE. Isolated yield after chromato-
c
d
graphy, based on boronic acid. Determined by chiral HPLC. Com-
mercial powdered 4 Å molecular sieves were activated at 150 1C under
vacuum for 1 h. rt = room temperature.
HFIP19 as an additive polar solvent of high ionizing power is well-
known to accelerate the Petasis reaction probably by favoring the
formation of the transient iminium species 6 (Scheme 2). However,
it also apparently favored the formation of enamine 7 that would
explain the erosion of the enantiomeric purity of 5 (Scheme 2). The
same effect was also observed with the less acidic TFE (pKa 12.4
versus 9.3 for HFIP) as an additive (entry 4) but to a lesser extent
(29% versus 8% ee at 50 1C).
Since the reaction in CH2Cl2 was very slow at room tem-
perature (19% yield after 36 h, entry 6), the three-component
coupling was attempted in the presence of 4 Å molecular sieves
(4 Å MS, entry 7). MS are also known to accelerate the PBM
reactions20 and proved to be effective also in our case for both
the yield and the enantiomeric purity with ees increasing up to
84%. However, the results were non-reproducible and the search
for other solvents was carried out. Among all the solvents tested
(entries 8 to 13), aromatic solvents provided higher ee values. In
particular with environmentally friendly trifluorotoluene,4,21
5
could be obtained in 50–53% yield and 95–98% ee (entry 13).
Therefore, PhCF3 was chosen as the standard solvent for further
exploration of the reaction conditions.
A short survey of the aldehyde component was performed
with N-nosylated amino aldehydes 3h, 3i and 3j derived from
L-valine, L-leucine and protected L-serine. Their combination
with 1a and 2a or 2c gave the corresponding desired products
Scheme 2 Possible pathway to explain the erosion of the enantiomeric
purity of PBM adduct 5.
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Table 2 Substrate scope for the Petasis borono-Mannich process with N-
protected a-amino aldehydesa,b
Fig. 1 Enantiomeric purity (blue bar) and chemical yield (red bar) of the
diamine products as a function of the calculated pKa (aqueous medium) of
N-protected aldehydes 3 derived from L-phenylalanine and condensed
with (E)-phenyl vinyl boronic acid 1a and N,N-diallylamine 2a.
Scheme 3 Orthogonal deprotection of 8. DMBA
=
N,N0-dimethyl-
barbituric acid.
K2CO3 in DMF at 50 1C for 5 h, leading to monoprotected
diamine 23 in 74% yield. The other monoprotected diamine,
24, was provided by the removal of allyl protecting groups using
N,N-dimethylbarbituric acid, and a catalytic amount of Pd(0).26
Finally, access to fully deprotected diamine 25 was carried out
from 24 after treatment with PhSH.
In summary, we have shown that N-tosylated or N-nosylated
a-amino aldehydes can be used successfully as substrates for
the Petasis borono-Mannich reaction. This establishes a new
way of producing enantioenriched 1,2-trans-diamines that may
be useful as ligands for transition metals27 or as motifs in
biologically active molecules.28 The preparation of such com-
pounds as well as mechanistic investigations are currently
underway in our laboratory.
We thank the ICSN-CNRS for a PhD grant (A.C.), the CHAR-
M3AT Labex program for financial support of this study (M.B.)
and the Institut Universitaire de France (IUF).
a
Reaction conditions: boronic acid (1 equiv.), N-protected a-amino-
aldehyde (1.3 equiv.), amine (1.25 equiv.), PhCF3, 4 Å MS, 48 h at rt,
b
Notes and references
unless otherwise stated. Isolated yield after chromatography, based
c
on boronic acid, ee determined by chiral HPLC. ee after recrystalliza-
d
‡ Representative procedure (synthesis of compound 9): 3b (59 mg,
0.176 mmol), diallylamine 2a (21 mL, 0.169 mmol), boronic acid 1a
(20 mg, 0.135 mmol) and activated 4 Å MS (100 mg) in PhCF3 (0.85 mL)
were stirred for 48 h at room temperature. After solvent evaporation, the
mixture was purified by preparative TLC on silica gel (AcOEt/heptane
2 : 8) to yield 8 (51 mg, 0.098 mmol, 71%, 94% ee).
tion. N-Protected a-amino aldehyde (2 equiv.) and amine (2 equiv.)
e
were used. Boronic acid (1 equiv.), a-hydroxyaldehyde (1.3 equiv.) and
amine (1 equiv.) were used, yield based on amine.
20, 21 and 22 in moderate to good yield (51 to 63%) with ees
from 82 to 87%.
As a preliminary evaluation for synthetic purposes, orthogo-
nal removal of the N-protecting groups was also carried out
(Scheme 3). Selective deprotection of the nosyl group was easily
achieved by treatment of 8 with thiophenol in the presence of
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