Diastereoselective Ugi reaction of chiral 1, 3-aminoalcohols derived from an organocatalytic Mannich reaction

Article abstract of DOI:10.3762/bjoc.12.15

Enantiomerically pure β-aminoalcohols, produced through an organocatalytic Mannich reaction, were subjected to an Ugi multi-component reaction under classical or Lewis acid-promoted conditions with diastereoselectivities ranging from moderate to good. Thi

Full text of DOI:10.3762/bjoc.12.15

Diastereoselective Ugi reaction of chiral 1,3-aminoalcohols
derived from an organocatalytic Mannich reaction
Samantha Caputo, Andrea Basso, Lisa Moni, Renata Riva, Valeria Rocca
and Luca Banfi*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 139–143.
Department of Chemistry and Industrial Chemistry, University of
Genova, I-16146 Genova, Italy
doi:10.3762/bjoc.12.15
Received: 14 November 2015
Accepted: 14 January 2016
Published: 26 January 2016
Email:
Luca Banfi* - banfi@chimica.unige.it
* Corresponding author
Associate Editor: T. J. J. Müller
Keywords:
© 2016 Caputo et al; licensee Beilstein-Institut.
License and terms: see end of document.
aminoalcohols; isocyanides; multicomponent reactions;
peptidomimetics; Ugi reaction
Abstract
Enantiomerically pure β-aminoalcohols, produced through an organocatalytic Mannich reaction, were subjected to an Ugi multi-
component reaction under classical or Lewis acid-promoted conditions with diastereoselectivities ranging from moderate to good.
This approach represents a step-economical path to enantiomerically pure, polyfunctionalized peptidomimetics endowed with three
stereogenic centers, allowing the introduction of five diversity inputs.
Findings
Isocyanide-based multicomponent reactions [1-3], such as the racemize/epimerize [13,14] and additionally, no report of valu-
Ugi reaction, were demonstrated to be very useful in the rapid able diastereocontrol by them has appeared so far. Successful
assembly of complex drug candidates [4], introducing three to examples of diastereoselective Ugi reactions have been re-
four diversity inputs. Furthermore, a nearly limitless variety of ported only with chiral amines [15-19] or with chiral cyclic
heterocycles can be accessed through post-condensation trans- imines (Ugi–Joullié reaction) [20-23], although in the latter
formations [5-7], adding only one to two steps to the synthetic case, racemization/epimerization can again be an issue in
sequence. However, the main drawback of the Ugi reaction is special cases [24]. However, the use of amines as chiral auxil-
the poor stereochemical control that is typically achieved [8,9], iaries has been seldom exploited in peptidomimetic synthesis
which hampers its utilization in the diversity-oriented or target- [16,25,26] because the need to remove the auxiliary reduces the
oriented synthesis of complex chiral peptidomimetics. No effi- number of diversity inputs and increases the number of synthe-
cient asymmetric catalytic classic Ugi reaction has been re- tic steps.
ported to date (whereas some success was obtained on simpler
variants) [10-12]. On the other hand, diastereoselective reac- From the point of view of atom- and step-economy, the use of
tions using at least one chiral component are troublesome. chiral amines that are retained in the final products will be more
Chiral isocyanides and chiral carboxylic acids invariably afford valuable [27]. In this case they are not "chiral auxiliaries" and
nearly 1:1 mixtures. α-Chiral aldehydes have a high tendency to are not removed after the multicomponent reaction, and they
139

Beilstein J. Org. Chem. 2016, 12, 139–143.
contribute to the diversity of the final products. However, the series of five Boc-protected β-aminoalcohols 4a–e (Scheme 2).
usefulness of this approach relies on an efficient and diversity- Using caesium carbonate, carbamoyl sulfones were converted
oriented preparation of the required amines in high enan- into the corresponding N-Boc-protected imines 2 that were
tiomeric excess.
immediately submitted to List's organocatalytic Mannich reac-
tion [29,30]. The resulting aldehydes 3 were not isolated (also
Chiral aminoalcohols can be ideal substrates for diastereoselec- in view of their known stereochemical lability) but directly
tive Ugi reactions: the additional hydroxy group can both help reduced to alcohols 4 [32,33]. Purification was carried out
in modulating diastereoselectivity and be employed for post- through chromatography and, in some cases, by additional crys-
condensation transformations in order to add further fragments tallization, affording these key intermediates in high ee and de
or to form heterocyclic structures. We have previously de- (syn relative configuration, see Supporting Information File 1).
veloped some syntheses of heterocycles through Ugi reactions
with 1,2-aminoalcohols followed by nucleophilic substitutions The tert-butyl urethane was then deblocked with trifluoroacetic
[28], whereas chiral 1,2-aminoalcohols have been proved by acid. Neutralization and extraction afforded crude aminoalco-
Nenajdenko and co-workers to be able to induce good levels of hols 5a–e, that were directly employed in the Ugi reaction. We
diastereoselectivity in the Ugi reaction [17].
first optimized this step using isobutyraldehyde, 5-chloro-2-
thiophenecarboxylic acid and cyclohexyl isocyanide, to give the
Our attention was drawn by 1,3-aminoalcohols of general two diastereomers of compound 6a (Table 1).
formula 5 (Scheme 1), which can be obtained by List's organo-
catalytic Mannich-type reaction of aldehydes with N-Boc When the reaction was carried out under the classical condi-
imines 2 and catalytic L-proline [29,30], followed by reduction tions (using methanol as the solvent), only a moderate dia-
of 3 and cleavage of the Boc group.
stereoselectivity was achieved (Table 1, entry 1), which could
be increased by changing the solvent to trifluoroethanol,
This short and straightforward synthesis allows the introduction especially effective at 0 °C. Considering the recent work by
of 2 diversity inputs (R1 and Ar), whereas stereochemical diver- Nenajdenko et al. [17], we explored the usage of Lewis acids in
sity can also be explored using D-proline or different, anti- an aprotic solvent in order to further improve the diastereoselec-
selective organocatalysts.
tivity. We had anticipated that the binding of the Lewis acid to
the free alcohol, followed by intramolecular activation of the
We prepared two known carbamoyl sulfones 1 [30,31] and aldehyde, would establish a cyclic transition state, thereby
transformed them without isolation of intermediates into a enabling better stereocontrol. It is indeed well-known that the
Scheme 1: Overall strategy.
Scheme 2: Boc-protected aminoalcohols used as inputs in a diastereoselective Ugi reaction.
140

Beilstein J. Org. Chem. 2016, 12, 139–143.
Table 1: Optimization of the synthesis of 6a.
Entry
Temp.
Time (h)
Solvent (M)
Lewis acid (equiv)
Yielda
drb
1
25 °C
12
48
12
12
48
48
48
48
48
48
48
48
48
48
MeOH (0.4)
MeOH (0.1)
CF3CH2OH (0.1)
CF3CH2OH (0.1)
THF (0.1)
none
65%
72:28
72:28
77:23
83:17
89:11
73:27
80:20
91:9
88:12
–
2
25 °C
none
72%
3
25 °C
none
65%
4
0 °C
none
61%
5
−38 °C
−38 °C
−38 °C
−38 °C
−38 °C
−38 °C
−38 °C
−38 °C
−38 °C
−38 °C
ZnCl2·Et2O (1.0)
ZnCl2 (1.0)
ZnCl2 (1.5)
ZnBr2 (1.0)
ZnI2 (1.0)
55%
6
THF (0.1)
63%
7
THF (0.1)
60%
8
THF (0.1)
82%
9
THF (0.1)
71%
10
11
12
13
14
THF (0.1)
CuBr2 (1.0)
Cu(OTf)2 (1.0)
MgCl2 (1.0)
MgBr2·Et2O (1.0)
Yb(OTf)3 (0.2)
no react.
no react.
no react.
no react.
no react.
THF (0.1)
–
THF (0.1)
–
THF (0.1)
–
THF (0.1)
–
aOverall yield from aminoalcohol. bRelative configuration not yet determined.
Ugi reaction does not proceed in aprotic solvents such as THF ucts 6e, 6f, 6i). However, in all cases, the two diastereomers
at low temperature, and therefore the background, uncatalyzed could be easily separated and the ratio was typically, with few
reaction should not interfere. As shown in Table 1, the best exceptions, around 3:1 to 5:1. As far as the isolated yields were
results were achieved by using 1 equiv of zinc bromide concerned, the Lewis acid-promoted reaction is typically less
(Table 1, entry 8), affording a 10:1 diastereomeric ratio and an efficient, especially with aromatic isocyanides or aldehydes
excellent overall yield. Other zinc-based catalysts were less (compounds 6e, 6f, 6g). The relative configuration of the major
efficient, whereas most of the other tested Lewis acids failed adduct has not yet been unambiguously determined. However,
to promote the reaction at all. The use of Lewis acids in metha- TLC, HPLC, polarimetric and NMR analogies suggest that the
nol or trifluoroethanol afforded lower yields with no improve- main diastereomer was always the same, with one notable
ment of diastereoselection. It is worth noting that a 10:1 dia- exception: product 6f obtained in the absence of Lewis acid. In
stereoselectivity is considered excellent for isocyanide-based this case, it was necessary to carry out the reaction in
multicomponent reactions, due to the very low steric biases of THF/iPrOH because the isocyanide was poorly soluble in
isocyanides.
MeOH, and thus the unexpected diastereoselectivity inversion
might be due to the different solvent and not to the structure of
We then moved on to establish the scope of the method, varying isocyanide.
the Boc-protected aminoalcohol, the carboxylic acid and the
isocyanide (see Table 2). For a comparison, we performed all The synthetic route from carbamoyl sulfones 1 to peptido-
Ugi reactions either under Lewis acid-promoted conditions, or mimetics 6 is quite short: intermediate purification was carried
under the classical Ugi conditions (MeOH, rt). The stereochem- out only at the level of the Boc-protected aminoalcohols 4 and
ical results were found to vary remarkably from case to case. of the final products 6. Thus, this method offers an opera-
While in some instances (products 6b–d) the activation with tionally simple route to enantiomerically pure complex
ZnBr2 brought about an increase of diastereoselectivity, in other structures like 6, introducing up to five diversity inputs and
combinations of substrates, the outcome was similar (products controlling three stereogenic centers (also thanks to the final
6h and 6j) or even better using the "classical" conditions (prod- chromatography).
141

Beilstein J. Org. Chem. 2016, 12, 139–143.
Table 2: Scope of the synthesis of Ugi adducts 6.
Prod.
Ar
R1
R2
R3
R4
Cond.a
Yieldb
dr
A
B
A
B
A
B
A
B
A
B
A
C
A
B
A
B
A
B
A
B
82%
72%
53%
82%
31%
40%
55%
82%
55%
95%
<5%
60%
<20%
79%
40%
70%
30%
54%
48%
77%
91:9
6a
6b
6c
6d
6e
6f
Ph
Me
Me
Me
Me
Me
Me
Me
iPr
iPr
Bn
iPr
iPr
iPr
iPr
iPr
iPr
Ph
iPr
iPr
iPr
cy-Hex
5-Cl-2-thienyl
5-Cl-2-thienyl
5-Cl-2-thienyl
Et
72:28
85:15
73:27
82:18
64:36
79:21
74:26
65:35
86:14
n.d.
Ph
n-C5H11
2-BnOC6H4
cyclohexyl
cyclohexyl
2,6-di-MeC6H3
Ph
Ph
5-Cl-2-thienyl
Ph
4-(BnOCO)-C6H4 5-Cl-2-thienyl
35:65
n.d.
6g
6h
6i
Ph
n-C5H11
cyclohexyl
cyclohexyl
t-Bu
5-Cl-2-thienyl
5-Cl-2-thienyl
5-Cl-2-thienyl
CbzNH-CH2
57:43
78:22
77:23
64:36
69:31
80:20
81:19
Ph
2-BnOC6H4
2-BnOC6H4
6j
aOverall yield from Boc aminoalcohols 4. bRelative configuration not yet determined. A: THF, −38 °C, 1 equiv of ZnBr2; B: MeOH, 25 °C; C: iPrOH/
THF 2:1, 25 °C. All reactions carried out for 48 h at 0.1 M concentration of aminoalcohol with 1.00 equiv of aminoalcohol 5, 1.05 equiv of aldehyde,
1.2 equiv of carboxylic acid and isocyanide and 100 mg of powdered 3 Å molecular sieves per mmol of aminoalcohol.
Compounds 6 are endowed with several functionalities that can Acknowledgements
be exploited for post-Ugi cyclization steps or as a handle for We thank Mr. Giulio Less and Dr. Alice Brambilla for practical
attaching further fragments: the primary alcohol and the second- collaboration in this work and Dr. Luca Bono for HRMS
ary amide (which are present in all products), a protected analysis.
phenol (for compounds 6c, 6i, 6j), and a protected amine (6j).
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