Diversity-Oriented Synthesis of Various Enantiopure Heterocycles by Coupling Organocatalysis with Multicomponent Reactions

Article abstract of DOI:10.1002/ejoc.201701328

Chiral, enantiopure 1,3-amino alcohols, obtained through an organocatalytic Mannich reaction, have been used as starting materials for a concise sequence involving a diastereoselective Ugi reaction followed by various types of S_N2 cyclization. In this way, different enantiopure heterocycles have been prepared, with both scaffold and decoration diversity (up to four diversity inputs).

Full text of DOI:10.1002/ejoc.201701328

A Journal of
Accepted Article
Title: Diversity-Oriented Synthesis of Various Enantiopure
Heterocycles by Coupling Organocatalysis with Multicomponent
Reactions
Authors: Samantha Caputo, Luca Banfi, Andrea Basso, Andrea
Galatini, Lisa Moni, Renata Riva, and Chiara Lambruschini
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701328
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10.1002/ejoc.201701328
European Journal of Organic Chemistry
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Diversity-Oriented Synthesis of Various Enantiopure
Heterocycles by Coupling Organocatalysis with Multicomponent
Reactions
Samantha Caputo,[a] Luca Banfi,*[a] Andrea Basso,[a] Andrea Galatini,[a] Lisa Moni,[a] Renata Riva,[a] and
Chiara Lambruschini[a]
Abstract: Chiral, enantiopure 1,3-aminoalcohols, obtained through
an organocatalytic Mannich reaction, have been used as inputs in a
concise sequence involving diastereoselective Ugi reaction followed
by various types of SN2 cyclization. In this way, different enantiopure
heterocycles have been prepared, exploring both scaffold and
decoration diversity (up to 4 diversity inputs).
imines.[7] The use of chiral auxiliaries in the amine component has
also met some success, but the need to remove the auxiliary
reduces the number of diversity inputs and increases the synthetic
steps.
Thus, in our group, we chose to pursue an alternative strategy for
the obtainment of chiral enantiopure heterocycles: the use of
chiral components whose structure is retained in the final products,
thus contributing to their diversity.[8] In order to be realistically
applicable, this approach requires a robust, and diversity-oriented,
method for obtaining the required chiral inputs. This may be done
by using a 2-component organocatalyzed process that precedes
the Ugi step. In this way, up to 5 diversity inputs may be
introduced in the whole synthetic sequence. Recently this
approach has been successfully employed by us and others.[9]
In this regard, we have been attracted by the very useful
organocatalytic Mannich reaction of aromatic N-Boc-imines with
aldehydes developed by List and coworkers (Scheme 1).[10] The
products 2 of this reaction, that proceeds with high e.e. and d.r.
using such a simple organocatalyst as proline, enclose two
functional groups (a protected amine and an aldehyde), both of
them exploitable in an Ugi MCR. In particular, we thought that 1,3-
aminoalcohols derived from reduction and Boc cleavage could be
ideal substrates for two reasons: a) the possibility to get good
degrees of diastereoselectivity, also in view of a recent report by
Nenajdenko, who used chiral 1,2-aminoalcohols;[6c] b) the
presence of an additional alcohol, that could be precious for post-
MCR cyclizations to afford heterocycles.
Introduction
A very powerful method for synthesizing a variety of heterocycles
in a diversity-oriented manner is represented by the combination
of the Ugi multicomponent reaction with a post condensation
cyclization step.[1] The Ugi reaction allows indeed the introduction,
in a single step, of up to 4 diversity inputs, represented by easily
available classes of molecules (carbonyl compounds, amines,
carboxylic acids and isocyanides), thus granting an extraordinary
rate of complexity increase per step, and hence a high step-
economy. Then, the number of possible cyclization modes
following the Ugi MCR is nearly limitless, allowing an ample
exploration of scaffold diversity, and giving access to a wide range
of nitrogen heterocycles, including unusual ones. Often it is also
possible to obtain different scaffolds from a single Ugi adduct,
making the MCR product a "pluripotent" intermediate.[2] Among
the many cyclization modes, in the last decade, we have been
particularly interested in nucleophilic aliphatic substitutions.[1c, 3]
During the Ugi reaction, generally a new stereogenic centre is
formed. Therefore, unless some aromatization takes place, also
the final heterocycles are chiral. However, in most cases reported
in the literature, due to the lack of efficient asymmetric catalysts
for the Ugi reaction, and to the use of achiral components, these
heterocycles have been typically obtained in racemic form.
In a preliminary work,[11] we have already reported the Ugi
reaction of aminoalcohols 4, which allows a quite fast entry into
adducts 5 with 5 points of diversity. Since aldehydes 2 and amines
4 are not isolated, the whole sequence involves just 2 steps from
Boc-imines
precursors).
1 (or, better, from their carbamoyl sulphone
The use of chiral inputs for the Ugi reaction may also be
troublesome. It is well known that chiral aldehydes with an α-
stereogenic centre are prone to racemize,[4] whereas chiral
isocyanides and carboxylic acids invariably lead to very poor
diastereoselection.[5] The only way to obtain reasonable
diastereomeric ratios is the use of chiral amines[6] or chiral cyclic
In this paper, we extend the scope of this Ugi reaction, using other
substrates (including functionalised ones), assign the relative
configuration to the diastereomeric products, and, most of all,
report the successful transformation of adducts 5 into a variety of
heterocyclic structures, through SN2 cyclizations, which take
advantage of the presence of an alcohol, of a secondary amide,
and of suitably placed additional functional groups.
[a]
Department of Chemistry and Industrial Chemistry
University of Genova,
via Dodecaneso 31, I-16146 Genova. E-mail:
banfi@chimica.unige.it. Homepage:
http://www.chimica.unige.it/en/BOG/home
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201701328
European Journal of Organic Chemistry
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B). Table 1 resumes the results of the Ugi reactions affording the
intermediates discussed in this paper. Apart from compounds 5a
and 5i, already described in our previous paper,[11] these Ugi
adducts are all new. While in most cases the ZnBr2 catalysed
reaction proved to be more efficient in terms of
diastereoselectivity, for some combinations of substrates, method
B
was found to be superior in terms of yield and/or
diastereoselectivity. In all cases, using method A, the major
diastereoisomer had always the S configuration (the same trend
was found in our preliminary paper).
However, when using aromatic isocyanides with method B, an
inversion of diastereoselection was observed (entries 2-4). This
inversion was particularly pronounced when Ar = 3-BrC6H4
(entries 2 and 4). If one compares the results of entries 3 and 4 of
Table 1, it is clear that the bromine atom has a remarkable effect,
notwithstanding its remoteness from the reacting centre.
In the case of Ugi adduct 5b (entry 2) also method A was poorly
diastereoselective. Interestingly, by shifting from methanol to
trifluoroethanol, the normal preference for the (S) isomer was
restored.
Scheme 1. General strategy.
Results and Discussion
For the synthesis of Ugi adducts 5 we used two general
methodologies: a) a ZnBr2 catalysed reaction in THF at -38°C
(method A) and b) a classical reaction at r.t. in methanol (method
Table 1. Table Caption. ((Note: Please do not include the table in a textbox or frame))
method A
d.r
method B
d.r
Entry
Ugi product
Ar
R2
R3
R4
Yield[a]
82%[c]
54%
Yielda
72%[c]
(S:R)[b]
(S:R)[b]
1
2
5a
5b
Ph
iPr
iPr
cyHex
5-Cl-2-
thienyl
91:9[c]
51:49
72:28[c]
3-BrC6H4
4-AllOC6H4
Et
67%
(68%)[d]
42:58
(64:36)[d]
3
4
5
6
7
8
9
5c
5d
5e
5f
Ph
iPr
4-AllOC6H4
4-AllOC6H4
tBu
ClCH2
ClCH2
ClCH2
ClCH2
ClCH2
Et
51%
68%
32%
48%
43%
60%
31%[c]
67:33
64%
69%
48:52
38:62
3-BrC6H4
Ph
iPr
66:34
PhCH2CH2
iPr
69:31[e]
85:15
2-AllOC6H4
Ph
cyHex
tBu
51%
62:38
5g
5h
5i
cyHex
60:40[f]
69:31
2-BnOC6H4
2-BnOC6H4
iPr
iPr
nBu
cyHex
5-Cl-2-
thienyl
82:18[c]
40%[c]
67%
64:36[c]
62:38
iPr
10
11
12
5j
2-BnOC6H4
2-BnOC6H4
2-BnOC6H4
cyHex
nPent
cyHex
ClCH2
ClCH2
ClCH2
51%
42%
35%
88:12
75:25
76:24
iPr
5k
5l
iPrCH2
[a] Isolated yield of 5 from Boc aminoalcohols 9, 15 or 16. Method A: ZnBr2, THF, −38°C. Method B: MeOH, r.t. [b] Determined by HPLC. [c] For compounds 5a
and 5i the yields are those already reported in our previous paper (ref. 11). [d] Reaction carried out in CF3CH2OH at 0°C. [e] Determined by weight of the isolated
diastereomers. [f] Determined by weight of the isolated diastereomers only after conversion into diketopiperazines 17g.
The two isomers could be in almost all cases separated at the
level of Ugi adducts 5. Only in one instance that was not possible
and separation was carried out at the level of the final heterocycle
(entry 7). Thus in all cases it has been possible to obtain the final
heterocycles in enantio- and diastereoisomeric pure form.
The Ugi adducts 5c-g and 5j-l, derived from chloroacetic acid,
proved to be somehow unstable on standing. Therefore, they
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were not fully characterized, but submitted to the cyclization
conditions soon after their chromatography.
For all Ugi adducts 5, both the ones described in this paper and
those previously reported in our preliminary work,[11] strong HPLC,
TLC and NMR analogies were found: a) the faster running isomer
in HPLC (reverse-phase) was always the slower running isomer
in TLC (petroleum ether/AcOEt). This was always the major
isomer when the Ugi reaction was carried out in THF with ZnBr2
as promoter (method A); b) 1H NMR of the faster running isomer
(HPLC) showed in all cases a strong upfield shift for the signals
of the isocyanide derived secondary amide (namely the NH
signals, and its neighbours). On the other hand, the slower
running isomer (HPLC) showed in all cases a strong upfield shift
for the isopropyl methyls (in particular for one of them the shift
Scheme 2. Preferred conformations of Ugi adducts 5.
It is less easy to explain the general preference for the (S) isomers
also under standard Ugi conditions in methanol (method B).
Maybe a similar preferred cyclic conformation of the chiral side
chain is also in this case operating, thanks to a hydrogen bond
between the OH and the imine (see formula B).
was around
1 ppm) or, when aldehydes different from
isobutyraldehyde were used, for the signals of R3 group.
These upfield shifts are due to the anisotropic effect of the aryl
group present in the starting aminoalcohol. The use of anisotropic
upfield shifts provoked by an aryl group is a well assessed
methodology for the assignment of relative configuration.[12]
However, in order to use this method, it is necessary to know the
preferred conformation of the examined compounds.
Therefore, in the case of Ugi adducts 5b, we have carried out a
thorough conformational analysis with the aid of 1H NMR
experiments. More details are contained in the S.I., but, to be brief,
the evidence coming from the vicinal coupling constants and from
2D-NOESY experiments, allowed to select, for both
diastereoisomers, the conformations depicted in Scheme 2. Other
three possible conformations (described in the S.I.) were ruled out,
being in contrast with the experimental NMR evidence. In the
preferred conformations shown in Scheme 2, H-4, C-4, N-3, C-2,
H-2 lie approximately on a plane, and H-4 and H-2 are opposite
each other. Therefore, the aryl group Ar1 is near to the isocyanide
derived secondary amide in isomer S, and near to the isopropyl
in isomer R. The great difference in the above quoted chemical
shifts is therefore due to the shielding effect of the Ar1 group,
demonstrating that the faster running isomer (HPLC) has an S
configuration. We recall that this is the favoured isomer in all
instances using method A and in most cases using method B, with
the notable exception of compounds 5b, 5c and 5d (employing
aromatic isocyanides).
Scheme 3. Proposed models for rationalization of diastereoselectivity.
As stated above, with aromatic isocyanides the induction is lower
with zinc bromide and even inverted in methanol. In this case, also
taking into account the remarkable difference observed between
5c and 5d, by simply adding a meta-bromine to the aryl ring, we
can suppose a cooperative effect, due to π bonding, between the
aryl group and the incoming isocyanide, which may favour attack
from the bottom face.
The first cyclization devised, which does not need any additional
functionalities, involves an SN2 where the alcoholic OH plays the
role of leaving group and the isocyanide derived secondary amide
acts as the nucleophile. This type of post-Ugi cyclization has been
previously used mainly with halides as leaving groups,[13] but also
with alcohols in Mitsunobu or Mitsunobu-like processes,[1c, 3a, 14] to
afford 4-membered,[1c] 5-membered[3a] or 6-membered[13-14]
lactams. No report on such type of cyclization to give 7-membered
lactams is known so far.
This assessment was further confirmed by 1H NMR data on
chromanyl diketopiperazines 20 (see S.I. for details).
Having established the relative configuration of Ugi adducts we
can try to rationalise the results. As stated above, in all cases
(including those previously reported), under ZnBr2 catalysis, the
(S) isomer is prevailing, usually with good d.r. (only in the case of
5b we obtained a 1:1 mixture). This can be explained by a
chelation model similar to the one proposed by Nenajdenko and
coworkers[6c] for the ZnBr2 catalysed Ugi reaction of 1,2-
aminoalcohols (Scheme 3). An intramolecular imine activation by
zinc would lead to a transition state A where the lower face is
clearly more encumbered.
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We explored this cyclization employing enantiomerically pure Ugi
adduct 5a-S expecting to obtain azepanone 6a (Scheme 4). 5a-S
was obtained with 91:9 d.r. using Ugi method A (Table 1). Due to
the high diastereoselectivity of the Ugi reaction, we performed
these attempts only on the pure major (S) diastereomer.
We tested a variety of classical Mitsunobu conditions, with DEAD,
TBAD or DIAD and PPh3, but no cyclized product was obtained.
On the other hand a clean reaction and a good yield was obtained
by the Hanessian method,[15] that employs sulphonyl diimidazole
(SDI) and NaH in DMF. Two new products (in a 60:40 ratio) were
detected according to TLC and HPLC-MS analyses, and both had
the expected nominal mass (472). However, a careful NMR
investigation showed that the obtained products were not the
diazepanone 6, but, instead, the interesting imidazoxazinones 7.
This also explains the presence of two isomers, due to the newly
generated stereogenic centre. In particular, 13C NMR showed only
one C=O signal, but two quaternary signals at 98.6-98.4 ppm,
characteristic of the orthoaminal carbon 8a of the two isomers.
HMBC bidimensional spectrum confirmed the connection of the
various carbons. Interestingly, the two diastereomers easily
interconvert on silica gel, making impossible their separation.
Apart from this, they appear to be quite stable towards hydrolysis.
A similar result, but with lower yield, was obtained in a two step
sequence, converting 5a-S into the mesylate followed by
treatment with NaH in DMF.
At this point we thought that formation of diazepanones could
possibly be favoured by employing as starting component an
aromatic isocyanide: the resulting aromatic secondary amide
would be more acidic, favouring the normal course of cyclization.
Thus, we used Ugi products 5b, prepared from the new Boc-
protected aminoalcohol 9, in turn derived from known carbamoyl
sulphone 8,[16] through the organocatalytic Mannich reaction
(Scheme 4).
Scheme 4. Synthesis of imidazoxazinones through cyclization of Ugi adducts 5.
As already described above, this reaction gave alternatively the
(S) or (R) isomer depending on the method used. In all cases we
separated the two diastereomers and submitted them
independently to the cyclization conditions with SDI. Once again,
we did not obtain a diazepanone 6, but imidazooxazinones 7b
instead. The reaction was remarkably stereoselective (92:8),
regarding the new stereogenic centre at C-8a, and surprisingly
both Ugi adducts 5b-S and 5b-R afforded the same major
diastereoisomer, as judged by TLC, HPLC, NMR and polarimetric
analyses. The configuration of all centres was determined to be
the one depicted in Scheme 2 by nOe experiments (see S.I.).
Evidently, 5b-R undergoes complete epimerization during the
cyclization reaction. In this case, also because of the high
diastereoselectivity regarding the stereogenic centre at C-8a, and
because the two diastereomers were not separated in TLC, we
could not assess if facile epimerization at C-8a takes place or not.
However, compound 7b was remarkably stable under acidic
conditions (pTSA in H2O-MeOH for several days).
To the best of our knowledge the imidazooxazinone scaffold 7 is
quite unprecedented in the literature. We could find only an
example of imidazooxazine,[17] although fused with two other rings
and lacking the carbonyl, while the analogous imidazooxazolone
motif, having
1 carbon atom less, has been previously
synthesized by us.[18] Thus, despite its orthoaminal nature, this
heterocycle may be, in our opinion, interesting in medicinal
chemistry, thanks to its relative rigidity and non-flat structure. A
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discussion on the conformations of this system is reported in the
S.I. With this methodology, up to 5 diverse appendages can be
positioned on it. The stereoconvergency of cyclization overcomes
the possible low diastereoselectivity in the Ugi reaction, affording
a complex product with 4 stereogenic centres in high e.e. and d.r.
Scheme 5 shows a possible mechanism for the formation of
imidazooxazinones. First of all the alcohol is transformed into
sulphonate 10 either by reaction with MsCl or, in situ, by reaction
able to synthesize, in a straightforward manner, diketopiperazines
17 (Scheme 6).
The best conditions for cyclization involved the use of cesium
carbonate, instead of KOH, previously employed by Marcaccini
on other chloroacetic acid derived Ugi adducts.[13d] We typically
preferred to separate the two diastereomers at the level of Ugi
adducts 5, with the exception of entry 5. Having performed the
cyclization on the separated diastereomers of 5 allowed us to
with SDI. Then the base (NaH) deprotonates the secondary amide. prove that this cyclization, contrary to the one leading to bicyclic
At this stage, instead of direct SN2 substitution of the sulphonate,
the anionic nitrogen attacks first the carbonyl of the tertiary amide,
that in turns attacks the sulphonate, resulting in compounds 7.
The complete epimerization and the easy equilibration on silica
gel of the two epimers at C-8a observed for 7, may be both
explained by supposing that 7 is in equilibrium with an open
zwitterion 12. Although this equilibrium is probably shifted towards
7, it can explain the facile interconversion of the epimers at C-8a
observed for 7a. Moreover, 12 may be in turn, through a simple
proton transfer, in equilibrium with mesoionic compound 13,
stabilized by its aromatic character. This can explain the easy
epimerization observed for 7b.
7, was not epimerizing at all.
The cyclization yields are typically high, except when R2 = tBu. In
the case of 17g we indeed isolated a side product, that had the
same molecular weight, by HPLC-MS, with the expected product,
and whose structure, elucidated by 1H, 13C NMR and HMBC
experiments, corresponds to a six-membered morpholin-3-one 16
derived from cyclization by the oxygen (instead of the nitrogen) of
the secondary amide (see S.I. for details). The bulkiness of tert-
butyl group may have favoured this side-reaction.
Scheme 5. Possible mechanism for imidazoxazinone formation.
Having set up a methodology to straightforwardly generate
imidazooxazinones 7, we moved to explore an alternative
cyclative SN2 process, employing Ugi adducts 5c-g, displaying an
additional alkyl halide in their structure. Preliminary attempts
using glycolic acid as the acid component were unsatisfactory.
While the Ugi reaction worked, attempted cyclization, again using
SDI/NaH led to complex mixture of products. Thus we chose to
use chloroacetic acid[13d] as carboxylic input for the Ugi, and were
Scheme 6. Synthesis of diketopiperazines 17. In the case of 17g, cyclization
was carried out on the unseparated diastereomeric mixture.
Ten different enantiopure diketopiperazines 17 have been
prepared by this approach. Although the overall yield is only
moderate, these complex compounds have been obtained
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10.1002/ejoc.201701328
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essentially in three steps from the starting carbamoyl sulphones,
introducing three stereogenic centres. Thus the step-economy
fully counterweighs the moderate yield from the "green synthesis"
point of view.[19]
catalysis to generate chirality, by the List's organocatalytic
Mannich reaction. We think that we have added further value to
this precious methodology by combing it with the Ugi
multicomponent reaction and intramolecular SN2 reactions,
showing that List's adducts are really "pluripotent" intermediates.
A third cyclative reaction was investigated with Ugi adducts 5h-i,
displaying an additional phenolic functionality (Scheme 7).
In this case the cyclization was carried out only on the major (S)
adduct. Hydrogenolysis of the benzyl protecting group followed by
Mitsunobu reaction with diethyl azodicarboxylate (DEAD) and
triphenylphosphine, gave the two chromanes 19h and 19i in good
yields. In the case of 19i the chlorine on the thiophene ring
underwent hydrogenolysis during removal of the benzyl.
Finally, we have performed in sequence two of the above
described cyclizations, obtaining complex compounds containing
two privileged structures, that is the chromane and the
diketopiperazine (Scheme 8).
Scheme 8. Synthesis of chromanyl diketopiperazines 20. In the case of 20l,
cyclization was carried out on the unseparated diastereomeric mixture.
Scheme 7. Synthesis of chromanes 19.
With aminoalcohol 18 and chloroacetic acid, the Ugi reactions
were rather diastereoselective, using ZnBr2 promoted conditions.
Anyway, in this case we converted both isomers into the final
products.
Experimental Section
General remarks. NMR spectra were taken at rt in CDCl3 at 300 MHz (1H),
and 75 MHz (13C), using, as internal standard, TMS (1H NMR: 0.000 ppm)
or the central peak of CDCl3 (13C: 77.02 ppm). Chemical shifts are reported
in ppm ( scale). Peak assignments were made with the aid of gCOSY,
gHSQC and gHMBC experiments. GC-MS were carried out using an HP-
1 column (12 m long, 0.2 mm wide), electron impact at 70 eV, and a mass
temperature of about 170 °C. Only m/z > 33 were detected. All analyses
were performed (unless otherwise stated) with a constant He flow of 1.0
ml/min with initial temp. of 70 °C, init. time 1 min, rate 20 °C/min, final temp.
260 °C, inj. temp. 250 °C, det. temp. 280 °C. HRMS: samples were
analysed with a Synapt G2 QToF mass spectrometer. MS signals were
acquired from 50 to 1200 m/z in ESI positive or negative ionization mode.
IR spectra were recorded with the ATR (attenuated total reflectance)
technique. TLC analyses were carried out on silica gel plates and viewed
at UV (254 nm) and developed with Hanessian stain (dipping into a
solution of (NH4)4MoO44 H2O (21 g) and Ce(SO4)24 H2O (1 g) in H2SO4
(31 ml) and H2O (469 ml) and warming) or with ninhydrin (in the case of
Boc aminoalcohols). Rf were measured after an elution of 7-9 cm. Column
chromatographies were done with the "flash" methodology using 220-400
mesh silica. Petroleum ether (40-60 °C) is abbreviated as PE. In extractive
Conclusions
In conclusion we have been able to prepare, through a concise
synthetic sequence, a small collection of complex heterocyclic
systems (including the unprecedented ortho-aminals 7 and 10).
We have explored both scaffold and decoration diversity,
reporting here 4 different scaffolds, and varying 4 diversity inputs
(a fifth one can in principle be modified too, by using different
aldehydes in the Mannich step). Most importantly, all the 13 final
compounds are enantiomerically pure, and their optical isomers
can be accessed simply using D-proline as the catalyst. Often,
libraries of potential drug candidates are prepared in racemic form
and, when a hit or lead is found, it is rather difficult to access the
pure enantiomers without exploiting resolution methods or chiral
auxiliaries. In this work we have employed only asymmetric
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10.1002/ejoc.201701328
European Journal of Organic Chemistry
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work-up, aqueous solutions were always reextracted thrice with the
appropriate organic solvent. Organic extracts were always dried over
Na2SO4 and filtered, before evaporation of the solvent under reduced
pressure. All reactions using dry solvents were carried out under a nitrogen
atmosphere.
OAll), 144.5, 134.4, 119.1 (quat.), 132.7 (CH=CH2), 130.9, 130.1, 129.40
(x2), 129.37 (x2), 121.0, 112.7 (ArCH), 117.8 (CH=CH2), 80.7 (C(CH3)3),
70.7 (ArCH), 69.5 (OCH2), 28.0 (C(CH3)3), 21.6 (ArCH3). I.R.: ῡ 3259,
3150, 3008, 2970, 2933, 2867, 1699, 1606, 1592, 1491, 1456, 1449, 1423,
1411, 1366, 1333, 1316, 1300, 1288, 1258, 1182, 1146, 1115, 1100, 1085,
1046, 1012, 985, 936, 925, 916, 873, 846, 821, 799, 773, 747, 719, 705,
692, 660, 630, 614 cm-1) = HRMS (ESI+) m/z [M + H+]: Calcd for
C22H28NO5S 418.1683; Found 418.1688.
(2S,3S)-3-(3-Bromophenyl)-3-((tert-butoxycarbonyl)amino)-2-
methylpropan-1-ol 9. Cs2CO3 (1.12 g, 3.44 mmol) was weighted in a flask,
put under argon and heated with a heating gun for 5 minutes. After cooling,
dry THF (17 mL), and carbamoyl sulfone 8[16] (600 mg, 1.72 mmol) were
added and the suspension heated at 50 °C for 3 h. After cooling, the white
suspension was rapidly filtered through a sintered funnel filled with celite,
dry Na2SO4, and celite layers,[10b] washing with THF. The filtrate was
evaporated, dissolved in dry CH3CN (17 mL), cooled to 0 °C, and treated
with L-proline (40 mg, 0.344 mmol) and with freshly distilled propanal (247
μL, 1.67 mmol). The mixture was stirred at 0 °C for 18 h, and then
quenched with water (5 mL). The mixture was extracted with CH2Cl2 (3 x
10 mL) and the organic extract dried (Na2SO4), evaporated to dryness,
dissolved in MeOH (9 mL), and cooled at 0°C. NaBH4 (100 mg, 2.58 mmol)
was added. After 5 min the cooling bath was removed and the reaction
stirred for 1 h at rt and then quenched with a 10:2 mixture of 5% aqueous
NH4H2PO4 and 2M HCl. Extraction with EtOAc, evaporation and
chromatography (PE/CH2Cl2/Diethyl ether 3:2:2) gave pure 9 as a solid
(338 mg, 57%). The enantiomeric ratio was determined to be > 99% by
HPLC on chiral stationary phase (Daicel Chiral Pak AD 250x4.6 mm
column: 25 °C: hexane / iPrOH 90:10; flow of 0.8 mL/min; temp= 26°C, UV
detection at 220 nm; Rt (S,S) = 10.2 min; Rt (R,R) = 11.9 min). In order to
have a reference of the (2R,3R) enantiomer, the same procedure was
repeated with D-proline as catalyst. The diastereomeric ratio was
determined by 1H NMR and was found to be = 97:3. The relative syn
configuration was assigned on the basis of spectral analogies with other
similar compounds. Rf = 0.18 ((PE/CH2Cl2/Diethyl ether 3:2:1). M.P.:
123.2-124.1 °C. [α]D -26.1 (c 1, CHCl3). 1H NMR: (300 MHz, CDCl3, 25 °C):
(2S,3S)-3-(2-Allyloxyphenyl)-3-((tert-butoxycarbonyl)amino)-2-
methylpropan-1-ol 15. It was prepared in 48% (from the carbamoyl
sulphone of 2-allyloxybenzaldehyde described above) using the same
methodology employed for 9. White foam. Syn:anti ratio (1H NMR): > 95:5.
The e.e. was demonstrated to be > 95% by Mosher's ester analysis. Rf =
0.18 (PE / AcOEt 5:1 + 2% MeOH). [α]D: -19.5 (c 0.5, CHCl3). 1H NMR (300
MHz, CDCl3, 25 °C) δ = 7.26-7.13 (m, 2 H, H-4 and H-6); 6.95 (td, 3JH,H
=
4
3
7.5 Hz, JH,H = 1.0 Hz, 1 H, H-5); 6.89 (d, JH,H = 8.2 Hz, 1 H, H-3); 6.08
(ddt, 3JH,H = 17.2, 10.5, 5.2 (t) Hz, 1 H, CH=CH2); 5.94 (d, 3JH,H = 9.6 Hz, 1
H, NH); 5.48 (1 H, dq, 3JH,H = 17.2, 2JH,H = JH,H = 1.3 Hz, 1 H, CHH=CH);
5.32 (1 H, dq, 3JH,H = 10.5, 2JH,H = JH,H = 1.5 Hz, 1 H, CHH=CH); 5.17 (dd,
4
4
3JH,H = 4.8 9.7 Hz, 1 H, ArCH); 4.65-4.52 (m, 2 H, CH2OAr), 3.48-3.30 (m,
3 H, CH2OH); 2.10 (mc) (m, 1 H, CH-CH3); 1.44 (s, 9 H, (CH3)3C); 0.77 (d,
3JH,H = 7.0 Hz, 3 H, CH3CH). 13C NMR (75 MHz, CDCl3, 25 °C) δ = 156.6,
155.8 (C=O and C-OAll), 132.7 (CH=CH2), 128.9 (quat.), 128.7, 128.1,
121.0, 112.3 (ArCH), 117.9 (CH=CH2), 79.6 (C(CH3)3), 69.0 (CH2OAr),
65.2 (CH2OH), 52.6 (ArCH), 41.7 (CH-CH3), 28.3 (C(CH3)3), 11.3
(CH3CH). I.R.: ῡ 3442, 3064, 2974, 2942, 2854, 1661, 1605, 1555, 1496,
1455, 1413, 1381, 1364, 1325, 1295, 1284, 1248, 1165, 1136, 1100, 1079,
1038, 1024, 997, 929, 916, 886, 864, 823, 756, 732, 704, 668, 643, 616
cm-1. HRMS (ESI+) m/z [M + H+]: Calcd. For C18H28NO4 322.2018; Found
322.2015.
Typical procedures for the Ugi reactions: (S) and (R) N-(4-
(Allyloxy)phenyl)-2-(N-((1S,2S)-1-(3-bromophenyl)-3-hydroxy-2-
methylpropyl)propionamido)-3-methylbutanamide 5b. Preparation of
aminoalcohol. A solution of Boc aminoalcohol 9 (172 mg, 0.50 mmol) in
dry CH2Cl2 (8 mL), was cooled to 0 °C, and treated with trifluoroacetic acid
(4 mL). After stirring for 1 h at 0 °C, the solution was evaporated to dryness,
and taken up with AcOEt and 1 M aqueous NaOH so that pH = 9-10. The
phases were separated, and the organic extracts washed with saturated
aqueous NaCl and evaporated to dryness to give the crude aminoalcohol
as an oil.
3
 = 7.43-7.36 (m, 2 H); 7.26-7.16 (m, 2 H); 5.29 (d, JH,H = 8.5 Hz, 1 H,
NH); 5.04 (d, 3JH,H = 7.3 Hz, 1 H, ArCH); 3.58-3.28 (m, 2 H, CH2OH); 3.10
(mc) (m, 1 H, OH); 2.19 (mc) (m, 1 H, CHCH3); 1.46 (s, 9 H, (CH3)3CH);
0.69 (d, 3JH,H = 6.8 Hz, 3 H, CH3CH). 13C NMR (300 MHz, CDCl3, 20 °C):
 = 156.3 (C=O), 143.0, 122.6 (quat.), 130.0, 129.9, 129.6, 125.3 (ArCH),
80.2 (C(CH3)3), 64.7 (CH2OH), 54.2 (ArCH), 40.7 (CHCH3), 28.3 ((CH3)3C),
10.9 (CH3CH). GC-MS: R 10.11 min; m/z 286 (5.2) [M − CH(CH3)CH2OH
t
(81Br)]+, 284 (4.9) [M − CH(CH3)CH2OH (79Br)]+, 230 (21), 228 (21), 186
(27), 184 (32), 77 (5.0), 59 (21), 58 (5.4), 57 (100), 56 (7.8), 41 (19), 39
(5.0). HRMS (ESI+) m/z [M + H+]: Calcd. For C15H23BrNO3 344.0861;
Found 344.0861.
Method A. The crude aminoalcohol was taken up in dry THF (5 mL), cooled
to −38 °C, and treated, in this order, with isobutyraldehyde (48 µL, 0.525
mmol, 1.05 equiv), 3 Å powdered molecular sieves (50 mg), zinc dibromide
(113 mg, 0.50 mmol, 1 equiv), propionic acid (45 µL, 0.600 mmol, 1.2
equiv), and 4-allyloxyphenyl isocyanide (see S.I. for its preparation) (96
mg, 0.600 mmol, 1.2 equiv). The mixture was stirred for 48 h at −38 °C.
Then it was evaporated to dryness and chromatographed (CH2Cl2 / PE /
Et2O from 8:2:1 to 8:2:2) to give first the (R) diastereomer (70 mg) and then
the (S) one (73 mg) (54% overall yield). The diastereomeric ratio (S) : (R)
was determined to be 51:49 by HPLC on the crude product (Column
Phenyl C6 150 x 3 mm, 3 µ, conc.: 200µg/ml; flow=0,34ml/min; Vinj 5µl;
Temp: 25°C detection : 220nm; gradient (H2O+0,1% formic acid) / CH3CN
from 60:40 to 0:100 in 20 min. Rt (S): 12.7 min; Rt (R): 13.9 min).
tert-Butyl
((2-(allyloxy)phenyl)(tosyl)methyl)carbamate.
2-
allyloxybenzaldehyde[20] (3.06 g, 18.85 mmol, 1 equiv) was dissolved in
methanol (11 mL) and treated at rt with tert-butyl carbamate (2.21 g, 18.85
mmol, 1 equiv) and a solution of sodium p-toluenesulphinate (6.72 g, 37.7
mmol, 2 equiv) in H2O (22 mL). The resulting cloudy solution was treated
with HCO2H (1.56 mL, 41.47 mmol, 2.2 equiv) and vigorously stirred
overnight, during which time the desired product precipitates. The resulting
white solid was filtered through a Büchner funnel and washed with distilled
H2O (75 mL). The product was suspended in diisopropyl ether (10 mL) and
stirred for 2 hours. The product was collected by filtration and washed with
diisopropyl ether (40 mL) to give a white solid (4.94 g, 63%). M.p. 119.3 -
1
3
120.4 °C. H NMR (300 MHz, CDCl3) δ = 7.72 (d, JH,H = 8.2 Hz, 2 H, H
ortho to SO2); 7.45 – 7.30 (m, 2 H, H-4, H-6); 7.29 (d, 3JH,H = 8.2 Hz, 2 H,
H meta to SO2); 7.00 (t, 3JH,H = 7.4 Hz, 1 H, H-5); 6.86 (d, 3JH,H = 8.1 Hz, 1
H, H-3); 6.42–6.21 (m, 2 H, CHAr and NH); 6.01 (ddt, JH,H = 17.2, 10.4,
5.2 (t) Hz, 1 H, CH=CH2); 5.42 (1 H, dq, 3JH,H = 17.3, 2JH,H = JH,H = 1.4 Hz,
1 H, CHH=CH); 5.30 (1 H, dq, JH,H = 10.4, JH,H = JH,H = 1.3 Hz, 1 H,
CHH=CH); 4.57-4.40 (m, 2 H, ArCH2CH= CH2), 2.40 (s, 3 H, CH3Ar), 1.31
(s, 9 H, (CH3)3C). 13C NMR (75 MHz, CDCl3) δ = 156.9, 153.7 (C=O, C-
Method B. The crude aminoalcohol was taken up in dry MeOH (5 mL), and
treated, in this order, with isobutyraldehyde (48 µL, 0.525 mmol, 1.05
equiv), 3 Å powdered molecular sieves (50 mg), propionic acid (45 µL,
0.600 mmol, 1.2 equiv), and 4-allyloxyphenyl isocyanide (96 mg, 0.600
mmol, 1.2 equiv). The mixture was stirred for 48 h at r.t.. Then it was
evaporated to dryness and chromatographed as for method A (67% overall
3
4
3
2
4
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701328
European Journal of Organic Chemistry
FULL PAPER
yield). The diastereomeric ratio (S) : (R) was determined to be 42:58 by
HPLC on the crude product.
as a yellow oil (62 mg, 64%). Note: although two well separated spots are
well visible at TLC (Rf = 0.74 and 0.50 with PE / AcOEt 9:1),
chromatography fails to separate them. A simple two-dimensional TLC
showed that the two spots interconverts on silica gel. The diastereomeric
ratio between isomers A and B was 60:40 as determined by NMR. The
relative configuration was not established. 1H NMR: (300 MHz, CDCl3,
Method C. Exactly as method B, but using trifluoroethanol instead of
methanol as the solvent (68% overall yield). The diastereomeric ratio (S) :
(R) was determined to be 64 : 36 by HPLC on the crude product.
25 °C):  = 7.40-7.25 (m, 3 H); 7.15-7.05 (m, 1.2 H, diast. A); 7.02-6.95 (m,
3
0.8 H, diast. B); 7.00 (d, JH,H = 3.9 Hz, 0.6 H, H-3' of A); 6.88 (d, 3JH,H
=
5b-(R). Rf 0.34 (CH2Cl2 / PE / Et2O 8:2:2). [α]D -37.3 (c 2.13, CHCl3). 1H
NMR (300 MHz, CDCl3, 25 °C) (for numbering see Scheme 2):  = 10.47
(s, 1 H, NH), 7.56-7.47 (m, 2 H, H 2' and H-5'), 7.46 (d, 3JH,H = 9.0 Hz, 2 H,
H meta to O-allyl), 7.38 (broad d, 3JH,H = 7.8 Hz, H-6'); 7.30 (d, 3JH,H = 7.8
3.9 Hz, 0.4 H, H-3' of B); 6.84 (d, 3JH,H = 3.9 Hz, 0.6 H, H-4' of A); 6.64 (d,
3JH,H = 3.9 Hz, 0.4 H, H-4' of B); 4.43 (d, 3JH,H = 4.5 Hz, 0.6 H, H-5 of A);
4.21 (t, JH,H = JH,H = 10.9 Hz, 0.4 H, H-7 of B); 4.01 (d, JH,H = 6.3 Hz,
0.4 H, H-5 of B); 3.90 (dd, JH,H = 11.1, JH,H = 5.4 Hz, 0.4 H, H-7 of B);
3.84 (dd, 2JH,H = 10.2, 3JH,H = 6.9 Hz, 0.6 H, H-7 of A); 3.56 (d, 3JH,H = 3.0
Hz, 0.4 H, H-3 of B); 3.41 (t, 2JH,H = 3JH,H = 10.9 Hz, 0.6 H, H-7 of A); 3.28
(d, 3JH,H = 5.4 Hz, 0.6 H, H-3 of A); 3.20 (tt, 3JH,H = 3.6, 12.1 Hz, 0.6 H, CH
cyclohexyl of A); 2.97 (tt, 3JH,H = 3.6, 12.1 Hz, 0.4 H, CH cyclohexyl of A);
2.65-2.15 (m, 1 H, H-6); 2.08-1.85 (m, 1 H, CH(CH3)2); 1.85-1.45 (m, m);
3
2
3
2
3
Hz, H-4'), 6.87 (d, 3JH,H = 9.0 Hz, 2 H, H ortho to O-allyl), 6.04 (ddt, 3JH,H
=
2
5.3 (t), 10.5, 17.2 Hz, 1 H, CH=CH2), 5.40 (dq, 3JH,H = 17.1 Hz, JH,H and
4JH,H = 1.6 Hz), 5.40 (dq, JH,H = 17.1 Hz, JH,H and JH,H = 1.6 Hz, 1 H,
3
2
4
3
2
4
CH=CHH), 5.27 (dq, JH,H = 10.5 Hz, JH,H and JH,H = 1.5 Hz, 1 H,
CH=CHH), 5.02 (d, 3JH,H = 11.7 Hz, 1 H, H-4), 4.51 (dt, 3JH,H = 5.3 Hz, 4JH,H
= 1.4 Hz, 2 H, CH2O), 3.59 and 3.44 (slightly broad AB syst., 3JH,H = 10.0
Hz, 2 H, CH2OH), 3.29 (d, 3JH,H = 11.0 Hz, 1 H, H-2), 2.92-2.63 (m, 4 H, H-
3
1.35-0.80 (m, 6 H); 1.25 (d, JH,H = 7.2 Hz, 1.2 H, CH3CHCH3 of B); 1.07
(d, 3JH,H = 6.9 Hz, 1.2 H, CH3CHCH3 of B); 1.02 (d, 3JH,H = 6.9 Hz, 1.8 H,
CH3CHCH3 of A); 0.96 (d, 3JH,H = 6.9 Hz, 1.8 H, CH3CHCH3 of A); 0.80 (d,
3JH,H = 7.2 Hz, 1.2 H, CH3CH of B); 0.53 (d, 3JH,H = 6.6 Hz, 1.8 H, CH3CH
of A). 13C NMR (300 MHz, CDCl3, 20 °C):  = 171.5 (A), 170.9 (B) (C=O);
147.5 (A) (C-2'), 143.4 (B) (C-2'), 139.2 (B), 135.5 (A) (quat. Ph); 132.3 (B),
131.4 (A), 130.1 (A), 129.4 (B), 128.6 (A), 127.6 (B) (CH Ph), 127.1 (B) (C-
3'), 126.7 (A+B) (C-5'), 126.1 (A) (C-3'), 124.6 (B) (C-4'); 124.5 (A) (C-4'),
98.6 (B), 98.4 (A) (C-9); 67.91 (A), 67.9 (B) (C-3), 66.3 (A) (C-5); 65.51 (A),
65.47 (B) (C-7); 64.8 (A) (C-3); 61.9 (B) (C-5); 53.4 (A), 53.3 (B) (CH
cyclohexyl); 32.3 (A), 30.4 (B) (CH(CH3)2), 29.9 (A), 29.4 (B) (C-6), 29.7,
29.6, 29.5, 28.8, 27.3, 26.5, 26.32, 26.28, 26.2 (CH2 cyclohexyl), 19.4 (A),
19.2 (A), 18.7 (B), 16.7 (B) (CH3CHCH3), 15.3 (A), 14.4 (B) (CH3CH). At
gHMBC, the signal at 98.4 (diast. A) is coupled with the doublet at 3.28 (H-
3), with the doublet at 4.43 (H-5), and with the two signals of H-7. The
signal at 98.6 (diast. B) is coupled with the doublet at 3.56 (H-3), with the
doublet at 4.01 (H-5), and with the two signals of H-7. I.R.: ῡ = 3425, 2962,
2252, 1701, 1424, 1370, 1322, 1258, 1213, 1051, 1023, 1005, 865, 819,
791, 762, 702, 661, 625 cm-1. HRMS (ESI+) m/z [M + H+]: Calcd. For
C26H34ClN2O2S 473.2030; Found 473.2032.
3
3
5, H-8, CH(CH3)3), 1.27 (t, JH,H = 7.2 Hz, 3 H, CH3CH2), 1.05 (d, JH,H
=
6.6 Hz, 3 H, CH3CH-5), 0.79 (d, 3JH,H = 6.6 Hz, 3 H, CH3 isopropyl), -0.05
(d, 3JH,H = 6.6 Hz, 3 H, CH3 isopropyl) 13C NMR (75 MHz, CDCl3, 25°C): 
= 176.2, 170.3 (C=O), 155.1, 139.3, 131.6, 122.8 (quat.), 133.3 (CH=CH2),
132.8, 131.8, 130.2, 128.0, 121.4 (x2), 115.0 (x2) (ArCH), 117.6 (CH=CH2),
70.0 (C-2), 69.1 (CH2OAr), 63.9 (C-6), 63.4 (C-4), 35.0 (C-5), 28.5 (C-8),
27.2 (CH(CH3)2), 19.8, 18.6 ((CH3)2CH), 14.0 (CH3-C5), 9.6 (C-9). I.R.: ῡ
= 3413, 3250, 3132, 3063, 2969, 2934, 2874, 1657, 1594, 1545, 1509,
1461, 1425, 1389, 1370, 1331, 1271, 1232, 1172, 1156, 1113, 1075, 1024,
988, 923, 871, 828, 777, 681, 634 cm-1. HRMS (ESI-) m/z [M - H+]: Calcd.
For C27H34BrN2O4 529.1702; Found 529.1710.
5b-(S). Rf 0.21 (CH2Cl2 / PE / Et2O 8:2:2). [α]D +146.3 (c 2.15, CHCl3). 1H
NMR (300 MHz, CDCl3, 25 °C) (for numbering see Scheme 2):  = 9.55 (s,
1 H, NH), 7.42-7.30 (m, 2 H, H 2' and H-4'), 7.24 (broad d, 3JH,H = 7.5 Hz,
H-6'); 7.11 (t, 3JH,H = 7.8 Hz, H-5'), 6.99 (d, 3JH,H = 9.0 Hz, 2 H, H meta to
O-allyl), 6.75 (d, 3JH,H = 9.0 Hz, 2 H, H ortho to O-allyl), 6.02 (ddt, 3JH,H
=
2
5.3 (t), 10.5, 17.2 Hz, 1 H, CH=CH2), 5.38 (dq, 3JH,H = 17.2 Hz, JH,H and
3
2
4
4JH,H = 1.6 Hz), 5.40 (dq, JH,H = 17.1 Hz, JH,H and JH,H = 1.6 Hz, 1 H,
3
2
4
CH=CHH), 5.26 (dq, JH,H = 10.5 Hz, JH,H and JH,H = 1.5 Hz, 1 H,
CH=CHH), 4.93 (d, 3JH,H = 11.2 Hz, 1 H, H-4), 4.47 (dt, 3JH,H = 5.3 Hz, 4JH,H
= 1.4 Hz, 2 H, CH2O), 3.64 (broad d, 3JH,H = 10.5 Hz, 1 H, CHHOH), 3.48
(broad dd, 3JH,H = 3.9, 10.5 Hz, 1 H, CHHOH), 3.22 (d, 3JH,H = 9.6 Hz, 1 H,
H-2), 3.03-2.85 (m, 1 H, CH(CH3)3), 2.76-2.60 (m, 2 H, CH2CH3), 2.60-2.43
(3S,5S,6S,8aR)-1-(4-(Allyloxy)phenyl)-5-(3-bromophenyl)-8a-ethyl-3-
isopropyl-6-methyltetrahydro-1H-imidazo[2,1-b][1,3]oxazin-2(3H)-
one 7b. It was prepared either starting from 50 mg of 5b-S or from 50 mg
of 5b-R in 55% and 74% yields respectively, using the same method used
for preparation of 7a. Chromatography was carried out with PE/AcOEt
80:20. Rf 0.34 (PE/AcOEt 80:20). [α]D -53.5 (c 1.36, CHCl3). 1H NMR (300
MHz, CDCl3, 25 °C) (this compound contains an inseparable 8% of the
diastereomer at C-8a; only the signals of major diast. are reported):  =
7.62 (t, 4JH,H = 1.5 Hz, 1 H, H ortho to Br and C); 7.44-7.35 (m, 2 H, H of
Br-Ar); 7.27-7.17 (m, 1 H, H of Br-Ar); 7.23 (d, 3JH,H = 9.0 Hz, 2 H, H meta
to O); 76.92 (d, 3JH,H = 9.0 Hz, 2 H, H ortho to O); 6.05 (ddt, 3JH,H = 5.3 (t),
(m, 1 H, H-5), 1.28 (d, 3JH,H = 6.3 Hz, 3 H, CH3CH-5), 1.26 (t, JH,H = 7.2
3
3
Hz, 3 H, CH3CH2), 0.99 (d, JH,H = 6.6 Hz, 3 H, CH3 isopropyl), 0.97 (d,
3JH,H = 6.6 Hz, 3 H, CH3 isopropyl).13C NMR (75 MHz, CDCl3, 25°C):  =
177.5, 169.9 (C=O), 154.9, 138.6, 131.2, 122.6 (quat.), 133.3 (CH=CH2),
132.4, 131.4, 130.1, 127.7, 121.5 (x2), 114.7 (x2) (ArCH), 117.5 (CH=CH2),
72.0 (C-2), 69.1 (CH2OAr), 64.2 (C-6), 63.7 (C-4), 34.5 (C-5), 28.7 (C-8),
28.6 (CH(CH3)2), 22.0, 20.5 ((CH3)2CH), 14.9 (CH3-C5), 9.9 (C-9). I.R.: ῡ
= 3274, 3133, 3067, 2971, 2935, 2875, 1658, 1595, 1541, 1509, 1462,
1420, 1388, 1369, 1224, 1172, 1157, 1107, 1074, 1022, 989, 925, 870,
827, 802, 775, 680, 634 cm-1. HRMS (ESI-) m/z [M - H+]: Calcd. For
C27H34BrN2O4 529.1702; Found 529.1700.
10.5 (d), 17.2 (d) Hz, 1 H, CH=CH2); 5.41 (dq, 3JH,H = 17.2, 2JH,H = 4JH,H
1.5 Hz, 1 H, CH=CHH)); 5.29 (dq, JH,H = 10.5, JH,H
CH=CHH); 4.53 (dt, 3JH,H = 5.4, 2JH,H = 4JH,H = 1.4, 2 H, CH2O); 4.11 (dd,
=
3
2
=
4JH,H = 1.2, 1 H,
2JH,H = 11.4, JH,H = 4.7 Hz, 1 H, H-7); 3.96 (d, JH,H = 5.6 Hz, 1 H, H-5);
3.89 (dd, 2JH,H = 11.4, 3JH,H = 5.7 Hz, 1 H, H-7); 3.30 (d, 3JH,H = 6.8 Hz, 1
H, H-3); 2.39 (dtq, 3JH,H = 6.6 (q), 5.7 (t), 4.7 (d) Hz, 1 H, H-6); 2.10 (octuplet,
3JH,H = 6.9 Hz, 1 H, CH(CH3)2); 1.72 (dq, 3JH,H = 5.3 (q), 2JH,H = 10.6 (d) Hz,
1 H, CHHCH3); 1.55 (dq, 3JH,H = 5.3 (q), 2JH,H = 10.6 (d) Hz, 1 H, CHHCH3);
1.12 (d, 3JH,H = 6. Hz, 3 H, CH3 isopropyl), 1.09 (d, 3JH,H = 6.8 Hz, 3 H, CH3
isopropyl); 1.04 (d, 3JH,H = 7.2 Hz, 3 H, CH3CH-5), 0.70 (t, 3JH,H = 7.3 Hz,
3 H, CH3CH2). 13C NMR (75 MHz, CDCl3, 25°C):  = 173.2 (C=O), 157.6,
142.8, 127.9, 122.0 (quat.), 133.05 (C ortho to Br and C), 132.99
(CH=CH2), 130.3, 129.5, 128.4, 128.3 (x2), 115.0 (x2) (ArCH), 117.8
(CH=CH2), 104.0 (C-8a), 70.4 (C-3), 69.0 (CH2OAr), 64.7, 64.6 (C-7, C-5),
31.7 (CH(CH3)2), 30.8 (CH2CH3), 29.8 (C-6), 20.2, 19.1 ((CH3)2CH), 14.4
3
3
(3S,5S,6S,8aR) and (3S,5S,6S,8aS) 8a-(5-chlorothiophen-2-yl)-1-
cyclohexyl-3-isopropyl-6-methyl-5-phenyltetrahydro-1H-imidazo[2,1-
b][1,3]oxazin-2(3H)-ones 7a. Compound 5a-S[11] (100 mg, 204 µmol) was
dissolved in dry DMF (2 mL), cooled to 0°C, and treated with 1,1'-
sulfonyldiimidazole (SDI) (101 mg, 520 µmol). After 10 min, NaH (60% in
mineral oil) (24.5 mg, 612 µmol) was added. After 10 min the cooling bath
was removed and the mixture stirred at r.t. for 8 h, and then poured into a
10:2 mixture of 5% aqueous NH4H2PO4 and 2M HCl. Extraction (AcOEt)
was followed by washing with 5% aqueous LiCl (to remove DMF), and
brine. Evaporation and chromatography (PE / AcOEt 95 : 5) gave pure 7a
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10.1002/ejoc.201701328
European Journal of Organic Chemistry
FULL PAPER
132.9 (quat. and CH=CH2), 129.0 (x2), 128.9 (x2), 128.6, 126.6 (x2), 115.5
(x2) (ArCH), 117.9 (CH=CH2), 69.0 (CH2OAr), 65.0 (CH2OH), 64.3 (C-3),
61.5 (C-1'), 54.0 (C-6), 36.0 (CH-CH3), 33.1 (CH(CH3)3), 20.2, 17.2
(CH(CH3)2, 14.6 (CH3CH). I.R.: ῡ 3429, 2967, 2934, 2878, 1652, 1608,
1588, 1509, 1449, 1390, 1369, 1349, 1325, 1293, 1245, 1220, 1179, 1146,
1107, 1029, 990, 923, 865, 830, 801, 743, 702, 667, 628 cm-1. HRMS
(ESI+) m/z [M + H+]: Calcd. For C26H33N2O4 437.2440; Found 437.2451.
(CH3-C-6), 8.3 (CH3CH2). At gHMBC, the signal at 104.0 is coupled with
the doublet at 3.30 (H-6), with the doublet at 3.96 (H-5), with the two
signals of H-7, and finally with CH2CH3 and CH2CH3 signals. I.R.: ῡ = 2963,
2933, 2876, 1703, 1608, 1593, 1568, 1509, 1463, 1425, 1394, 1382, 1350,
1294, 1241, 1189, 1170, 1068, 1020, 997, 925, 902, 884, 826, 790, 733,
700, 665, 606 cm-1 HRMS (ESI+) m/z [M + H+]: Calcd. For C27H34BrN2O3
513.1753; Found 513.1740.
(S)-1-(4-(Allyloxy)phenyl)-4-((1S,2S)-3-hydroxy-2-methyl-1-
(S)-3-Methyl-2-(N-((3S,4S)-3-methylchroman-4-yl)propionamido)-N-
pentylbutanamide 19h. The mixture of Ugi adducts 5h-S and 5h-R was
prepared in 60% overall yield from Boc-aminoalcohol 18 according to
method A (see the synthesis of 5b). After separation of the two
diastereomers, the major one (slower running) 5h-S (150 mg, 311 µmol)
was dissolved in 96% EtOH (10 mL) and hydrogenated over 10% Pd-C
(45 mg) at r.t. and under the slight overpressure of an inflated balloon.
After stirring overnight, the suspension was filtered through a celite cake,
washing with CH2Cl2, and evaporated to dryness. The residue was taken
up in dry THF (10 mL), cooled to 0°C, and treated with triphenylphosphine
(122 mg, 466 µmol) and diethyl azodicarboxylate (40% solution in toluene)
(212 µL, 466 µmol). The solution was stirred for 5 h at 0°C. Evaporation
and chromatography afforded pure 19h as an oil. Rf = 0.28 (AcOEt/PE 1:4
+ 1% MeOH). [α]D = + 68.4 (c 0.50, CHCl3). 1H NMR (300 MHz, CDCl3) δ
= 8.02 (broad s, 1 H, NH); 7.16 (t, 3JH,H = 7.8 Hz, 1 H); 6.97 (d, 3JH,H = 7.5
Hz, 1 H); 6.86-6.77 (m, 2 H); 4.84 (d, 3JH,H = 9.5 Hz, 1 H, H-4); 4.27-4-13
(m, 2 H, H-6 and CHiPr); 3.75 (t, 2JH,H = 3JH,H = 11.1 Hz, 1 H, H-6); 3.05 (q,
3JH,H = 6.2 Hz, 2 H, CH2NH); 2.97-2.80 (m, 1 H, CH(CH3)2); 2.65-2.45 (m,
2 H, CH2CO); 2.46-2.28 (m, 1 H, H-3); 1.55-1.17 (m, 9 H, CH2 of pentyl
phenylpropyl)-3-isopropylpiperazine-2,5-dione 17c-S. Boc-protected
aminoalcohol 14 was converted, according to method A or method B (see
preparation of 5b), by reaction with 4-allyloxyphenyl isocyanide,
isobutyraldehyde and chloroacetic acid, into the diastereomeric mixture of
5c. The two isomers 5c-S, and 5c-R where separated by chromatography,
1
and recognized by H NMR (selected data are reported in the S.I.). The
slower running (major) isomer (60 mg, 127 µmol) was dissolved in dry DMF
(2 mL), and treated, at r.t., with cesium carbonate (82.7 mg, 250 µmol).
After 6 h the reaction was complete, as judged by TLC. The mixture was
quenched with 5% aqueous NH4H2PO4 (final pH = 7) and extracted with
EtOAc. The organic layer was washed with 5% aqueous LiCl and then with
brine, and evaporated under reduced pressure. The crude was purified by
column cromatography to afford pure 2,5-diketopiperazine 17c-S (34.8 mg,
63%) as an oil. Rf = 0.39 (PE / AcOEt 50:50 + 1% MeOH). [α]D = +37.7 (c
1
1, CHCl3). H NMR (300 MHz, CDCl3)(for numbering see Scheme 6) δ =
7.61 (dd, 3JH,H = 7.9, 4JH,H = 1.5 Hz, 2 H, H ortho of Ph); 7.39-7.29 (m, 3 H,
other CH of Ph); 7.14 (d, 3JH,H = 9.0 Hz, 2 H, H meta to OAll); 6.93 (d, 3JH,H
3
= 9.0 Hz, 2 H, H ortho to OAll); 6.03 (ddt, JH,H = 17.3, 10.5, 5.3 (t) Hz, 1
3
2
4
3
H, CH=CH2); 5.40 (1 H, dq, JH,H = 17.3, JH,H JH,H 1.6 Hz, 1 H,
and CH3CH2); 1.11 (d, JH,H = 6.6 Hz, CH3CH); 0.97-0.84 (m, 9 H, other
=
=
CHH=CH); 5.29 (1 H, dq, 3JH,H = 10.5, 2JH,H = JH,H = 1.4 Hz, 1 H, CHH=CH);
CH3). 13C NMR (75 MHz, CDCl3, 25 °C) δ = 176.8, 171.3 (C=O), 156.4
(quat.)(the other quat. carbon is not visible, probably because of its
broadiness), 129.3, 128.1, 121.1, 117.6 (Ar CH), 71.6 (CHiPr), 70.6 (C-2),
60.9 (C-4), 39.1 (CH2NH), 31.7 (C-3), 29.2, 28.9 (CH2 pentyl), 28.6
(COCH2CH3), 28.2 (CH(CH3)2), 22.4 (CH2 pentyl), 20.8, 20.1 (CH(CH3)2,
15.4, 14.0 (CH3CH and CH3 of pentyl), 9.9 (CH3CH2CO). I.R.: ῡ 3299,
2961, 2932, 2873, 1716, 1656, 1623, 1585, 1542, 1489, 1451, 1368, 1314,
1260, 1227, 1173, 1102, 1072, 1049, 1024, 960, 930, 892, 852, 799, 752,
723, 698, 667, 643, 604 cm-1. HRMS (ESI+) m/z [M + H+]: Calcd. For
C23H37N2O3 389.2804; Found 389.2815.
4
4.53 (dt, 3JH,H = 5.4 (d), 4JH,H = 1.5 Hz, 2 H, CH2OAr); 4.51 (d, 2JH,H = 17.1
Hz, 1 H, H-6); 4.48 (d, 3JH,H = 11.1 Hz, 1 H, H-1'); 4.12 (d, 2JH,H = 17.3 Hz,
1 H, H-6); 3.93 (d, 3JH,H = 4.5 Hz, 1 H, H-3); 3.51 (dd, 3JH,H = 3.9, JH,H
=
2
10.8 Hz, 1 H, H-3'); 3.27 (dd, 3JH,H = 4.7, 2JH,H = 10.8 Hz, 1 H, H-3'); 3.04
3
(mc) (m, 1 H, H-2'); 2.22 (d of heptuplet, JH,H = 6.9, 4.5 (d) Hz, 1 H,
CH(CH3)2); 1.21 (d, 3JH,H = 6.6 Hz, 3 H, CH3CH); 1.04 (d, 3JH,H = 7.2 Hz, 3
H, (CH3)2CH); 0.92 (d, 3JH,H = 6.9 Hz, 3 H, (CH3)2CH). 13C NMR (75 MHz,
CDCl3, 25 °C) δ = 165.0, 164.9 (C=O), 157.6 (C-OAll), 139.2 (quat.), 132.9,
132.8 (quat. and CH=CH2), 129.4 (x2), 128.8 (x2), 128.2, 126.6 (x2), 115.5
(x2) (ArCH), 117.9 (CH=CH2), 70.2 (C-3), 69.0 (CH2OAr and C-1'), 64.8
(CH2OH), 54.1 (C-6), 37.4 (CH-CH3), 33.3 (CH(CH3)3), 20.6, 17.0
(CH(CH3)2, 15.0 (CH3CH). I.R.: ῡ 3432, 2967, 2933, 2878, 1656, 1607,
1587, 1509, 1449, 1425, 1390, 1368, 1326, 1293, 1244, 1221, 1187, 1151,
1109, 1062, 1028, 986, 924, 866, 830, 804, 746, 702, 666, 632 cm-1.
HRMS (ESI+) m/z [M + H+]: Calcd. For C26H33N2O4 437.2440; Found
437.2444.
(S)-1-Cyclohexyl-3-isopropyl-4-((3S,4S)-3-methylchroman-4-
yl)piperazine-2,5-dione 20j-S. The mixture of Ugi adducts 5j-S and 5j-R
was prepared in 51% overall yield from Boc-aminoalcohol 18[11] according
to method A (see the synthesis of 5b). The two isomers 5j-S, and 5j-R
where separated by chromatography, and recognized by 1H NMR
(selected data are reported in the S.I.). The slower running (major) isomer
(75 mg, 142 µmol) was dissolved in dry DMF (1.5 mL), and treated, at r.t.,
with cesium carbonate (92.5 mg, 284 µmol). After 4 h the reaction was
complete, as judged by TLC. The mixture was quenched with 5% aqueous
NH4H2PO4 (final pH = 7) and extracted with EtOAc. The organic layer was
washed with 5% aqueous LiCl and then with brine, and evaporated under
reduced pressure. The crude was dissolved in 96% EtOH (5 mL) and
hydrogenated over 10% Pd-C (22 mg) at r.t. and under the slight
overpressure of an inflated balloon. After stirring overnight, the suspension
was filtered through a celite cake, washing with CH2Cl2, and evaporated to
dryness. The residue was taken up in dry THF (5 mL), cooled to 0°C, and
treated with triphenylphosphine (56 mg, 213 µmol) and diethyl
azodicarboxylate (40% solution in toluene) (97 µL, 466 µmol). The solution
was stirred for 1 h at 0°C. Evaporation and chromatography afforded pure
20j-S as an oil (38 mg, 69%). Rf = 0.33 (AcOEt/PE 1:3 + 1% MeOH). [α]D
(R)-1-(4-(Allyloxy)phenyl)-4-((1S,2S)-3-hydroxy-2-methyl-1-
phenylpropyl)-3-isopropylpiperazine-2,5-dione 17c-R. It was prepared
as described above from the faster running (minor) isomer 5c-R (36 mg,
76 µmol) to give pure 17c-R as an oil (26.8 mg, 80%). Rf = 0.50 (PE /
AcOEt 50:50 + 1% MeOH). [α]D = -35.1 (c 1, CHCl3). 1H NMR (300 MHz,
CDCl3)(for numbering see Scheme 6) δ = 7.54-7.47 (m, 2 H, H ortho of
3
Ph); 7.41-7.30 (m, 3 H, other CH of Ph); 7.13 (d, JH,H = 9.0 Hz, 2 H, H
meta to OAll); 6.93 (d, 3JH,H = 9.0 Hz, 2 H, H ortho to OAll); 6.03 (ddt, 3JH,H
= 17.3, 10.5, 5.2 (t) Hz, 1 H, CH=CH2); 5.40 (1 H, dq, 3JH,H = 17.3, 2JH,H =
4JH,H = 1.5 Hz, 1 H, CHH=CH); 5.29 (1 H, dq, 3JH,H = 10.5, 2JH,H = JH,H = 1.5
4
3
2
Hz, 1 H, CHH=CH); 5.22 (d, JH,H = 11.5 Hz, 1 H, H-1'); 4.55 (d, JH,H
=
17.3 Hz, 1 H, H-6); 4.52 (dt, 3JH,H = 5.4 (d), 4JH,H = 1.5 Hz, 2 H, CH2OAr);
4.12 (d, 2JH,H = 17.3 Hz, 1 H, H-6); 3.89 (d, 3JH,H = 4.2 Hz, 1 H, H-3); 3.59
3
2
3
2
(dd, JH,H = 3.0, JH,H = 10.8 Hz, 1 H, H-3'); 3.37 (dd, JH,H = 5.3, JH,H
=
= + 30.5 (c 0.52, CHCl3). 1H NMR (300 MHz, CDCl3) δ = 7.14 (ddt, 3JH,H
=
10.8 Hz, 1 H, H-3'); 2.93 (mc) (m, 1 H, H-2'); 1.66-1.42 (m, 1 H, CH(CH3)2);
8.1 Hz (t), 2JH,H = 0.6, 1.8 Hz, 1 H); 6.90-6.81 (m, 2 H); 6.72 (d, 3JH,H = 7.8
Hz, 1 H); 5.45 (d, 3JH,H = 10.8 Hz, 1 H, H-4); 4.50-4.36 (mc = 4.43) (m, 1
H, CHN); 4.23 (dd, JH,H = 3.8 Hz, JH,H = 11.2 Hz, 1 H, H-2); 4.08, 4.01
(AB syst., 3JH,H = 17.7 Hz, 2 H, CH2N); 3.85 (t, 3JH,H = 2JH,H = 11.0 Hz, 1 H,
3
3
1.17 (d, JH,H = 6.7 Hz, 3 H, CH3CH); 0.94 (d, JH,H = 6.9 Hz, 3 H,
3
3
2
(CH3)2CH); 0.85 (d, JH,H = 6.9 Hz, 3 H, (CH3)2CH). 13C NMR (75 MHz,
CDCl3, 25 °C) δ = 165.30, 165.27 (C=O), 157.6 (C-OAll), 138.3 (quat.),
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10.1002/ejoc.201701328
European Journal of Organic Chemistry
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H-2); 3.56 (d, 3JH,H = 11.4 Hz, 1 H, CHiPr); 2.41-2.24 (m, 1 H, H-3); 2.22-
2.09 (m, 1 H, CH(CH3)2); 1.90-1.80 (m, 2 H); 1.75-1.65 (m, 2 H); 1.60-1.00
[9]
a) R. Echemendia, A. F. de La Torre, J. L. Monteiro, M. Pila, A. G. Correa,
B. Westermann, D. G. Rivera, M. W. Paixao, Angew. Chem., Int. Ed.
2015, 54, 7621-7625; b) L. Moni, L. Banfi, A. Basso, A. Galatini, M.
Spallarossa, R. Riva, J. Org. Chem. 2014, 79, 339-351; c) E. Riguet, J.
Org. Chem. 2011, 76, 8143-8150; d) F. Morana, A. Basso, M. Bella, R.
Riva, L. Banfi, Adv. Synth. Cat. 2012, 354, 2199-2210; e) A. F. de la
Torre, D. G. Rivera, O. Concepcion, R. Echemendia, A. G. Correa, M. W.
Paixao, J. Org. Chem. 2016, 81, 803-809.
3
3
(m, 6 H); 1.09 (d, JH,H = 7.2 Hz, 3 H, CH3); 1.08 (d, JH,H = 6.6 Hz, 3 H,
CH3); 1.07 (d, 3JH,H = 6.9 Hz, 3 H, CH3). 13C NMR (75 MHz, CDCl3, 25 °C)
δ = 167.4, 164.2 (C=O), 156.0, 119.9 (quat.), 129.0, 126.0, 121.5, 117.3
(Ar CH), 71.0 (C-2), 63.7 (CHiPr), 57.8 (C-4), 52.3 (CHN), 45.9 (CH2N);
34.7 (CH(CH3)2), 31.4 (C-3), 30.1, 29.3, 25.5, 25.4, 25.3 (CH2 cyclohexyl),
20.9, 17.5 (CH(CH3)2, 14.3 (CH3CH). I.R.: ῡ 2984, 2937, 2885, 2857, 1656,
1643, 1605, 1580, 1488, 1469, 1450, 1391, 1380, 1364, 1346, 1327, 1318,
1298, 1282, 1232, 1207, 1182, 1153, 1125, 1112, 1102, 1045, 1023, 994,
968, 923, 893, 882, 843, 829, 815, 794, 755, 743, 664, 651, 624, 608 cm-1.
HRMS (ESI+) m/z [M + H+]: Calcd. For C23H33N2O3 385.2491; Found
385.2495.
[10] a) J. W. Yang, M. Stadler, B. List, Angew. Chem, Int. Ed. 2007, 46, 609-
611; b) J. W. Yang, S. C. Pan, B. List, Org. Synth. 2009, 86, 11-17.
[11] S. Caputo, A. Basso, L. Moni, R. Riva, V. Rocca, L. Banfi, Beilstein J.
Org. Chem. 2016, 12, 139-143.
[12] a) J. A. Dale, H. S. Mosher, J. Amer. Chem. Soc. 1973, 95, 512-519; b)
T. J. Wenzel, J. D. Wilcox, Chirality 2003, 15, 256-270.
[13] a) M. Corredor, M. Garrido, J. Bujons, M. Orzaez, E. Perez-Paya, I.
Alfonso, A. Messeguer, Chem. Eur. J. 2015, 21, 14122-14128; b) B.
Alcaide, P. Almendros, C. Aragoncillo, R. Callejo, M. P. Ruiz, M. R.
Torres, Org. Biomol. Chem. 2015, 13, 1387-1394; c) M. Stucchi, S.
Cairati, R. Cetin-Atalay, M. S. Christodoulou, G. Grazioso, G. Pescitelli,
A. Silvani, D. C. Yildirim, G. Lesma, Org. Biomol. Chem. 2015, 13, 4993-
5005; d) S. Marcaccini, R. Pepino, M. Cruz Pozo, Tetrahedron Lett. 2001,
42, 2727-2728.
Acknowledgements
We wish to thank Mr. Alessandro Cerveri for practical
collaboration to the work, Dr. Valeria Rocca for performing HPLC
analyses, Mr. Walter Sgroi for IR spectra and Dr. Giuliana
Ottonello and Dr. Clarissa Braccia for HMRS spectra.
[14] L. Moni, L. Banfi, A. Basso, E. Martino, R. Riva, Org. Lett. 2016, 18, 1638-
1641.
Keywords: Multicomponent reactions; Nucleophilic substitution;
[15] a) S. Hanessian, C. Couture, H. Wiss, Can. J. Chem. 1985, 63, 3613; b)
S. Hanessian, G. McNaughton-Smith, H.-G. Lombart, W. D. Lubell,
Tetrahedron 1997, 53, 12789-12854.
Organocatalysis; Molecular diversity
[16] F. Morana, A. Basso, R. Riva, V. Rocca, L. Banfi, Chem. Eur. J. 2013,
19, 4563-4569.
[1]
a) L. Banfi, A. Basso, C. Lambruschini, L. Moni, R. Riva, Chem.
Heterocycl. Compd. 2017, 53, 382-408; b) L. Banfi, A. Basso, R. Riva, in
Synthesis of Heterocycles via Multicomponent Reactions I (Eds.: R. V. A.
Orru, E. Ruijter), Springer Berlin Heidelberg, Berlin, Heidelberg, 2010, pp.
1-39; c) L. Banfi, R. Riva, A. Basso, Synlett 2010, 23-41; d) A. V.
Ivachtchenko, Y. A. Ivanenkov, V. M. Kysil, M. Y. Krasavin, A. P. Ilyin,
Russian Chem. Rev. 2010, 79, 787-817; e) S. Sadjadi, M. M. Heravi,
Tetrahedron 2011, 67, 2707-2752; f) U. K. Sharma, N. Sharma, D. D.
Vachhani, E. V. Van der Eycken, Chem. Soc. Rev. 2015, 44, 1836-1860;
g) A. Varadi, T. C. Palmer, R. Notis Dardashti, S. Majumdar, Molecules
2015, 21; h) L. G. Voskressensky, Chem. Heterocycl. Compd. 2012, 48,
535-535.
[17] R. I. Fryer, J. V. Earley, J. F. Blount, J. Org. Chem. 1977, 42, 2212-2219.
[18] L. Banfi, A. Basso, G. Guanti, N. Kielland, C. Repetto, R. Riva, J. Org.
Chem. 2007, 72, 2151-2160.
[19] H. Eckert, Molecules 2017, 22, 349.
[20] F. Miege, C. Meyer, J. Cossy, Angew. Chem., Int. Ed. 2011, 50, 5932-
5937.
[2]
[3]
M. D. Burke, S. L. Schreiber, Angew. Chem., Int. Ed. 2004, 43, 46-58.
a) L. Moni, L. Banfi, A. Basso, L. Carcone, M. Rasparini, R. Riva, J. Org.
Chem. 2015, 80, 3411-3428; b) L. Moni, L. Banfi, A. Basso, A. Brambilla,
R. Riva, Beilstein J. Org. Chem. 2014, 10, 209-212; c) L. Banfi, A. Basso,
L. Giardini, R. Riva, V. Rocca, G. Guanti, Eur. J. Org. Chem. 2011, 100-
109.
[4]
[5]
G. L. Kelly, K. W. M. Lawrie, P. Morgan, C. L. Willis, Tetrahedron Lett.
2000, 41, 8001-8005.
a) S. S. van Berkel, B. G. M. Bogels, M. A. Wijdeven, B. Westermann, F.
P. J. T. Rutjes, Eur. J. Org. Chem. 2012, 3543-3559; b) C. de Graaff, E.
Ruijter, R. V. A. Orru, Chem. Soc. Rev. 2012, 41, 3969-4009.
a) G. F. Ross, E. Herdtweck, I. Ugi, Tetrahedron 2002, 58, 6127-6133;
b) C. Hebach, U. Kazmaier, Chem. Commun. 2003, 596-597; c) V. G.
Nenajdenko, A. V. Gulevich, K. Y. Chernichenko, N. V. Sokolova, E. S.
Balenkova, Mendeleev Commun. 2011, 21, 245-246; d) S. Klossowski,
A. Brodzka, M. Zysk, R. Ostaszewski, Tetrahedron: Asymm. 2014, 25,
435-442.
[6]
[7]
[8]
a) T. Ramanivas, G. Gayatri, D. Priyanka, V. L. Nayak, K. K. Singarapu,
A. K. Srivastava, Rsc Advances 2015, 5, 73373-73380; b) C. S. Azad, A.
K. Saxena, Org. Chem. Front. 2015, 2, 665-669; c) A. Katsuyama, A.
Matsuda, S. Ichikawa, Org. Lett. 2016, 18, 2552-2555; d) L. Banfi, A.
Bagno, A. Basso, C. De Santis, R. Riva, F. Rastrelli, Eur. J. Org. Chem.
2013, 2013, 5064-5075.
L. Banfi, A. Basso, L. Moni, R. Riva, Eur. J. Org. Chem. 2014, 2014,
2005-2015.
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Entry for the Table of Contents
FULL PAPER
Multicomponent Reactions
S. Caputo, L. Banfi,* A. Basso, A.
Galatini, L. Moni, R. Riva, C.
Lambruschini
Page No. – Page No.
Different enantiopure heterocycles have been prepared, exploring both scaffold and
decoration diversity, by a sequence of an enantioselective Mannich reaction, a
diastereoselective U-4CR, and various cyclizations.
Diversity-Oriented Synthesis of
Various Enantiopure Heterocycles by
Coupling Organocatalysis with
Multicomponent Reactions
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