Lithium Chloride Catalyzed Asymmetric Domino Aza-Michael Addition/[3 + 2] Cycloaddition Reactions for the Synthesis of Spiro- and Bicyclic α,β,γ-Triamino Acid Derivatives

Article abstract of DOI:10.1002/ejoc.201800585

Angularly and peri-fused tricyclic pyrrolidinopyrazolines are efficiently prepared by LiCl-catalyzed domino aza-Michael addition-1,3-dipolar cycloaddition reactions. The absolute stereochemistry is controlled in the aza-Michael addition step, nonaflyl azide serves as effective diazo transfer reagent to the formed enolate and the resulting diazo dipole engages in the 1,3-dipolar cycloaddition step. The resulting tricyclic pyrrolidinopyrazolines can be easily transformed to enantiomerically enriched nonproteinogenic spirocyclic α,β,γ-triamino acids, angularly or peri-fused tricyclic β-prolines or pyrimidines. The activity of the tricyclic amino acid derivatives against the hepatitis C virus was determined.

Full text of DOI:10.1002/ejoc.201800585

A Journal of
Accepted Article
Title: Lithium Chloride-Catalyzed Asymmetric Domino Aza-Michael
Addition/[3 + 2] Cycloaddition Reactions for the Synthesis of
Spiro- and Bicyclic α,β,γ-Triamino Acid Derivatives
Authors: David Just, Daniel Hernandez-Guerra, Susanne Kritsch,
Radek Pohl, Ivana Cisarova, Peter G. Jones, Richard
Mackman, Gina Bahador, and Ullrich Jahn
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800585
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800585
Supported by

10.1002/ejoc.201800585
European Journal of Organic Chemistry
FULL PAPER
Lithium Chloride Catalyzed Asymmetric Domino Aza-Michael
Addition/[3 + 2] Cycloaddition Reactions for the Synthesis of
Spiro- and Bicyclic α,β,γ-Triamino Acid Derivatives
David Just,[a] Daniel Hernandez-Guerra,[a] Susanne Kritsch,[b] Radek Pohl,[a] Ivana Císařová,[c] Peter G.
Jones,[b] Richard Mackman,[d] Gina Bahador,[d] and Ullrich Jahn*[a]
Abstract: Angularly and peri-fused tricyclic pyrrolidinopyrazolines are
efficiently prepared by LiCl-catalyzed domino aza-Michael addition-
1,3-dipolar cycloaddition reactions. The absolute stereochemistry is
controlled in the aza-Michael addition step, nonaflyl azide serves as
effective diazo transfer reagent to the formed enolate and the resulting
diazo dipole engages in the 1,3-dipolar cycloaddition step. The
resulting tricyclic pyrrolidinopyrazolines can be easily transformed to
enantiomerically enriched nonproteinogenic spirocyclic α,β,γ-triamino
acids, angularly or peri-fused tricyclic β-prolines or pyrimidines. The
activity of the tricyclic amino acid derivatives against the hepatitis C
virus was determined.
because they are usually resistant to cleavage.5 The insertion of
an additional substituted carbon atom next to the carboxylic group
leads to β-amino acids, which may create new stereocenters, thus
making them structurally more diverse then their α-relatives.6 This
formal insertion process can be repeated and, despite the fact that
another homologation to γ-amino acids reduces the number of
potential hydrogen bonds within the backbone, such peptides
have been shown to adopt various stable conformations, such as
helices, sheets and turns.7 In particular, cyclic amino acids have
proved to be of high importance, because of their conformational
rigidity and tunable steric properties.8
Previous works
R3
A
XOC
XOC
R1
Introduction
R3
+
R2
R1
R2
R3
N
N
Non-natural amino acids are an important compound class that
plays a significant role in chemistry and the life sciences. They
are interesting building blocks, often with atypical substitution
patterns and stereochemistry. This provides ample opportunities
to modulate the physical and chemical properties of products
containing them. In material chemistry, non-natural amino acids
have attracted considerable interest, particularly as building
blocks of foldamers1 and dendrimers.2 They are frequently
applied in medicinal chemistry as replacements for native amino
acids, leading to better hydrolytic stability, biological activity and
selectivity at their receptors.3
Peptides containing proteinogenic α-amino acids typically
have low in vivo stability because of easy digestion by proteases,
and the introduction of non-standard α-amino acids has therefore
been exploited for the preparation of variously substituted chiral
scaffolds that were applied in drug discovery, the preparation of
bioconjugates, catalysis and biopolymers.4 Another tool to
increase the stability of conjugates are α,α-dialkyl a-amino acids,
H
H
N
R3
N
R3
R2
B
H2N
R2
N
N
+
H2N
R2
R1
XOC
R1
R1
XOC
XOC
C Our previous work
Nf
N
R4
R3
R2
R4
R3
R2
COX
H2N
H2N
N
N
N
N
R4
+
XOC
XOC
R1
R1
R3
Nf
R1
LiN
R
N
N
R
R2
H
D This work
XOC
H2N
N
N
COX
+
N
N
NH2
NH2
N
XOC
R1
R1
N
H
XOC
R1
N
R
RLiN
H2N
R1
N
H
[a]
Institute of Organic Chemistry and Biochemistry, Academy of
Sciences of the Czech Republic, Flemingovo nam. 2, 166 10,
Prague 6, Czech Republic
Scheme 1. (A-C) Previous approaches to cyclic non-natural amino acids. (D)
Tricyclic a,b,g-triamino acids by tandem aza-Michael addition/1,3-dipolar
cycloaddition reactions.
E-mail: ullrich.jahn@uochb.cas.cz
[b]
[c]
[d]
Fachbereich Chemie, Technische Universität Braunschweig,
Hagenring 30, 38106 Braunschweig, Germany
Department of Inorganic Chemistry, Faculty of Science, Charles
University, Hlavova 2030/8, 128 43, Prague 2, Czech Republic
Gilead Sciences, Inc. 333 Lakeside Drive, Foster City, CA 94404,
U.S.A.
The prospect of combining all these amino acid classes to
either homopeptides or heteropeptides (ααβ, αββ, αβγ …) opens
access to an essentially unlimited structural and conformational
space of peptides, with the potential to access defined secondary
and tertiary structures in peptides. Therefore, the synthesis of
Supporting information for this article is given via a link at the end of
the document.
1
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10.1002/ejoc.201800585
European Journal of Organic Chemistry
FULL PAPER
polyfunctional monomer units appears to be one of the most
limiting factors because it is often a complex task and involves
tedious sequences. Although a large number of methodologies for
the synthesis of non-standard polyfunctional amino acids has
been reported,9 the most powerful are dipolar cycloadditions,
because they generate constrained cyclic structures, are
regioselective, diastereoselective and offer opportunities to apply
catalytic asymmetric conditions (Scheme 1A).10 Two strategic
approaches towards amino acid synthesis by 1,3-dipolar
cycloadditions have been pursued. On the one hand, the
heterocycle formed by the cycloaddition is preserved as the amino
acid itself; e.g. proline analogs can be approached by azomethine
ylide cycloaddition reactions.11 On the other hand the initially
formed cycloadduct may be subsequently transformed to amino
acids, as demonstrated for the conversion of simple pyrazolines
to diamino acids (Scheme 1B).12
cycloalkenecarboxylates 1a,b. Their reduction by lithium
aluminum hydride and nucleophilic exchange of the resulting
alcohols provided bromides 2a,b in good yields. Subsequent
alkylation of (R)-1-phenylethylamine with 2a,b furnished cyclic
amines 3a,b in 62-64% yields over three steps. (R)-N-Benzyl
cyclohexenyl amine 5a was synthesized with 86% ee by
asymmetric palladium-catalyzed allylic amination of cyclohexenyl
chloride 4a and benzylamine using Trost’s DACH ligand. This
methodology failed for the preparation of cyclopentenylamine 5b,
which was therefore approached in racemic form by alkylation of
benzylamine with cyclopentenyl bromide 4b.
NH2
O
Br
1) LiAlH4
2) PBr3
HN
Ph
Ph
n
MeO
n
n
3a n = 2 74%
3b n = 1 88%
1a n = 2
1b n = 1
2a 86%
2b 70%
Polyfunctional nonproteinogenic amino acids have more
recently become the focus of our interest.13 Ideally, proteolytic
stability, but similarity to natural amino acids should be kept and
epimerization-sensitive structural features should be avoided in
the design. Structural constraints to limit the number of
energetically similar conformations should be an important
criterion for the design. The polyfunctionality should provide
branching points to three-dimensional peptides or analogous
structures that nature cannot access because of the functionality
pattern of proteinogenic amino acids. Previously, we reported a
domino approach to bicyclic enantiopure highly substituted
pyrrolidinopyrazolines by anionic aza-Michael addition followed
by 1,3-dipolar cycloaddition, utilizing easily accessible starting
materials such as crotonates or cinnamates and simple chiral
allylic lithium amides (Scheme 1C).14 Nonaflyl azide proved to be
the reagent of choice for the generation of α-diazo derivatives
from the corresponding enolates, thus introducing two sterically
different nitrogen atoms, which allowed the construction of
enantiopure products containing four stereocenters. These
pyrrolidinopyrazolines were modified to highly substituted
monocyclic amino acids, which are applicable for peptide
synthesis, in which each of the amino functions can be selectively
addressed. We hypothesized that these structures would provide
spatially better defined motifs by introduction of additional rings,
which can be further diversified to conformationally even more
constrained and at the same time sterically demanding building
blocks for peptides (Scheme 1D).
BnNH2, 2 mol% [(allyl)PdCl]2,
5 mol% (R,R)-Naphthyl-DACH
n
HN
Ph
n
X
4a n = 2 X = Cl
4b n = 1 X = Br
5a n = 2 83%, 86% ee
5b n = 1 80%, racemic
BnNH2
Scheme 2. Preparation of starting amines 3 and 5.
The envisaged tandem aza-Michael/cycloaddition sequences
occur spontaneously with simple allylic amines;[15] however,
previous experience showed that increasing steric demand at the
allylic amine unit may stall the aza-Michael addition. Therefore,
the investigation commenced with the tandem reaction between
enantiomerically pure cyclohexenylmethyl amine 3a and tert-butyl
crotonate 6a as substrates. Deprotonation of amine 3a by
n-butyllithium at –78 °C and addition of 6a based on Davies
procedure,15 followed by addition nonaflyl azide and acetic acid
provided the cyclized products trans-7a and cis-8a in low (31%)
yield and moderate diastereoselectivity (Table 1, entry 1).
Decoupling the reaction sequence and performing the steps
individually revealed that the aza-Michael addition was the
inefficient step (not shown). Based on Collum’s results and our
own experience, the low efficiency was traced to aggregation of
the lithium amide.13b,16 Therefore, a catalytic amount of LiCl was
added to the reaction mixture and the yield of tricyclic angularly
fused spiranoids trans-7a and cis-8a improved to 76% with a 12:1
diastereomeric ratio. (entry 2 vs. 1). The optimized reaction
conditions were successfully employed for domino reactions
using cycloalkenylmethyl amines 3a-b having five- or six-
membered rings and α,β-unsaturated esters 6a-f bearing alkyl or
aryl substituents in β-position. It was shown that tert-butyl esters
6a,b with alkyl or aryl substituents in the β-position of the Michael
acceptors are equally well applicable in the tandem process, with
both types of amines 3a-b providing products 7a-d in 68-84%
yields with good diastereoselectivity (entries 2-5). Methyl
cinnamate 6c furnished tricyclic products trans-7e,f in reasonable
to good yield, but with significantly reduced 4.5-6:1 7:8
Here, we report an efficient synthetic strategy to approach
enantiopure 5,5,5- and 5,5,6-tricyclic fused and spirocyclic
pyrrolidinopyrazolines utilizing chiral cyclic allylic lithium amides
bearing their chirality either in the α-methylbenzyl group or directly
in the cyclic alkenylamine moiety. Their antiviral activities against
the hepatitis C virus are also reported.
Results and Discussion
An efficient access to the starting cyclic allylic amines 3 and 5 is
crucial for the approach to polycyclic functional amino acids
(Scheme 2). Chiral amines 3a,b with cycloalkenylmethyl units
were
efficiently
prepared
over
three
steps
from
2
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10.1002/ejoc.201800585
European Journal of Organic Chemistry
FULL PAPER
diastereomeric ratio (entries 6,7 vs. 4,5); however, isopropyl
crotonate 6d provided product 7g in 78% yield with very good
diastereoselectivity comparable to that observed for tert-butyl
The structure and configuration of tricycles 7h and 7i were
unambiguously determined by X-ray crystallography (Figure 1).
The C-N bond lengths of the pyrazoline ring are 1.50 Å and 1.48
Å, respectively, whereas the N=N bond of the diazene unit is 1.25
Å long. The annulated cyclohexane ring in 7h adopts a distorted
boat conformation, whereas the cyclopentane ring in 7i has an
envelope conformation. The configuration of the other angularly
annulated tricyclic pyrrolidinopyrazolines was assigned by
analogy of their NMR spectral data.
esters
6a,b
(entry
8).
Substituted
arylpyrrolidinopyrazolinecarboxylates trans-7h-k were obtained in
60-83% yields with good diastereoselectivities regardless of the
electronic nature of the substituents at the aryl ring (entries 9-12).
Encouraged by the successful application of cyclic amines 3 in
the domino reactions, the reaction of amines with the amine
functions directly attached to the ring were explored. Initial
Table 1. Scope of the domino reaction with respect to allylic amines 3a,b and
esters 6a-f
attempts
to
employ
chiral
N-cycloalkenyl-N-(1-
H
H
O
N
N
N
N
phenylethyl)amines analogous to 3 were not successful because
of their too low reactivity in the aza-Michael addition step, even
with LiCl catalysis. However, the conjugate addition proceeded
with less bulky N-benzyl-N-((R)-cyclohexenyl)amine 5a (86% ee)
and crotonate 6a (Table 2). Subsequent diazo transfer with
nonaflyl azide and cycloaddition afforded peri-fused 5,5,6-
tricycles trans-9a and cis-10a in good yield, but moderate 2.6:1
diastereoselectivity (entry 1). The corresponding cinnamate 6b
reacted similarly (entry 2). Products trans-9a,b and cis-10a,b
crystallized easily to give enantiomerically pure compounds (See
the Supporting information). Racemic trans-9b and cis-10b were
also obtained in a very early experiment in moderate yields by
using ethylsulfonyl azide because diazo transfer was much less
efficient than with nonaflyl azide (not shown).
BuLi, THF
1 mol% LiCl
NfN3, –78 °C
N
N
R1
6a-f
OR2
R2O2C
R1
R2O2C
R1
n
n
+
+
then AcOH
–78 to 25 °C
HN
n
Ph
Ph
Ph
trans-7a-k
3a n = 2
3b n = 1
cis-8a-k
entry
3
6
a
a
a
b
b
c
c
d
e
e
f
R1
R2
7 (%)
a 31
a 72
b 68
c 68
d 84
e 47
f 64
7:8[a]
5:1
1[b]
2
a
a
b
a
b
a
b
a
a
b
a
b
Me
Me
Me
Ph
Ph
Ph
Ph
Me
tBu
tBu
tBu
tBu
tBu
Me
Me
iPr
12:1
12:1
12:1
12:1
4.5:1
6:1
3
4
Employing racemic five-membered amine 5b resulted in similar
yields of 5,5,5-tricycles trans-9c,d and cis-10c,d, but the
diastereoselectivity was even lower (entries 3,4). It must be noted
that the aza-Michael addition step was much slower with amines
5 than with amines 3.
5
6
7
8
g 78
h 60
i 83
15:1
24:1
21:1
8:1
9
p-MeOC6H4
tBu
tBu
tBu
tBu
Table 2. Domino reaction with allylic amines 5a-b
10
11
12
p-MeOC6H4
p-FC6H4
j 80
O
N
N
N
N
N
N
BuLi, THF
1 mol% LiCl
NfN3, –78 °C
R1
6a,b
f
p-FC6H4
k 69
12:1
OtBu
tBuO2C
H
tBuO2C
H
+
n
n
R1
R1
+
[a] Determined from the 1H NMR spectra of the crude reaction mixtures. [b]
without LiCl.
then AcOH
–78 to 25 °C
n
Ph
N
Ph
trans-9a-d
Ph
cis-10a-d
H
5a n = 2 (86% ee)
5b n = 1 (racemic)
entry
6
a
b
a
b
R1
5
a
a
b
b
9+10 (%)
a 72
9:10[a]
2.6:1
3.2:1
1.4:1
1.7:1
1
2
3
4
Me
Ph
Me
Ph
b 70
c 85
d 72
[a] Determined from the 1H NMR spectra of the crude reaction mixture.
Figure 1. X-Ray crystal structure of 7h and 7i. The cyclohexane unit in 7h is
disordered and only one orientation of atoms C9, C10 is depicted for clarity. The
tert-butyl ester group in 7i is also disordered and only one orientation is depicted
for clarity. The displacement ellipsoids are drawn at 30% probability level.
The relative configurations of the major and minor peri-fused
products 9b, 10b and 9d, 10d, respectively, were assigned by X-
3
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10.1002/ejoc.201800585
European Journal of Organic Chemistry
FULL PAPER
ray crystallographic analysis (Figure 2). Both the aryl and ester
units are easily accommodated in the bowl-shaped structures.
The bond length around the diazene unit were with 1.49-1.52 Å
for the C-N bond and 1.24 Å for the N=N bonds very similar to
those determined for 7h and 7i, indicating that steric constraints
are not significant.
ratios, thus indicating that the cycloaddition occurred with very
high diastereoselectivity for both, trans-9b,c and cis-10b,c. b-
Amino-a-(acetoxy) amides 12b-c were, however, also isolated.
O
NMe2
BuLi, THF
LDA, THF
NfN3, –78 °C
NMe2
N
O
1 mol% LiCl
3a
+
–78 °C
then AcOH
–78 to 25 °C
6g
Ph
11a 75%
H
O
N
N
N
O
NMe2
N
+ AcO
Me2N
Ph
12a 10%
Ph
7l
48%
O
NMe2
Ph
N
BuLi, THF
1 mol% LiCl
LDA, THF
NfN3, –78 °C
6g + 5a,b
–78 °C
then AcOH
–78 to 25 °C
n
11b n = 2 73%, d.r. 1.9:1
11c n = 1 71%, d.r. 1:1
O
N
N
N
N
O
O
NMe2
Ph
H
H
AcO
Figure 2. X-Ray crystallographic structures of diastereomeric racemic peri-
annulated pyrrolidinopyrazolines trans-9b, cis-10b and trans-9d, cis-10d. the
displacement ellipsoids are drawn at 30% probability level.
Me2N
Me2N
N
n
n
+
+
N
N
Ph
trans-9e
trans-9f
Ph
n
cis-10e
cis-10f
68%, trans/cis 1.7:1
49%, trans/cis 1:1.2
12b 22%
12c 21%
The reactivity of α,β-unsaturated amide 6g toward lithium amides
derived from amines 3a and 5a was also investigated and proved
to be somewhat different. The tandem reactions analogous to
those reported in tables 1 and 2 gave the products 7l as well as
9e,f/10e,f in low yields (not shown). Moreover, acetoxylation
products 12a-c formed in substantial amounts (see Scheme 3).
This hinted to the fact that the aza-Michael addition proceeded
satisfactorily, but that diazo transfer and cycloaddition were
Scheme 3. Reactivity of α,β-unsaturated amide 4g.
The good stereoselectivity observed for the formation of
tricyclic angularly fused pyrrolidinopyrazolines 7 rests on several
factors. The absolute stereochemistry is reliably set in the aza-
Michael addition step for amines bearing cyclic allylic groups (as
in amines 3a,b) and is assumed to proceed by precoordination of
the lithium amide to the Michael acceptors 6 as shown in transition
state 13.13-15 It must be noted that in contrast to simpler
unhindered N-allylic 1-phenylethylamines,14 the aza-Michael
addition is sensititve to the bulk of the allylic unit. The lithium
amides derived from amines 3 are probably dimers in solution.13b
In this state, the conjugate addition is apparently not efficient
because of steric hindrance, raising the transition state energy.
The addition of a catalytic amount of anhydrous lithium chloride
accelerates the conjugate addition significantly,16 probably by
forming sterically less demanding mixed dimers of the lithium
amide with LiCl, which coordinate more efficiently to 6 and add
thus faster. The stereoselectivity is not compromised by LiCl
problematic. Therefore,
a stepwise protocol was pursued
(Scheme 3). The aza-Michael addition between 6g and amines
3a or 5a,b, respectively, proceeded uneventfully, provided that
LiCl was present, and was similarly efficient to that of the esters
6a-f. b-Amino amides 11a-c were isolated in 70-75% yield as a
single enantiomer for 11a, whereas 11b,c were isolated as 1-
1.9:1 diastereomeric mixtures, in line with the previous results.
Deprotonation of 11a followed by diazo transfer with nonaflyl
azide and treatment with acetic acid provided tricyclic amide 7l in
48% yield as a single diastereomer together with small amounts
of a-acetoxy-b-amino amide 12a. Amino amides 11b,c also
provided tricycles trans-9e,f and cis-10e,f in improved 49-68%
yields when using the stepwise protocol. Only two diastereomers
were formed from the diastereomeric mixtures of 11b,c in similar
4
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10.1002/ejoc.201800585
European Journal of Organic Chemistry
FULL PAPER
addition. The resulting (Z)-enolates 14 subsequently add to the
terminus of the electrophilic nonaflyl azide. The triazenide thus
formed is subsequently quenched by addition of acetic acid14 and
transforms to b-amino-a-diazo esters 15 (X = OR2).
substrate 15. This is consistent with a preferred transition state
boat-16, in which the bulkier carbonyl and R1 groups occupy
diequatorial positions thus minimizing steric interactions. This
forces the diazo unit into axial orientation and the cycloaddition
proceeds in turn through a boat-like transition state. The minor
isomers cis-8 result from reaction via chair-like transition state 17,
which is disfavored because of the cis orientation of the carbonyl
and R1 groups.
Surprisingly, amide 6g gave only low yields of tricycle 7l in
the tandem aza-Michael addition/diazo transfer/cycloaddition
reactions. The reactivity difference was traced to the diazo
transfer step to enolates 14, as the aza-Michael addition
proceeded reliably with unsaturated amide 6g. When the resulting
b-amino amide 11a was deprotonated with LDA and the resulting
enolate subjected to nonaflyl azide, the diazo transfer proceeded
smoothly. Reasoning that the enolate geometry may be a factor
that causes this reactivity difference, both enolates, either formed
by 1,4-addition or by deprotonation with LDA, were reacted with
chlorotrimethylsilane (see the Supporting Information),13b,d,15 and
the resulting silyl ketene aminals were studied by ROESY NMR
spectroscopy. The investigation confirmed that (Z)-enolates form
in large excess in both cases as indicated by the contact of the
vinyl proton with one of the N-methyl groups. This rules out
enolate geometry as a factor and therefore the reason for this
surprising reactivity difference based on the difference of enolate
generation is still not understood.
6a,b + 5a,b
BuLi
R2O
Bn
R1
O
H
N
Li
N
n
R2O
Li
N
R1
O
Bn
H
n
19
18
LDA
Bn
Bn
R1
NfN3
AcOH
n
N
n
+
COX
COX
11b,c
R1
21
N
N
N
11a
LDA, NfN3
AcOH
6a-f + 3
BuLi
20
N
n
n
R3
R1
n
H
Ph
N–
n
+
N
COX
n
NfN3
AcOH
Li
Bn
N
R1
Ph
N
O
R1
Li
N
H
Ph
N
N+
N–
R2O
N
Bn
COX
R1
XOC
OR2
O
R
H
chair-23
boat-22
N
13
(Z)-14
15
N
N
N
N
N
N–
+
N
XOC
R1
H
XOC
R1
H
COX
R1
H
n
R1
n
H
N
N
N
N
N+
–N
H
H
Ph
n
Ph
XOC
Bn
Bn
cis-10
trans-9
n
boat-16
chair-17
Scheme 5. Stereochemical rationale of the domino process for the formation of
peri-fused tricycles 6 and 7.
H
H
N
N
N
N
N
N
XOC
R1
XOC
n
n
In contrast to amines 3, where a single branching point at
the amine function is present and the stereoselectivity of the
overall process is strictly dictated by the stereocenter in the 1-
phenylethyl unit, amines 5a,b having the stereocenter as a part of
the cycle are only little different with respect to steric demand at
the stereocenter (Scheme 5). Therefore, the face selectivity of
their aza-Michael addition to esters 6a,b is not very high, lying in
the range of 2:1 for the preferred attack from the bottom face via
transition state 18, where less steric interactions of the substituent
R1 with the cycloalkenyl unit are present compared to the
arrangement in transition state 19. The resulting b-amino-a-diazo
carbonyl derivatives 20 and 21 undergo the cycloaddition with
exclusive diastereoselectivity, since no other diastereomers than
trans-9 and cis-10 were detected in the reaction mixtures. The
R1
Ph
cis-8a-l
Ph
trans-7a-l
Scheme 4. Stereochemical rationale of the domino process forming the
configuration of tricyclic angularly fused spiranoids.
The final 1,3-dipolar cycloaddition step proceeded in all
cases smoothly, but subtle differences in the diastereoselectivity
became apparent. High diastereoselectivity for the formation of
tricycles trans-7 was observed with bulky tert-butyl or isopropyl
ester groups or the dimethyl amide unit, but the selectivity
decreased using a methyl ester function in the cycloaddition
5
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10.1002/ejoc.201800585
European Journal of Organic Chemistry
FULL PAPER
N
H
N
1,3-dipolar cycloaddition of 20 apparently proceeds most
favorably via transition state boat-22, in which the larger
substituents occupy trans-diequatorial positions and thus force
the diazo and alkene units into axial orientations, furnishing
isomers trans-9. The diastereomeric amino diazo compounds 21
can in contrast only react via transition state chair-23 providing
the cis isomers 10.
Tricyclic spiranoid 7a was chosen as a representative
example for demonstration of scaffold diversity. Hydrogenolytic
cleavage of the N=N double bond serves as a tool to approach
spiro α,β,γ-triamino acid derivatives (Scheme 6). Free amine 24
was obtained in 59% yield using Raney nickel under 20 bar of
tBuO
N
20 bar H2, Ra-Ni
HN
tBuO
H
H
O
MeOH, 50 °C, 24 h
O
N
N
Bn
9a
Bn
30 50%
1) Zn, AcOH
2) TFAA, Et3N
CH2Cl2
O
CF3
H2N
H2N
N
tBuO
HN
tBuO
1) SmI2, MeOH, THF
2) K2CO3, MeOH, reflux
H
dihydrogen,
which
was
accompanied
by
separable
H
O
pyrazolidinopyrrolidine 25. Surprisingly, the latter was
spontaneously reoxidized to starting material 7a on exposure to
air and can thus be recycled. Product 24 was selectively protected
by Boc2O at the secondary position affording orthogonally
diprotected triamino ester 26. In contrast, hydrogenation/acylation
of 7a by Raney nickel (A) in the presence of Boc2O did not furnish
the desired protected amine 26 but provided Boc-protected
pyrazolidine 27 and the product of N-N bond cleavage and
competitive hydrogenolysis of the phenylethyl unit, di-Boc-
triamino ester 28, in almost the same amounts. Pyrazolidine 27,
which also appears to be an attractive scaffold, was selectively
obtained by reduction of 7a with zinc in acetic acid and
subsequent protection by Boc2O (B).17 Further hydrogenolysis of
27 selectively afforded triamino ester 29 bearing a free amino
function in a- and b-position.
O
N
N
Bn
Bn
32 75%
31 75%
Scheme 7. Two-step reductive access to fused α,β,γ-triamino acids 32 under
single-electron reductive conditions.
Tricycle 9a was selected as a representative model to
explore the reactivity of peri-fused ring systems. For convenience,
these investigations were performed with racemic material; the
results should, however, be the same with enantiomerically
enriched derivatives. Hydrogenolytic ring opening of the
pyrazoline ring was not possible (Scheme 7). Free N-H
pyrazolidine-containing tricycle 30 was obtained in moderate yield
and minor debenzylation products were competitively formed (not
shown), but N-N bond cleavage did not occur. Therefore, 9a was
first transformed in good yield to trifluoroacetylpyrazolidine 31 by
reduction with zinc in acetic acid, followed by trifluoroacetylation.
Single electron reduction by SmI2 followed by immediate
deprotection of the trifluoroacetyl group resulted in annulated
bicyclic b-protected triamino acid 32.
air
H
H
H
N
N
N
H2N
Ph
HN
Ph
tBuO
tBuO
20 bar H2
Ra-Ni, MeOH
N
tBuO
+
O
O
O
NH2
50 °C, 24 h
N
N
Ph
24 59%
7a
25 35%
F3C
CF3
H
O
F3C
tBuO HN
O
B
A
O
Boc2O, Et3N, DCM
N
1) AcOH, Zn
2) Boc2O
N
N
HN
20 bar H2,
Ra-Ni, Boc2O
MeOH, 50 °C
5 h
SmI2
HN
tBuO
H2N
tBuO
MeOH
H2N
H
Et3N, DCM
tBuO
H
THF
O
O
N
N
O
NHBoc
83%
Bn
Bn
N
Bn
33
31
34 74%
Ph
Boc
26
H
F3C
N
N
H2N
tBuO
HN
Ph
H2N
Ph
H2N
tBuO
tBuO
TFAA
Et3N
tBuO
HN
tBuO
+
O
O
NHBoc
O
O
DCM
NH
CF3
NH2
N
O
N
N
N
Boc
N
O
H
Boc
27
28
N
Ph
HN
A 50% 43%
B 84% 0%
tBuO
Ph
36 69%
24
35
O
5 bar H2, Pd(OH)2, MeOH, rt, 3 h
N
H
Scheme 8. Access to annulated 2-trifluoromethyltetrahydropyrimidines 34 and
36.
29
99%
Scheme 6. Access to spiro-α,β,γ-triamino esters 24 and 26 by hydrogenolysis
conditions and formation of differentially protected a-hydrazino esters 27-29.
On attempted isolation and spectroscopic characterization of
bicyclic γ-trifluoroacetyl-protected triamino acid 33,
a
slow
6
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10.1002/ejoc.201800585
European Journal of Organic Chemistry
FULL PAPER
formation of 2-trifluoromethyltetrahydropyrimidine 34 was
observed. This transformation was completed within a day upon
standing in an NMR tube in CDCl3 (Scheme 8). This process
seems to be general, since tetrahydropyrimidine formation also
occurred spontaneously from amino acid 35 when spiro triamino
acid 24 was protected by trifluoroacetic anhydride.
Trifluoromethylated pyridmidine 36 was isolated from 35 in 69%
yield after standing in an NMR tube in CDCl3 for a day.
Tricyclic scaffolds 7a and 9a containing the 1-pyrazoline unit
are not only precursors for triamino acid derivatives but are also
b-amino acid surrogates by extrusion of molecular nitrogen.
Irradiation of both compounds by a high pressure mercury lamp
furnished angularly fused and peri-fused cyclopropanes 37 and
39, respectively, in good yields as single diastereomers (Scheme
9).18 Removal of the phenylethyl groups by hydrogenolysis over
Pearlman's catalyst provided conformationally constrained
tricyclic β-amino acids 38 and 40 reminiscent of alkaloid
structures,19 which exemplify the potential applicability of the
method toward natural product synthesis and also for the
preparation of β-peptide foldamers20 or pharmaceutical
analogs.17b
bicyclic pyrrolidinopyrazolines[14] revealed that ester 41 showed
activity in the 1B replicon assay, but not in the 2A replicon assay
(entry 12 vs. 1-11). It is important to note that 3-methyl-substituted
derivatives 7a,d, 9a,c, 10a,c as well as all 3-methyl-substituted
bicyclic analogs of 41 showed low or no activity against HCV in
these assays (not shown). These trends indicate that the inhibition
is probably related to a common specific binding site for
compounds 7, 9 and 41 (entries 1-10,12). Surprisingly, 3-methyl-
substituted N-Boc-protected tricyclic pyrazolidine 27 as well as
previously prepared bicyclic derivative 42[14] proved to be active
in both assays, but the additional annulation in 27 induced again
higher activity compared to 42 (entries 13 vs. 14).
Table 3. Antiviral activity of the synthesized compounds in two HCV replicon
assays.[a]
N
N
N
N
N
N
N
N
E
E
3
E
H
E
H
Ar
Ar
N
N
n
Ph
Ph
N
N
Ph
7c Ar = Ph
7h Ar = 4-MeOC6H4 7i Ar = 4-MeOC6H4
Ph
7d Ar = Ph
Bn
cis-10d
Bn
trans-9b n = 2
trans-9d n = 1
7j Ar = 4-FC6H4
7k Ar = 4-FC6H4
H
H
H
N
N
tBuO
tBuO
E = tBuO2C
N
tBuO
F3C
Boc
N
N
O
O
H
H
N
H2, Pd(OH)2
MeOH, rt, 4 h
hν, PhH
N
R
H
O
HN
E
HN
E
E
H
N
N
E
rt, 8h
H
H
E
H
R
Ph
N
Ph
Ph
N
38 99%
N
N
N
37 78%
7a
N
Ph
trans-41
(ref. 14)
Ph
Ph
27 R-R = -(CH2)4-
42 R, R = H (Ref. 14)
Ph
Bn
N
tBuO
H
36
37
39
tBuO
H
tBuO
H
H
H
H
H
O
O
H2, Pd(OH)2
MeOH, rt, 4 h
hν, PhH
O
entry
1B
2A
entry
1B
2A
rt, 8h
N
N
EC50
(µM)
EC50
(µM)
EC50
(µM)
EC50
(µM)
N
H
Bn
9a
Bn
40 99%
39 79%
1
2
3
4
5
6
7
8
7c
7d
7e
7f
6.1
4.9
9.2
6.2
12.5
6.9
3.5
1.7
14.4
14.8
10.7
12.8
15.6
8.3
9[b]
10[b]
11[b]
12
9b
9d
10d
41
27
42
36
37
39
15.5
7.9
29.6
11.5
20.0
>44
17.2
35.7
27.8
˃50
˃50
Scheme 9. Photochemical nitrogen extrusion reactions to b-prolinates 38 and
40.
11.2
7.2
All compounds were tested against various genotypes of the
hepatitis C virus in the 1B and 2A replicon assays (Table 3). 3-
Aryl-substituted angular tricyclic triamino tert-butyl esters 7c,d,h-
k display low micromolar activity in the replicon 1B assay (entries
1,2,5-8). The corresponding methyl esters 7e,f displayed similar
activities (entries 3,4). The activity is enhanced by fluoride in para-
position of the aryl ring (entries 7,8), while the activity was slightly
decreased with electron-donating groups in para-position (entry
5,6). In contrast to the replicon 1B assay the EWG/EDG effect is
opposite in the replicon 2A assay (entries 5-8). In all cases the
substrates with five-membered carbocyclic rings 7d,f,i,k showed
higher activity than substrates with annulated six-membered
carbocyclic rings 7c,e,h,j in the replicon 1B assay (entries 2,4,6,8
vs. 1,3,5,7). A similar trend was observed for peri-fused tricycles
9, where aryl-substituted five-membered derivative 9d was more
active than six-membered 9b, (entry 9 vs. 10). Minor peri-fused
product cis-10d was less active compared to trans-9d (entry 11
vs. 10). Interestingly, comparison with the previously synthesized
7h
7i
13
5.8
14
10.7
11.1
13.0
11.6
7j
27.6
19.5
15
7k
16
17[b]
[a] Cytotoxycity values (CC50) were determined in Huh-7 cells and are ˃50
µM for all compound except 7i (20.7 µM), 7e (22.0 µM). [b] racemic.
Remarkably, cyclohexane-annulated, but methyl-substituted
tetrahydropyrimidine 36 and both bicyclo[4.1.0]heptane-fused b-
proline derivatives 37 and 39 were active despite the fact, that
they contain neither an aryl substituent at C-3 nor a five-
membered carbocyclic ring (entries 15-17). The compounds were
7
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10.1002/ejoc.201800585
European Journal of Organic Chemistry
FULL PAPER
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pyrrolidino-
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Acknowledgements
This work was generously supported by the Gilead Sciences at
IOCB research center, the Institute of Organic Chemistry and
Biochemistry
of the
Czech
Academy
of Sciences
(RVO:61388963) and the European Regional Development Fund;
OP RDE; Project: Chemical biology for drugging undruggable
targets
(ChemBioDrug)
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Keywords: Tandem reactions • Nitrogen heterocycles •
Non-natural amino acids • β-prolines • Michael addition • Diazo
transfer • 1,3 dipolar cycloaddition
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8
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10.1002/ejoc.201800585
European Journal of Organic Chemistry
FULL PAPER
FULL PAPER
Angularly and peri-fused tricyclic
pyrrolidinopyrazolines are efficiently
prepared by LiCl catalyzed domino
aza-Michael addition-1,3-dipolar
cycloaddition. The resulting tricyclic
pyrrolidinopyrazolines can be easily
transformed to spirocyclic or
Tandem Reactions
David Just, Daniel Hernandez-Guerra,
Susanne Kritsch, Radek Pohl, Ivana
Císařová, Peter G. Jones, Richard
Mackman, Gina Bahador, Ullrich Jahn*
Page No. – Page No.
condensed bicyclic α,β,γ-triamino
acids derivatives.
Lithium Chloride Catalyzed
Asymmetric Domino Aza-Michael
Addition/[3 + 2] Cycloaddition
Reactions for the Synthesis of
Spiro- and Bicyclic α,β,γ-Triamino
Acid Derivatives
9
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