Asymmetric Vinylogous Mukaiyama-Mannich Reactions of Heterocyclic Siloxy Dienes with Ellman's Fluorinated Aldimines

Article abstract of DOI:10.1002/adsc.201900464

Vinylogous Mukaiyama Mannich reactions of furan and pyrrole based dienoxy silanes with α-fluoroalkyl sulfinyl imines provide a powerful synthetic access to a variety of amino fluoroalkyl γ-butenolide-type and butyrolactam frameworks with high regio- and diastereoselectivity. Anti-configured adducts were obtained in all cases, independent of the nature of the heteroatom (O or N) present in the dienoxy silane. The absolute configuration of the adducts prepared was unequivocally established by X-ray crystallographic analysis. It is noteworthy that the introduction of substituents at the γ-position of the heterocyclic partner allows the generation of adducts bearing chiral quaternary centers. (Figure presented.).

Full text of DOI:10.1002/adsc.201900464

Title: Asymmetric Vinylogous Mukaiyama-Mannich Reactions of
Heterocyclic Siloxy Dienes with Ellman’s Fluorinated Aldimines
Authors: Santos Fustero, Miriam Rodenes, Raquel Roman, Daniel M.
Sedgwick, Jose Enrique Arroyo, Vadim Soloshonok, Jianlin
Han, Haibo Mei, Mercedes Medio-Simon, and Pablo Barrio
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900464
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10.1002/adsc.201900464
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Asymmetric Vinylogous Mukaiyama-Mannich Reactions of
Heterocyclic Siloxy Dienes with Ellman’s Fluorinated Aldimines
Santos Fustero,*a,b Miriam Rodenes,a Raquel Román,a Daniel M. Sedgwick,a José
Enrique Aguado,a Vadim A. Soloshonok,*c,d Jianlin Han,*e Haibo Mei, e Mercedes
Medio-Simon*a and Pablo Barrio*a
a. Departamento de Química Orgánica, Universidad de Valencia, 46100 Burjassot, Valencia, Spain. Email:
santos.fustero@uv.es; pablo.barrio@uv.es; mercedes.medio@uv.es
b. Laboratorio de Moléculas Orgánicas, Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain
c. Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country, UPV/EHU, 20018
San Sebastian, Spain. Email:
d. IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain
e. Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical
Engineering, Nanjing Forestry University, Nanjing 210037 Jiangsu China. Email: hanjl@njfu.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
the
amino
group,
can
modify their
and more
Abstract. Vinylogous Mukaiyama Mannich
reactions of furan and pyrrole based dienoxy
silanes with -fluoroalkyl sulfinyl imines provide
a powerful synthetic access to a variety of amino
fluoroalkyl -butenolide-type and butyrolactams
physicochemical
properties,
specifically basicity. Consequently, biological
activity[2] can be modulated by a straightforward
tactic based on the incorporation of fluoroalkyl
groups.
In this context, strategies for
frameworks
with
high
regio-
and
introduction of fluorinated moieties in amino-
derivative compounds are of particular interest. [3]
Among the different existing approaches for the
preparation of amines, the addition reaction of
nucleophiles to imines represents a simple and
relevant approach. Against that backdrop, the
addition reaction of an enolizable alkylidene [4],[5]
to an imine—known as vinylogous Mukaiyama
Mannich-type reactions (VMMnR)—constitutes
a fertile methodology, since this kind of reaction
allows functionalization beyond the regular  or
 positions and can give rise directly to versatile
unsaturated synthetic intermediates. Among the
diastereoselectivity. Anti-configured adducts
were obtained in all cases, independent of the
nature of the heteroatom (O or N) present in the
dienoxy silane. The absolute configuration of the
adducts prepared was unequivocally established
by X-ray crystallographic analysis. It is
noteworthy that the introduction of substituents at
the -position of the heterocyclic partner allows
the generation of adducts bearing chiral
quaternary centers.
Keywords:
siloxy
dienes;
asymmetric
vinylogous Mukaiyama-Mannich; fluorinated
sulfinyl imines; chiral butenolide; chiral
butyrolactam.
various
donors
available,
siloxydiene
heterocycles are a useful subset of preformed
enolates that afford -amino-,-unsaturated
carbonyls. These frameworks are shared by many
natural products and exhibit a variety of
biological activities (Figure 1). [6],[7] Furan-based
siloxy dienes provide access to the corresponding
Introduction
Amines are extremely important functional
groups
in
bioorganic
chemistry.
This
functionality is present in many natural products
and drugs, where, in most cases, the biological nitrogen-containing
-butenolides
and
-
butyrolactones, substructures which have a high
activity correlates with intrinsic basic properties.
[1]
Fluorine-containing amino derivatives,
especially those bearing fluoroalkyl moieties near
1
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10.1002/adsc.201900464
Advanced Synthesis & Catalysis
compound A-315675 or 1-aminopyrrolizidine
alkaloids.
HO
H3C
O
COOH
R
H3C
O
H
O
O
In the context of asymmetric VMMnRs,
N
OH
O
H
O
[16]
Ellman’s N-tert-butanesulfinimines
should be
Avenolide
(antibiotic)
Jatropham
(antitumor)
Paraconic acids
(antibiotic & antitumor)
taken into account as versatile chiral amine
templates. In fact, the synthetic potential of the
combination of a powerful methodology based on
Figure 1. Biorelevant compounds containing the -
butyrolactam and -butenolide-type frameworks.
prevalence in Nature[7] and therefore represent
attractive reference substrates in the context of
drug discovery. The first catalytic asymmetric
versions of VMMnRs based on these starting
a d4 donor and a chiral sulfinimine acceptor has
[15],[17]
already been recognized,
albeit scarcely
explored. So far, only a few examples of the
synthesis of highly functionalized non-
fluorinated heterocycles have been reported by
[15],[17]
Huang
by means of a sequence in which
the VMMnR was the key step, using imines
bearing a tert-butyl sulfinyl group as a chiral
auxiliary acting as acceptors. The possibility of
the introduction of substituents at the -position
of the heterocyclic partner is noteworthy,
allowing the generation of adducts bearing chiral
quaternary centers, a structural feature that is not
[18]
easily accomplished.
Furthermore, the
strategy can easily be extended to the preparation
of nitrogen-containing fluorinated compounds
such as fluorine-containing imines. [19] It is now
well established that the incorporation of fluorine
in target molecules can positively modify their
[2]
biological activities,
and consequently the
development of an efficient asymmetric method
for the synthesis of these compounds is highly
desirable.[20] Nevertheless, only a few examples
of the use of fluorinated imines in VMMn
[21],[22]
reactions are found in the literature.
In a
communication, Crousse and Bonnet-Delpon
briefly studied the vinylogous Mannich reaction
involving fluorinated aldimines.[21] However,
only trifluoromethyl aldimines were explored,
and although the corresponding butenolides were
Scheme 1. Vinylogous Mukaiyama Mannich-type reactions
(VMMnRs) with fluorinated imines.
materials were described by Martin providing the
corresponding
adducts
in
moderate
[8]
enantioselectivity and chemical yields.
Later,
obtained
in
high
yields
and
good
Carretero, [9] Shi, [10] and more recently Hoveyda,
diastereoselectivities, the reaction was conducted
in a non-asymmetric manner. Thereafter, Shi[22a]
described a catalytic asymmetric version using a
wide range of aldimines that included various
difluorinated derivatives. The combination of
chiral phosphine-oxazolidine ligands and
silver(I)-catalysis afforded the corresponding
adducts in moderate enantioselectivities (66-81%
ee). The additional incorporation of the (S)-
Me(Ph)CH grouping as a chiral auxiliary under
the aforementioned catalytic conditions allowed
the synthesis of fluorine-containing butenolides
in >95% ee (Scheme1). [22b] The requirement of
both the chiral complex catalyst and the chiral
[11]
reported the preparation of valuable -amino
-butenolide fragments with high chemical and
optical efficiency, although each of them
employed
different
catalytic
conditions.
Expansion of the scope of the catalytic
asymmetric VMMnRs encompasses the use of
pyrrole-based silicon dienolates, first developed
by Casiraghi and coworkers. [12] The efficiency of
the VMMnRs of siloxy pyrroles and aldimines as
a key step of a designed reaction sequence has
been shown by DeGoey, [13] McLaughlin[14] and
Huang, [15] who reported the synthesis of valuable
-butyrolactam derivatives such as anti-influenza
2
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10.1002/adsc.201900464
Advanced Synthesis & Catalysis
auxiliary to obtain fluorinated butenolides with silver acetate as a Lewis acid catalyst and THF as
high optical purity illustrates the difficulty of this solvent at low temperatures (-78 oC). The
goal perfectly well. On the other hand Qing reaction
took
place
with
complete
reported the use of several -fluoroalkyl regioselectivity at the -position, moderate yield
sulfinylimines in Lewis acid catalyzed and acceptable anti diastereoselectivity (entry 1,
[21],[23]
diastereoselective additions with different acyclic Table 1).
Switching the Lewis acid to
siloxydienes. This procedure was also applicable TMSOTf in the same solvent and temperature
to trimethylsiloxyfurane as an example of a slightly improved the diastereoselectivity, while
cyclic dienolate (Scheme 1). [22c]
the yield was comparable (entries 2 and 3, Table
1). Dichloromethane gave an improved
asymmetric induction (96:4 dr), possibly due to
its non-coordinating nature, when compared to
the coordinating THF (93:7 dr). Reaction times
Results and Discussion
Herein, we report our findings in the preparation
of chiral -monosubstituted and ,-disubstituted of more than 2 hours notably eroded the
butenolides and butyrolactams through diastereoselectivity, suggesting the formation of
a
diastereoselective Mukaiyama-Mannich reaction an equilibration of isomers under the reaction
between heterocyclic silyloxy dienes 1a-c and conditions. Since an acceptable yield (70%) and
fluorinated aldimines 2a-g bearing an N-tert- excellent dr (96:4) were attained when the
o
butanesulfinyl group as the chiral auxiliary.
reaction was conducted at -78 C for 2 hours in
dichloromethane and TMSOTf as Lewis acid, we
selected these conditions as appropriate for our
method (entry 4, Table 1).
1a X = O ; R = H ; R’ = Me3
1b X = O ; R = Me ; R’ = Me3
1c X = NBoc ; R = H ; R’ = tBuMe2
OSiR’
R
X
With suitable reaction conditions in hand, the
scope of the reaction with respect to the optically
active fluorinated aldimines was subsequently
examined (Table 2 (R=H)). The size of the
substituent on imine 2 slightly influenced the
yields that ranged from moderate to good for the
set of imines tested. Conversely, the
diastereoselectivity was better with the less
sterically-demanding substituents of imine 2. The
configuration of the major diastereoisomer
obtained was established as anti by X-ray
analysis (Figure 4) (see SI for details). [24]
O
S
2a: RF = CF3 , 2b: RF = CF2H
2c: RF = CF2Cl, 2d: RF = CF2Br
2e: RF = C2F5, 2f: RF = C3F7
2g: RF = C4F9
N
RF
Figure 2. Starting materials used in the VMMnRs.
Siloxy furan 1a and imine 2a were selected as
model substrates for the initial catalyst and
solvent screening (Table 1). First, we assayed
Table 1. Optimization of the reaction conditions of siloxy
furan 1a and imine 2a. [a],[b]
A
plausible interpretation of the simple
diastereoselectivity (4,5-anti) found in 3a could
be that it might be governed by transition state
TS1 (Figure 3) where the carbon-carbon bond
forming
‡
t
(h)
1
dr
(anti/syn)
85:15
88:12
93:7
yield
(%)
53
tBu
tBu
NH
5
LA
S
S
entry solvent Lewis acid
O
O
N
O
H
ul
approach
RF
H
RF
4
1
2
3
4
THF
THF
THF
DCM
AgOAc
TMSOTf
TMSOTf
TMSOTf
O
TMSO
O
1
57
(SS,4S,5S)-3a
(the major anti-adduct)
TS1 (re, si)
(favored)
2
52
Figure 3. Suggested TS1 accounting for anti
diastereoselectivity of 3a.
2
96:4
70
[a] All reaction yields are isolated yields.
[b] Dr values were determined by 19F NMR spectroscopy.
3
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10.1002/adsc.201900464
Advanced Synthesis & Catalysis
trajectory (ul approach, re face of the dienolate requirements. On the other hand, for facial
vs si face of imine) would seemingly be diastereoselection, a monocoordinated species
preserved due to favorable stereoelectronic
with a preferred conformation—where the re face
of the imine is shielded by the O-LA group—can
be supposed.
O
S
‡
HN
‡
tBu
tBu
LA
S
LA
S
F3C
O
O
O
N
N
R
R
O
H
RF
H
RF
O
(SS,S,S)-3aa
O
O
TMSO
OTMS
S
HN
TS1 (re, si) (R=H)
TS3 (re, si) (R=Me)
TS2 (si, si) (R=H)
TS4 (si, si) (R=Me)
(less favored)
F3C
O
(favored)
Figure 5. Postulated transition states for the VMMnR of 3a
and 3b.
O
(SS,S,S)-3ba
Subsequently, -substituted dienol silane 1b was
tested. The corresponding 5,5-disubstituted
butenolides 3ba-3bg possessing a quaternary
chiral center at the -position were obtained with
moderate to good yields and excellent
diastereoselectivities (dr > 99%) in all cases
(Table 2). The absolute anti-configuration of the
Figure 4. Absolute configuration of compounds 3aa and
3ba.
Table 2. Scope of the reaction of siloxy furans 1a-b and
imines 2.[a],[b],[c]
single
unequivocally
diastereoisomer
determined
obtained
by
was
X-ray
crystallographic analysis of butenolide 3ba as
Ss,4S,5S (Figure 4) (see SI for details). [24]
Table 3. Reaction of siloxy pyrrole 1c and imines 2. [a],[b],[c]
[a]
Reaction conditions: 1c (0.5 mmol), 2 (0.6 mmol),
[a]
TMSOTf (0.5 mmol), DCM (2.5 mL). [b]All reaction yields
Reaction conditions: 1a and 1b (0.5 mmol), 2 (0.6
mmol), TMSOTf (0.5 mmol), DCM (2.5 mL). [b]All
reaction yields were isolated yields.
determined by 19F NMR spectroscopy.[d] Dr>99:1
were isolated yields. Dr values were determined by 19F
[c]
[c]
Dr values were
NMR spectroscopy.
4
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10.1002/adsc.201900464
Advanced Synthesis & Catalysis
Comparison of the results obtained with decline in the yields was observed with the
unsubstituted furan derivative 1a and methyl increase of the steric hindrance in the imine
substituted 1b shows that the increase of the substituent. No reaction was observed in the case
steric demand of the butenolide precursor slightly of imines 2f and 2g, bearing perfluorinated
decreases the yields, most likely as
a
propyl and butyl groups respectively.
consequence of the decreased nucleophilicity at
the -carbon due to the steric effect of the
substituent.
O
S
HN
F3C
Regarding the asymmetric induction, the effect of
the substitution is markedly positive and the anti-
adduct clearly predominates despite the major
steric hindrance between methyl (R=Me) and the
RF substituent found in TS3 compared with the
equivalent interaction existing in TS1 (ul
approach) (Figure 5). Assuming that adducts 3a
do not equilibrate under the reaction conditions,
the observed increase in diastereoselectivity
when switching from unsubstituted siloxy furan
1a to substituted analog 1b would be a
consequence of the major difference between
TS4 and TS3 compared with TS2 and TS1 (lk
approach vs ul approach) (Figure 5). Given the
less favorable interaction existing in TS4
between the methyl group and the O-LA
grouping, the anti-approach through TS3 would
be more favored, thus explaining the greater
diastereoselectivity.
BocN
O
(SS,S,S)-3ca
Figure 7. Absolute configuration of compound 3ca.
By contrast, the diastereoselectivity remained
high, around 90% dr, with the sole exception of
the difluoromethyl adduct 3cb. The declined
reactivity of the pyrrole derivative 1c with
respect to the furan analogs 1a and 1b could be
explained by steric interactions in the
corresponding transition state (TS5, Figure 6)
between the voluminous protective Boc group
present in diene 1c and the RF substituent of the
imine 2 (ul approach) in agreement with the
model proposed by Huang for related substrates.
[17]
O
S
O
S
HN
F3C
HN
H2, Pd/C 5%
F3C
BocN
‡
AcOEt, rt, 48 h
tBu
tBu
BocN
LA
S
S
O
O
N
NH
O
H
O
ul
3ca
4 (97%)
approach
5
H
RF
RF
4
N
Scheme 2. Hydrogenation of unsaturated lactam 3ca.
N
PG
PG
TBSO
O
TS5 (re, si)
(favored)
(SS,4S,5S)-3c
(the major anti-adduct)
On
the
other
hand,
the
abnormal
diastereoselectivity obtained in the case of the
reaction of imine 2b bearing a difluoromethyl
group and diene 1c could be related to the weak
O
‡
S
H
tBu
tBu
tBu
N
LA
S
S
O
O
N
F2C
NH
H
lk
approach
PG
H
H
RF
5
RF
4
N
hydrogen-bond donating character of the
N
N
TBSO
[25]
PG
OTBS
PG
difluoromethyl group.
As a consequence, a
O
(SS,4R,5S)-3c
(the minor syn-adduct)
TS6 (si, si)
(less favored)
possible secondary interaction between the
hydrogen donor of the difluoromethyl group and
RF= CHF2
the pyrrole heterocyclic moiety, acting as an
Figure 6. Plausible transition states for the VMMnR of
diene 1c and imines 2.
[26]
acceptor
could occur in the corresponding
transition state (TS6, Figure 6), making the
approach to the si face of the dienolate (lk
approach) more competitive and thereby
increasing the percentage of the syn adduct.
The absolute anti-configuration of the major
diastereoisomer of derivative 3ca was also
determined by X-ray diffraction analysis,
exhibiting three consecutive stereocenters (Figure
7).[27] Furthermore, unsaturated lactam 3ca could
Next, we extended the vinylogous Mukaiyama
Mannich-type reaction (VMMnR) to the pyrrole-
based siloxy diene 1c aiming at the preparation of
functionalized butyrolactams derivatives 3c
(Table 3).
In sharp contrast with the furan dienes 1a and 1b,
siloxy pyrrole 1c was very sensitive to the
substitution at the imine, and a progressive
5
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10.1002/adsc.201900464
Advanced Synthesis & Catalysis
O
from CaH2. All reactions were monitored by gas
chromatography. GC analyses were performed on
an Agilent 6950 GC system equipped with a
HP5-MSI column (length 30 m, internal diameter
0.25 mm, film thickness 0.25 μm) and flame
ionization detection under a constant flow 1
mL/min helium carrier gas. GC-MS analyses
were performed on an Agilent 6890N GC system
equipped with a (5%-phenyl)-methylpolysiloxane
capillary column (length 30 m, internal diameter
0.25 mm, film thickness 0.25 μm) coupled to a
Agilent 5973N MS low resolution quadrupole.
Commercial aluminum sheets precoated (0.2 mm
layer thickness) with silica gel 60 F254 were
used for analytical thin layer chromatography.
Visualization was carried out with UV light.
Product purification by flash chromatography
was performed using Silica gel (230-400 mesh).
S
. HCl
HN
NH2
HCl, dioxane
F3C
R
F3C
0 ºC, 1h
R
O
O
O
O
3aa (R= H)
3ba (R= Me)
5a (>99 %)
5b (90 %)
Scheme 3. Removal of the chiral sulfoxide auxiliary on
compounds 3aa and 3ab.
be efficiently transformed into the diamine
protected derivative 4 by catalytic hydrogenation
(Scheme 2).
Finally, we were able to successfully remove the
tert-butylsulfinyl
representative substrates simply by treating
adducts 3aa and 3ba with HCl in dioxane at low
temperature with good yield and without loss of
optical purity, rendering the free amines 5 as the
chiral
auxiliary
from
1H (300, 400 and 500 MHz), and C NMR (75,
corresponding hydrochloride salts (Scheme 3).
13
[28]
100 and 126 MHz) spectra were recorded with a
Bruker instrument. Chemical shifts are reported
in δ ppm relative to TMS (δ 1H= 0.0 ppm) and
CDCl3 (δ 13C= 77.16 ppm) and coupling
constants (J) are given in Hertz (Hz).
Multiplicities are abbreviated as follows: singlet
(s), doublet (d), triplet (t), quartet (q), quintet
(quint), septet (sept), multiplet (m), and broad
(br). High Resolution Mass Spectra were
determined on a TripleTOFTM 5600 (ABSciex,
USA) spectrometer by using electrospray in
positive mode (ESI+). Melting points were
recorded on a Cambridge Instruments apparatus
and are uncorrected.
Conclusion
-Fluoroalkyl sulfinyl imines behave as excellent
acceptors in Mukaiyama Mannich-type reactions
with furan or pyrrole based dienoxy silanes as d4
donors. The method provides facile access to
,-unsaturated lactones and lactams bearing
different amino fluoroalkyl moieties at the -
position. The reaction was highly regio- and
diastereoselective for both furan dienes 1a and
1b, and siloxy pyrrole 1c. When furan-based
dienoxysilanes substituted at the -position were
used, the corresponding disubstituted butenolides
bearing a quaternary chiral center at this position
were obtained with moderate to good yields and
excellent diastereoselectivities. Anti-configured
adducts were obtained in all cases and their
absolute configuration was unequivocally
Starting materials.
Siloxy diene 1a is commercial available. Siloxy
dienes 1b[29] and 1c[30] and fluorinated aldimines
2a-g[19] were prepared according described
procedures.
established
by
single-crystal
X-ray
crystallographic analysis. Cleavage of the chiral
auxiliary in butenolides 3aa and 3ba was easily
accomplished under mild conditions allowing
preservation of the stereochemical integrity of the
two newly-generated chiral centers.
General
Procedure
for
Vinylogous
Mukaiyama Mannich Reactions (VMMnR)
An oven-dried resealable test tube was filled with
a solution of optically active fluorinated aldimine
2 (2a-2g) (0.5 mmol) in CH2Cl2 (2.5 mL), and
the solution was allowed to cool to -78 oC. At the
same temperature, siloxydiene 1 (1a-1c) (0.6
mmol, 1.2 equiv) was added, and then TMSOTf
(0.5 mmol, 1.0 equiv) was slowly added in a
dropwise manner to the solution. After the
appropriate reaction time, a saturated aqueous
Experimental Section
All reactions were carried out in oven-dried
resealable test tubes under an atmosphere of
argon. Dichloromethane (DCM) was distilled
6
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10.1002/adsc.201900464
Advanced Synthesis & Catalysis
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removed under reduced pressure and the residue
was purified by flash column chromatography on
silica gel.
Acknowledgements
The authors are grateful to the Spanish MINECO
(CTQ2017-84249-P) for financial support and
the SCSIE (Universidad de Valencia) for access
to instrumental facilities. Technical and human
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7
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Advanced Synthesis & Catalysis
UPDATE
Asymmetric Vinylogous Mukaiyama-Mannich
Reactions of Heterocyclic Siloxy Dienes with
Ellman’s Fluorinated Aldimines
Adv. Synth. Catal. Year, Volume, Page – Page
Santos Fustero,* Miriam Rodenes, Raquel Román,
Daniel M. Sedgwick, José Enrique Aguado, Vadim A.
Soloshonok,* Jianlin Han,* Haibo Mei, Mercedes
Medio-Simon* and Pablo Barrio*
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